C

Comorbidities

Alzheimer Disease <-> Type 2 Diabetes Mellitus

Atopic Dermatitis <-> Type 2 Diabetes Mellitus

Major Depressive Disorder <-> Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus <-> Union of Lichen Simplex Chronicus, Prurigo Nodularis

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Mechanistic Hypotheses

1

Amplification of polygenic T2D risk in adverse metabolic contexts via shared insulin-resistance convergence

pgs_context_amplification EMERGING

Evidence balance 2 support

Polygenic-score-by-context (PGS×C) interactions reported for type 2 diabetes in the UK Biobank appear to reflect amplification rather than context-specific causal variants: the same susceptibility loci (e.g. TCF7L2, PPARG, KCNJ11, SLC30A8) exert systematically larger effects in disease-promoting metabolic contexts. This entry proposes that the amplification arises because polygenic liability and adverse exposures converge on the shared Insulin Resistance node (with Beta Cell Dysfunction as a parallel target), so their joint effect on the liability-threshold scale is super-additive rather than additive. Nagpal & Gibson (Nat Genet 2026, PMID:42443528) highlight the interaction between reduced polyunsaturated fatty acids (low omega-6) and high glucose, which elevates T2D risk increasingly as the PGS rises, and identify sex and sex-adjusted testosterone as further amplifying contexts.

EMERGING hypothesis motivated by population-scale PGS×context analyses (primary source PMID:42443528; general amplification mechanism corroborated by PMID:37228747, which documents testosterone-mediated amplification). The convergence claim (polygenic liability + adverse metabolic context → Insulin Resistance) is a mechanistic interpretation and is not itself established as causal — see the reverse-causation knowledge gap under discussions.

Show evidence (2 references)

PMID:42443528 SUPPORT Computational

"The predominant mechanism for PGS×C is the amplification of genetic effects in adverse contexts, such as low polyunsaturated fatty acids or social determinants of ill health"

Direct source (Nagpal & Gibson 2026): across seven UK Biobank diseases and 75 contexts, amplification of genetic effects in adverse contexts is identified as the predominant mechanism of PGS×context interaction — the mechanism applied in this hypothesis.

PMID:37228747 SUPPORT Computational

"GxSex is pervasive but acts primarily through systematic sex differences in the magnitude of many genetic effects"

Establishes amplification — systematic differences in the magnitude of polygenic effects rather than in the identity of causal variants — as the primary mode of gene-by-sex interaction across physiological traits, and notes that testosterone may mediate this amplification. Cited as general support for amplification as a mode of PGS×context interaction; the paper is not T2D-specific.

?

Discussions and Knowledge Gaps

3

Are the T2D PGS×context interactions driven by adverse exposures causally amplifying genetic risk, or are some "contexts" (notably circulating glucose) actually downstream readouts of incipient disease (reverse causation)?

KNOWLEDGE GAP OPEN t2d_pgsxc_reverse_causation

Attached to

pathophysiology#Insulin Resistance environmental#Sedentary Lifestyle environmental#High-Calorie Diet

Population PGS×context analyses (Nagpal & Gibson 2026, PMID:42443528) are largely unable to establish the causality of specific contexts. For T2D this is especially acute for circulating glucose, a major amplifying "context" in the paper that is also nearly definitional of the disease and therefore substantially downstream of incipient hyperglycemia rather than a purely upstream driver. Behavioural contexts such as reduced physical activity and higher-calorie diet may also be partly responses to early metabolic decline. Distinguishing genuine amplification from reverse causation determines whether the modelled lifestyle interventions would actually reduce risk.

Proposed experiments

Mendelian randomization of exposure-to-T2D direction across PGS strata

t2d_pgsxc_mr_direction

Use bidirectional / multivariable Mendelian randomization to test whether each candidate context (glucose, omega-6 fatty acids, sex-adjusted testosterone, physical activity) causally affects T2D versus being a consequence of subclinical disease, and whether the causal effect estimate scales with polygenic liability as the amplification model predicts.

Decision criterion

A context is retained as a causal amplifier if MR supports exposure-to-disease directionality and the exposure-attributable risk difference increases across increasing PGS strata; it is flagged as a reverse-causation suspect otherwise.

Prospective incident-T2D analysis restricted to pre-diagnosis exposure windows

t2d_pgsxc_prospective_temporal

Restrict exposures to measurements taken well before diagnosis and repeat the PGS×context liability-threshold modelling on incident cases only, to reduce the chance that exposure values (particularly glucose) reflect early disease rather than antecedent risk.

Decision criterion

Amplification is supported if the PGS×context deviation from additivity persists when only pre-diagnosis exposure windows and incident cases are used.

Is beta-cell dedifferentiation and beta-to-alpha-like trajectory switching in type 2 diabetes a reversible driver of beta-cell failure, or mostly a late marker of intrapancreatic adiposity, inflammation, and metabolic stress?

KNOWLEDGE GAP OPEN gap_t2d_beta_cell_dedifferentiation_reversibility

Attached to

pathophysiology#Beta Cell Dysfunction pathophysiology#Insulin Resistance pathophysiology#Incretin Axis Dysfunction

The entry links insulin resistance to beta-cell dysfunction, but recent human-islet work points to a specific beta-cell identity-loss axis involving intrapancreatic adipocytes, immune recruitment, alpha-like trajectories, and SMOC1. Resolving whether this state is causally reversible would determine whether beta-cell recovery should be modeled as a targetable mechanism rather than only as clinical glycemic improvement.

Proposed experiments

Human islet-adipocyte beta-cell dedifferentiation rescue assay

human islet microphysiological perturbation experiment

exp_t2d_islet_adipocyte_beta_dedifferentiation_rescue

Co-culture human pancreatic islets with intrapancreatic adipocytes and autologous immune cells in a microphysiological system; impose glucolipotoxic stress; perturb SMOC1 and incretin signaling; and test whether beta-cell identity, insulin secretion, and beta-to-alpha-like trajectory markers recover when the adipocyte-inflammatory niche is removed or therapeutically modulated.

Model systems

Human islet-adipocyte-immune microphysiological system

Human islet organ-on-chip or perifusion coculture pairing islets with adipocytes and immune cells to model the pancreatic fat-associated microenvironment implicated in beta-cell identity loss.

ORGAN ON CHIP namo:OrganOnChip link

human NCBITaxon:9606

pancreas UBERON:0001264

pancreatic beta cell CL:0000169 pancreatic alpha cell CL:0000171 adipocyte CL:0000136 T cell CL:0000084

Perturbations

Pancreatic adipocyte inflammatory niche

pathophysiology#Beta Cell Dysfunction

Adipocyte proximity plus inflammatory immune-cell recruitment used to model intrapancreatic fat-associated beta-cell stress.

inflammatory response GO:0006954

SMOC1 gain and loss of function

pathophysiology#Beta Cell Dysfunction

Beta-cell SMOC1 overexpression and knockdown used to test whether the alpha-cell-associated trajectory gene is sufficient and necessary for beta-cell dedifferentiation.

SMOC1 hgnc:20318

GLP-1/GIP receptor agonist rescue

pathophysiology#Incretin Axis Dysfunction

Incretin receptor agonist exposure used to test whether clinically relevant treatment restores beta-cell function and identity under an adipocyte-inflammatory niche.

targeted therapy NCIT:C93352

Readouts

Glucose-stimulated insulin secretion

pathophysiology#Beta Cell Dysfunction

Dynamic insulin secretion normalized to beta-cell abundance.

insulin secretion GO:0030073

glucose-stimulated insulin secretion assay

Direction: NEGATIVE

Beta-cell identity and alpha-like trajectory markers

pathophysiology#Beta Cell Dysfunction

Single-cell expression of INS, MAFA, INSM1, NPY, ALDH1A3, GCG, and SMOC1 interpreted as mature beta-cell identity versus dedifferentiated or alpha-like trajectory state.

single-cell transcriptomic profiling immunofluorescence assay

Direction: POSITIVE

Adipocyte-associated immune recruitment

pathophysiology#Insulin Resistance

T-cell proximity and inflammatory-cytokine readouts around adipocyte-islet interfaces.

inflammatory response GO:0006954

multiplex cytokine profiling spatial transcriptomic profiling

Direction: POSITIVE

Controls

Islet-only culture

Donor-matched islets cultured without adipocytes or immune cells.

Non-diabetic donor islet-adipocyte coculture

Parallel coculture built from non-diabetic donor material.

Vehicle-treated stressed coculture

Stressed coculture receiving vehicle instead of incretin or SMOC1 perturbation.

Decision criterion

Dedifferentiation is supported as a reversible causal mechanism if adipocyte-inflammatory challenge induces beta-cell identity loss and impaired insulin secretion, and if SMOC1 suppression or incretin rescue restores mature beta-cell markers and insulin secretion before cell-loss dominates.

Would support

pathophysiology#Beta Cell Dysfunction pathophysiology#Incretin Axis Dysfunction

Show evidence (3 references)

PMID:40072535 SUPPORT Human Clinical

"Higher pancreatic fat content was accompanied by increased beta cell dedifferentiation in the individuals with diabetes."

Supports the human association between pancreatic adiposity and beta-cell dedifferentiation that this experiment tries to make causal and reversible.

PMID:40072535 SUPPORT Human Clinical

"the interactions among adipocytes, immune cells and beta cells in the pancreas microenvironment might contribute to beta cell failure and dedifferentiation"

Motivates modeling the islet-adipocyte-immune microenvironment rather than studying isolated beta cells alone.

+ 1 more reference

Inflamed adipose tissue loses the insulin-stimulated fatty acid uptake arm — tumor necrosis factor alpha suppresses it and lowers FATP1 protein — yet mice that lack that arm from birth are completely protected from diet-induced obesity and insulin desensitization. Is losing it a pathogenic feature of the insulin-resistant adipocyte, a protective adaptation, or an epiphenomenon?

KNOWLEDGE GAP OPEN kgap_t2d_fatp1_insulin_stimulated_fatty_acid_uptake

Attached to

pathophysiology#Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1 pathophysiology#White Adipose Tissue Inflammation

The two curated results point in opposite directions and the entry does not resolve them, which is why no causal edge is drawn from the fatty acid uptake node into Insulin Resistance. On one side, tumor necrosis factor alpha — the cytokine the adipose inflammation node produces — inhibits both basal and insulin-stimulated long-chain fatty acid uptake in adipocytes and reduces FATP1 and FATP4 protein, so the inflamed adipocyte demonstrably loses this arm alongside the GLUT4 arm. Read straightforwardly, that makes the loss part of the insulin-resistant phenotype. On the other side, FATP1-null mice, in which insulin-stimulated adipocyte fatty acid uptake is abolished outright, are completely protected from diet-induced obesity and insulin desensitization, and the authors propose FATP1 as an antidiabetic target. If the loss were simply pathogenic, that experiment should have gone the other way. Three readings survive the curated evidence and it does not discriminate between them. The loss may be a compensatory brake that limits adipocyte lipid loading, in which case it is protective and the cytokine effect is not the lesion. It may be pathogenic acutely but confounded in the knockout by lifelong adaptation and by the redistribution of postprandial lipid to the liver that the same paper reports — a redistribution that spares adipose at a hepatic cost this entry does not model. Or the timing may matter: a transient suppression during an established inflammatory state is not the same intervention as congenital absence. The discriminating experiment is unusually close to hand. Human adipose microphysiological systems already use insulin-stimulated fatty acid uptake as one of their three validated insulin-sensitivity assays, so the readout exists in a human non-animal system; what has not been reported is that assay run against an acute FATP1 knockdown, with and without the inflammatory stimulus.

Proposed experiments

Acute FATP1 knockdown in the human iPSC adipose microphysiological system with and without proinflammatory macrophages

transporter knockdown in a human adipose microphysiological system

exp_t2d_fatp1_knockdown_human_adipose_mps

Silence SLC27A1 in the iPSC-derived adipocyte compartment of the metabolically competent adipose microphysiological system, after the tissue has been shown insulin-responsive on all three validated assays, and run the same assays in four arms: knockdown or control, each with and without co-cultured M1 macrophages. Because the knockdown is acute and applied to already-mature tissue, it separates the consequence of losing the transport arm from the lifelong adaptation that confounds the germline knockout, and because the chip has no liver compartment, the hepatic lipid redistribution seen in the mouse cannot rescue or mask the adipose readout.

Perturbations

Adipocyte SLC27A1 knockdown

pathophysiology#Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1

RNA-interference or CRISPR-interference silencing of SLC27A1 in mature iPSC-derived adipocytes, applied after insulin responsiveness has been confirmed.

SLC27A1 hgnc:10995

Proinflammatory macrophage co-culture

pathophysiology#White Adipose Tissue Inflammation

Addition of M1-polarized iPSC-derived macrophages to impose the inflammatory state, with M0 macrophages as the polarization control.

Readouts

Insulin-stimulated fatty acid uptake after knockdown

pathophysiology#Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1

Insulin-Stimulated Long-Chain Fatty Acid Import GO:0044539

Direction: DECREASED

Interpretation: On-target confirmation, and the test of whether human FATP1 carries the hormone-responsive arm as mouse FATP1 does.

Insulin-stimulated glucose uptake and lipolysis suppression

pathophysiology#Insulin Resistance

Insulin Receptor Signaling GO:0008286

Direction: UNCHANGED

Interpretation: The discriminating measurement. Direction is written as the compensatory reading — if losing the fatty acid arm is a brake rather than a lesion, the other two insulin-sensitivity assays should not deteriorate and may improve under inflammation.

Controls

Non-targeting knockdown construct

Scrambled construct on the same delivery schedule, controlling for the procedure rather than for the transporter.

M0 macrophage arm

Non-activated macrophages in matched numbers, the polarization control that distinguishes an inflammatory effect from the presence of a second cell type.

Uninflamed knockdown arm

Knockdown without macrophages, so the effect of losing the transport arm is measured against a healthy background as well as an inflamed one.

Decision criterion

If knockdown worsens insulin-stimulated glucose uptake and lipolysis suppression, the loss of this arm is pathogenic and an edge into Insulin Resistance should be drawn. If knockdown leaves them unchanged or improves them under inflammation, the loss is a brake or an epiphenomenon, the node stays terminal, and the FATP1-null protection is explained without appealing to lifelong adaptation. A result that depends on whether macrophages are present supports the timing reading and neither of the other two.

Would support

pathophysiology#Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1

Would refute

pathophysiology#Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1

Supporting outcome

Confirmed SLC27A1 knockdown reduces insulin-stimulated fatty acid uptake and is accompanied by deterioration of insulin-stimulated glucose uptake and loss of lipolysis suppression, most markedly in the inflamed arm.

Refuting outcome

Confirmed knockdown reduces insulin-stimulated fatty acid uptake while glucose uptake and lipolysis suppression are unchanged or improved, reproducing in human tissue the protection seen in FATP1-null mice.
Knockdown fails to reduce insulin-stimulated fatty acid uptake in human adipocytes despite confirmed loss of transcript, which would mean the human hormone-responsive arm is not carried by FATP1 and the node needs rewriting rather than rewiring.

Show evidence (4 references)

PMID:11970897 SUPPORT In Vitro

"In contrast, treatment with TNF-alpha inhibited basal and insulin-induced LCFA uptake and reduced FATP1 and -4 levels."

The arm of the tension that makes loss of this transport step look like part of the inflamed, insulin-resistant adipocyte phenotype.

PMID:16611988 REFUTE Model Organism

"led to a complete protection from diet-induced obesity and insulin desensitization."

Graded REFUTE against the reading that losing this arm drives insulin resistance: animals lacking it entirely are protected, not harmed. This is the result that keeps the node terminal rather than wired into Insulin Resistance.

PMID:16611988 SUPPORT Model Organism

"causing a redistribution of lipids from adipocyte tissue and muscle to the liver"

Names the confound in the knockout that a whole-animal protection result cannot separate from the adipocyte effect, and the hepatic cost that this entry, having no steatosis node, would otherwise not record at all.

+ 1 more reference

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Pathophysiology

12

White Adipose Tissue Inflammation

With expanding adiposity, bone-marrow-derived macrophages accumulate in white adipose tissue, shift toward classical (M1) proinflammatory activation, and surround damaged adipocytes as crown-like structures. The resulting local and systemic tumor necrosis factor alpha, together with other proinflammatory cytokines, impairs adipocyte insulin signalling and releases lipolysis from insulin restraint, so non-esterified fatty acids and cytokines are exported to liver and muscle. This node is the adipose-tissue origin of the insulin resistance the entry otherwise begins with: the Insulin Resistance node names adipose as a resistant tissue but does not say what makes it resistant. The causal direction is anchored by an intervention rather than an association: neutralizing tumor necrosis factor alpha in obese rats restores insulin-stimulated peripheral glucose uptake.

White Adipocyte CL:0000448 Proinflammatory (M1) Adipose Tissue Macrophage CL:0000863

TNF hgnc:11892

Adipose Tissue Inflammation GO:0006954 ↑ INCREASED Tumor Necrosis Factor Production GO:0032640 ↑ INCREASED Dysregulated Adipocyte Lipolysis GO:0019433 ↑ INCREASED

White Adipose Tissue UBERON:0001347

Experimental models

Isogenic iPSC macrophage-adipocyte microphysiological system (iMAC-iADIPO-MPS) ORGAN ON CHIP Reproduces this node in human cells down to its histologic signature, and supplies the polarization control the rodent literature reaches by cytokine neutralization: M2 macrophages present in the same numbers do not produce the phenotype.

Isogenic iPSC adipocyte-hepatocyte-macrophage microphysiological system (M1-iADIPO-iHEP-MPS) ORGAN ON CHIP Carries the same inflamed adipose compartment as the two-cell system, now with a downstream tissue attached, so the consequences of this node can be measured outside the tissue in which it occurs.

Downstream

Insulin Resistance Macrophage-derived tumor necrosis factor alpha and the accompanying cytokines impair insulin action in adipose tissue and, through cytokine and fatty acid export, in muscle and liver. The edge is drawn causally because the cytokine can be removed and the insulin response recovers.

Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1 Tumor necrosis factor alpha suppresses both basal and insulin-stimulated long-chain fatty acid uptake in adipocytes and lowers FATP1 and FATP4 protein levels, so the inflamed adipocyte loses the fatty acid arm of the insulin response as well as the glucose arm.

Show evidence (4 references)

PMID:14679176 SUPPORT Model Organism

"the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass"

Establishes the macrophage accumulation that defines this node, and scales it with adiposity rather than treating it as present or absent.

PMID:14679176 SUPPORT Human Clinical

"Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68."

The human arm of the same study, cited separately so the node does not rest on rodent adipose tissue alone.

PMID:7678183 SUPPORT Model Organism

"An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes."

Supplies the cytokine content of the node across four independent obesity and diabetes models, which is what makes it a general feature rather than a property of one model.

+ 1 more reference

Impaired GLUT4-Mediated Glucose Uptake

Dysregulation of GLUT4 trafficking in adipocytes and skeletal muscle reduces insulin-stimulated glucose uptake. GULP1 facilitates GLUT4 translocation to the plasma membrane by counteracting ACAP1 inhibition of ARF6 activity. Reduced GULP1 activity therefore decreases peripheral glucose disposal and contributes to systemic insulin resistance. TBC1D4 is bound here as the human-genetic entry point to the same step: muscle biopsies show TBC1D4 and GLUT4 protein falling with increasing count of the common Greenlandic p.Arg684Ter allele, alongside severely decreased insulin-stimulated glucose uptake in muscle.

Adipocyte CL:0000136 Skeletal Muscle Cell CL:0000188

GULP1 hgnc:18649 ACAP1 hgnc:16467 ARF6 hgnc:659 TBC1D4 hgnc:19165

Insulin Receptor Signaling GO:0008286 Protein Transport GO:0015031

Downstream

Insulin Resistance Impaired GLUT4-mediated uptake reduces peripheral glucose disposal and contributes to systemic insulin resistance.

Show evidence (4 references)

PMID:42436120 SUPPORT Model Organism

"GULP1 significantly enhanced glucose uptake in adipocytes and muscle cells by promoting GLUT4 translocation to the plasma membrane. In obese mice, GULP1 overexpression improved insulin sensitivity and glucose tolerance."

Demonstrates GULP1-dependent GLUT4 trafficking and improved insulin sensitivity in metabolic tissues and obese mice.

PMID:42436120 SUPPORT Model Organism

"Mechanistically, GULP1 counteracted ACAP1's inhibition of ARF6 activity, thereby facilitating insulin-stimulated GLUT4 trafficking."

Establishes the GULP1-ACAP1-ARF6 regulatory mechanism.

PMID:25043022 SUPPORT Human Clinical

"Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles."

Measures the GLUT4 protein loss this node asserts, in human muscle, as a function of TBC1D4 genotype.

+ 1 more reference

Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1

Insulin acts on the adipocyte through two transporter arms, not one. Alongside GLUT4, insulin drives translocation of fatty acid transport proteins — FATP1 (SLC27A1) and FATP4 (SLC27A4) — from an intracellular perinuclear compartment to the plasma membrane within minutes, and long-chain fatty acid uptake rises in parallel. In FATP1-null adipocytes the insulin-stimulated component of fatty acid uptake is entirely absent while basal uptake is unaffected, so FATP1 specifically carries the hormone-responsive arm. Tumor necrosis factor alpha from inflamed adipose tissue suppresses this arm and lowers FATP1 and FATP4 protein. This node is deliberately terminal. Whether losing the arm drives systemic insulin resistance is genuinely unsettled — FATP1-null mice, which lack it from birth, are completely protected from diet-induced insulin desensitization — so no edge is drawn into Insulin Resistance and the tension is carried by the kgap_t2d_fatp1_insulin_stimulated_fatty_acid_uptake discussion instead. The node is curated because it is a real, measurable arm of adipocyte insulin action that the entry otherwise omits, and because it is one of the three functional assays the human adipose microphysiological systems use to score insulin sensitivity.

White Adipocyte CL:0000448 Skeletal Muscle Cell CL:0000188

SLC27A1 hgnc:10995 SLC27A4 hgnc:10998

Insulin-Stimulated Long-Chain Fatty Acid Import GO:0044539 ↓ DECREASED Insulin Receptor Signaling GO:0008286

FATP1/FATP4 long-chain fatty acid transport activity GO:0005324

White Adipose Tissue UBERON:0001347

Experimental models

Metabolically competent iPSC white adipose tissue microphysiological system (iADIPO-MPS) ORGAN ON CHIP Insulin-stimulated fatty acid uptake is one of the three assays the platform is validated on, so the arm this node represents is directly measurable in human adipose tissue rather than only in mouse adipocytes.

Animal models

FATP1 (Slc27a1) knockout mouse on high-fat diet Mouse perturbs Removes the hormone-responsive arm of adipocyte fatty acid uptake genetically, and shows the loss is specific to the insulin-stimulated component rather than to fatty acid handling generally.

Show evidence (2 references)

PMID:11970897 SUPPORT In Vitro

"in adipocytes, insulin induces plasma membrane translocation of FATPs from an intracellular perinuclear compartment to the plasma membrane."

Establishes the regulated trafficking step this node represents, and its parallel to the GLUT4 translocation the entry already models.

PMID:16611988 SUPPORT Model Organism

"insulin-stimulated fatty acid uptake is completely abolished in FATP1-null adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals while basal LCFA uptake by both tissues was unaffected."

Assigns the hormone-responsive component specifically to FATP1 — basal uptake is untouched — which is what makes this a distinct node rather than a restatement of fatty acid handling in general.

Insulin Resistance

Peripheral tissues (muscle, liver, adipose) become resistant to insulin action, requiring higher insulin levels to maintain glucose homeostasis. This leads to compensatory hyperinsulinemia and eventually beta cell exhaustion.

Hepatocyte CL:0000182 Skeletal Muscle Cell CL:0000188 Adipocyte CL:0000136

PPARG hgnc:9236

Insulin Signaling GO:0008286

Experimental models

Metabolically competent iPSC white adipose tissue microphysiological system (iADIPO-MPS) ORGAN ON CHIP Provides a calibrated human, non-animal assay for the adipose limb of this node, with the dynamic range needed to score a compound as sensitizing or desensitizing rather than merely to observe a resistant state.

Isogenic iPSC adipocyte-hepatocyte-macrophage microphysiological system (M1-iADIPO-iHEP-MPS) ORGAN ON CHIP Produces insulin resistance across two connected human tissues from a single upstream manipulation, and adjudicates between adipose inflammation and adipose expansion as its cause. Expansion alone produced hepatic insulin resistance only at an extreme adipocyte-to-hepatocyte ratio; inflammation produced it readily.

Computational models

Topp Beta-Cell Mass / Insulin / Glucose Model KINETIC COPASI Reduced whole-body insulin sensitivity is the model parameter si; lowering si (or PPARG/thiazolidinedione perturbation of si) reproduces the insulin-resistance driver of type 2 diabetes.

Downstream

Beta Cell Dysfunction Sustained insulin resistance increases compensatory beta-cell insulin demand, contributing to eventual beta-cell failure.

Hepatic Glucose Overproduction Hepatic insulin resistance reduces insulin-mediated suppression of liver glucose production.

Show evidence (4 references)

PMID:12231074 SUPPORT

"Insulin resistance is caused by the decreased ability of peripheral target tissues (especially muscle) to respond properly to normal circulating concentrations of insulin."

This establishes that skeletal muscle is a key site of insulin resistance in type 2 diabetes, with impaired response to normal insulin levels.

PMID:12231074 SUPPORT

"These alterations in glucose transport activity are likely the result of dysregulation of intramyocellular fatty acid metabolism, whereby fatty acids cause insulin resistance by activation of a serine kinase cascade, leading to decreased insulin-stimulated insulin receptor substrate (IRS)-1..."

This describes the molecular mechanism of insulin resistance involving fatty acid-induced serine kinase activation that impairs insulin receptor signaling through IRS-1 and PI3K.

PMID:29939616 SUPPORT

"Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta-cell insulin production and hyperinsulinemia."

This confirms that insulin resistance leads to compensatory hyperinsulinemia as beta cells attempt to overcome impaired glucose disposal in peripheral tissues.

+ 1 more reference

Beta Cell Dysfunction

Progressive loss of pancreatic beta cell function and mass leads to inadequate insulin secretion relative to insulin demand. Beta cell failure is the key determinant of disease progression.

Pancreatic Beta Cell CL:0000169

KCNJ11 hgnc:6257 SLC30A8 hgnc:20303

Insulin Secretion GO:0030073

Computational models

Topp Beta-Cell Mass / Insulin / Glucose Model KINETIC COPASI Maximal per-beta-cell secretory capacity (sigma) and the beta-cell-mass state variable (B) capture secretory failure and glucotoxic beta-cell-mass loss; TCF7L2/KCNJ11/HNF1A perturbations act here.

Downstream

Hyperglycemia Insufficient beta-cell insulin secretion limits glucose control and drives hyperglycemia.

Show evidence (5 references)

PMID:37035220 SUPPORT

"Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D)."

This establishes beta cell dysfunction as a core pathological mechanism in type 2 diabetes development alongside insulin resistance.

PMID:37035220 SUPPORT

"Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with T2D."

This demonstrates that inflammatory markers are associated with beta cell failure, indicating inflammation contributes to beta cell dysfunction.

PMID:37035220 SUPPORT

"Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D."

This confirms that oxidative stress, characterized by increased ROS and depleted antioxidants, contributes to pancreatic beta cell damage in type 2 diabetes.

+ 2 more references

Hepatic Glucose Overproduction

Impaired suppression of hepatic gluconeogenesis leads to elevated fasting glucose levels. The liver fails to respond appropriately to insulin signals.

Hepatocyte CL:0000182

Gluconeogenesis GO:0006094

Experimental models

Isogenic iPSC adipocyte-hepatocyte-macrophage microphysiological system (M1-iADIPO-iHEP-MPS) ORGAN ON CHIP Hepatic glucose production and its suppression by insulin are primary endpoints of the chip, alongside PCK1 expression, so this node has a direct human non-animal assay. The chip also shows the node responding to metformin.

Computational models

Topp Beta-Cell Mass / Insulin / Glucose Model KINETIC COPASI Insulin-independent hepatic glucose output is the parameter R0, the target reduced by metformin in the simulated treatment scenarios.

Downstream

Hyperglycemia Excess hepatic glucose production contributes directly to impaired glucose homeostasis.

Show evidence (3 references)

PMID:30150719 SUPPORT

"Diabetes is characterized by impaired glucose homeostasis partly due to abnormally elevated hepatic glucose production (HGP)."

This establishes that elevated hepatic glucose production is a key feature of diabetes pathophysiology.

PMID:30150719 SUPPORT

"Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP)."

This confirms that hepatic glucose overproduction is central to diabetes hyperglycemia, as metformin's primary mechanism targets HGP suppression.

PMID:30150719 SUPPORT

"FBP1 catalyzes the irreversible hydrolysis of fructose-1,6-bisphosphate (F-1,6-P2) to fructose-6-phosphate (F6P) and inorganic phosphate (Pi) in the presence of divalent cations. FBP1 is a key rate-controlling enzyme in the gluconeogenic pathway."

This identifies fructose-1,6-bisphosphatase (FBP1) as a key rate-controlling enzyme in hepatic gluconeogenesis, the pathway responsible for glucose overproduction in diabetes.

Mitochondrial Dysfunction and Oxidative Stress

Early-onset mitochondrial dysfunction and pathological reactive oxygen species (ROS) generation occur across multiple metabolic tissues including pancreatic beta cells, skeletal muscle, and adipose tissue. Impaired mitophagy and mitochondrial dynamics contribute to disease progression. Extracellular vesicle-mediated inter-organ miscommunication propagates oxidative damage.

Pancreatic Beta Cell CL:0000169 Skeletal Muscle Cell CL:0000188

Oxidative Stress Response GO:0006979 Mitophagy GO:0000422

Show evidence (3 references)

PMID:38338783 SUPPORT

"New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple..."

This establishes that mitochondrial dysfunction and oxidative damage occur early and may drive T2D progression regardless of whether insulin resistance or beta cell dysfunction is the primary event.

PMID:38338783 SUPPORT

"Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs."

This describes the novel mechanism of extracellular vesicle-mediated oxidative stress propagation between tissues in T2D pathogenesis.

PMID:37035220 SUPPORT

"Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D."

This confirms that oxidative stress characterized by increased ROS and depleted antioxidants contributes to beta cell damage.

Ceramide Accumulation

Ectopic accumulation of ceramides, sphingolipids formed from saturated fatty acids such as palmitate, in skeletal muscle, liver, and pancreatic beta cells. Ceramides impair insulin signaling through PP2A-mediated dephosphorylation of Akt, and within the beta cell they induce ER stress, mitochondrial dysfunction, and mitochondrial-mediated apoptosis.

Skeletal Muscle Cell CL:0000188 Pancreatic Beta Cell CL:0000169

ceramide formation from saturated fatty acids GO:0046513 ↑ INCREASED

Downstream

Insulin Resistance Intramyocellular ceramide impairs insulin signaling in skeletal muscle, in part through PP2A-mediated dephosphorylation of Akt.

Beta Cell Dysfunction Ceramide accumulation in beta cells induces ER stress, mitochondrial dysfunction, and mitochondrial-mediated apoptosis, reducing functional beta-cell mass.

Show evidence (2 references)

PMID:42549109 SUPPORT REVIEW SYNTHESIS Other

"Among the most potent lipotoxic molecules are ceramides, sphingolipids that act as central mediators of both IR and β-cell apoptosis."

Review synthesis identifying ceramides as central lipotoxic mediators of insulin resistance and beta-cell apoptosis in T2D.

PMID:42549109 SUPPORT REVIEW SYNTHESIS Other

"Beyond insulin signaling, ceramides are powerful inducers of mitochondrial-mediated apoptosis."

Review synthesis describing the apoptotic action of ceramides beyond their effect on insulin signaling.

Diacylglycerol Accumulation

Ectopic accumulation of diacylglycerols (DAG) in liver and skeletal muscle. DAG acts as a second messenger that activates novel PKC isoforms (PKC-theta in muscle, PKC-epsilon in liver), which phosphorylate insulin receptor substrate proteins on inhibitory serine residues and so blunt insulin signaling.

Skeletal Muscle Cell CL:0000188

DAG-activated novel PKC (PKC-theta/epsilon) activity GO:0004697 ↑ INCREASED

Downstream

Insulin Resistance DAG-activated PKC-theta phosphorylates IRS-1 on inhibitory serine residues, impairing insulin signaling in skeletal muscle.

Show evidence (2 references)

PMID:42549109 SUPPORT REVIEW SYNTHESIS Other

"The accumulation of DAGs in nonadipose tissues like liver, skeletal muscle, and pancreatic islets is another major driver of lipotoxicity."

Review synthesis identifying ectopic DAG accumulation as a lipotoxic driver in T2D.

PMID:42549109 SUPPORT REVIEW SYNTHESIS Other

"Thus, DAG serves as a key lipid intermediate that disrupts insulin sensitivity in metabolic tissues, primarily through PKC signaling cascades."

Review synthesis stating that DAG acts on insulin sensitivity through PKC signaling.

Islet Amyloid Polypeptide Oligomer Proteotoxicity

Human IAPP (amylin), co-secreted with insulin, misfolds into soluble toxic oligomers under the insulin hypersecretion of the compensatory phase of T2D. These oligomers, rather than the inert extracellular amyloid fibrils of late-stage disease, are the cytotoxic species: they impair beta-cell mitochondrial function, overwhelm ER folding capacity, and activate the NLRP3 inflammasome. Declining autophagic clearance lets them persist.

Pancreatic Beta Cell CL:0000169

hIAPP toxic oligomer formation GO:0051260 ↑ INCREASED

Downstream

Beta Cell Dysfunction Soluble hIAPP oligomers impair beta-cell mitochondrial function, trigger chronic ER stress, and activate the NLRP3 inflammasome, adding proteotoxic stress to beta cells that already carry lipotoxic and inflammatory load.

Show evidence (2 references)

PMID:42549109 SUPPORT REVIEW SYNTHESIS Other

"Cosecreted with insulin, hIAPP is prone to misfolding and forming toxic oligomers, particularly under the demanding conditions of insulin hypersecretion that characterize the compensatory phase of T2D"

Review synthesis describing hIAPP oligomer formation under compensatory insulin hypersecretion.

PMID:42549109 SUPPORT REVIEW SYNTHESIS Other

"Unlike the inert, extracellular amyloid fibrils found in late-stage disease, these soluble oligomers are the primary cytotoxic species"

Review synthesis identifying soluble oligomers, not fibrils, as the cytotoxic hIAPP species, which is why this node is bound to oligomerization.

Incretin Axis Dysfunction

Impaired incretin hormone signaling, particularly blunted glucose-dependent insulinotropic peptide (GIP) action in beta cells. GLP-1 action is relatively preserved. The incretin effect amplifies insulin secretion in response to oral glucose via cAMP-PKA signaling pathways.

Pancreatic Beta Cell CL:0000169 Enteroendocrine Cell CL:0000164

TCF7L2 hgnc:11641

cAMP Signaling GO:0141156 Insulin Secretion Regulation GO:0050796

Downstream

Beta Cell Dysfunction Reduced beta-cell sensitivity to incretins impairs oral-glucose-stimulated insulin secretion.

Show evidence (3 references)

PMID:38831203 SUPPORT

"Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge."

This establishes the importance of the GLP-1/GIP incretin axis in T2D pathophysiology and its targeting by dual agonist therapies.

PMID:38831203 SUPPORT

"Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity."

This demonstrates the clinical relevance of incretin axis dysfunction by showing dual GLP-1/GIP agonism is effective for T2D treatment.

PMID:19934000 SUPPORT Human Clinical

"The TCF7L2 variant rs7903146 appears to affect risk of type 2 diabetes, at least in part, by modifying the effect of incretins on insulin secretion."

Supports TCF7L2 as a genetic contributor to incretin-axis effects on insulin secretion in humans.

Chronic Hyperglycemia

Sustained hyperglycemia arising from the combined insulin resistance, beta-cell secretory failure, and hepatic glucose overproduction is the shared driver of long-term diabetic tissue injury and the entry point to the conserved diabetic vascular-complication cascade captured by the diabetic_vascular_complications module (chronic hyperglycemia -> oxidative and AGE-RAGE stress -> endothelial dysfunction and vascular inflammation -> micro- and macrovascular injury -> end-organ complications). In type 2 diabetes this cascade manifests clinically as diabetic retinopathy, neuropathy, nephropathy, and atherosclerotic cardiovascular disease.

glucose homeostasis GO:0042593 ⚠ ABNORMAL

Downstream

Diabetic Retinopathy Sustained hyperglycemia drives the microvascular injury that produces diabetic retinopathy, one of the shared end-organ complications captured by the diabetic_vascular_complications module this node conforms to.

Peripheral Neuropathy Sustained hyperglycemia drives the microvascular and metabolic nerve injury that produces diabetic peripheral neuropathy, another shared end-organ complication of the conserved vascular-complication cascade.

Show evidence (1 reference)

PMID:29939616 SUPPORT Other

"This vicious cycle continues until pancreatic beta-cell activity can no longer adequately meet the insulin demand created by insulin resistance, resulting in hyperglycemia."

Supports sustained hyperglycemia arising from beta-cell failure to compensate for insulin resistance, the shared trigger that feeds the diabetic vascular-complication cascade.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

10

Endocrine 1

Hyperinsulinemia FREQUENT HP:0000842

Compensatory response to insulin resistance

Show evidence (1 reference)

PMID:29939616 SUPPORT

"Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta-cell insulin production and hyperinsulinemia."

This establishes hyperinsulinemia as a compensatory response to insulin resistance in T2D.

Eye 1

Diabetic Retinopathy OCCASIONAL HP:0000488

Long-term microvascular complication

Genitourinary 1

Polyuria FREQUENT HP:0000103

Show evidence (1 reference)

PMID:9398128 SUPPORT

"Polyuria due to a glucose-induced osmotic diuresis is common in patients with hyperglycemia. This diuresis usually abates when the plasma glucose level approaches its renal threshold."

This describes the mechanism of polyuria in diabetes as glucose-induced osmotic diuresis when plasma glucose exceeds the renal threshold.

Metabolism 3

Hyperglycemia VERY_FREQUENT HP:0003074

Show evidence (2 references)

PMID:29939616 SUPPORT

"This vicious cycle continues until pancreatic beta-cell activity can no longer adequately meet the insulin demand created by insulin resistance, resulting in hyperglycemia."

This describes how the failure of beta cells to compensate for insulin resistance results in hyperglycemia, the hallmark of type 2 diabetes.

PMID:30150719 SUPPORT

"Diabetes is characterized by impaired glucose homeostasis partly due to abnormally elevated hepatic glucose production (HGP)."

This confirms that hyperglycemia in diabetes results from elevated hepatic glucose production and impaired glucose homeostasis.

Insulin Resistance VERY_FREQUENT HP:0000855

Show evidence (1 reference)

PMID:12231074 SUPPORT

"Insulin resistance is caused by the decreased ability of peripheral target tissues (especially muscle) to respond properly to normal circulating concentrations of insulin."

This establishes insulin resistance as a hallmark feature of T2D pathophysiology.

Impaired Glucose Tolerance VERY_FREQUENT Glucose intolerance HP:0001952

Nervous System 2

Polydipsia FREQUENT HP:0001959

Show evidence (1 reference)

PMID:9398128 SUPPORT

"Polyuria due to a glucose-induced osmotic diuresis is common in patients with hyperglycemia."

This establishes that polyuria results from glucose-induced osmotic diuresis in hyperglycemia, which in turn leads to polydipsia as a compensatory response to fluid loss.

Peripheral Neuropathy OCCASIONAL HP:0009830

Long-term microvascular complication

Constitutional 1

Fatigue FREQUENT HP:0012378

Growth 1

Obesity FREQUENT HP:0001513

🧬

Genetic Associations

6

TCF7L2 (Risk Factor)

Gene: TCF7L2 hgnc:11641 gene page

PPARG (Risk Factor)

Gene: PPARG hgnc:9236 gene page

KCNJ11 (Risk Factor)

Gene: KCNJ11 hgnc:6257 gene page

SLC30A8 (Risk Factor)

Gene: SLC30A8 hgnc:20303 gene page

TBC1D4 (Founder nonsense variant, recessive effect)

Gene: TBC1D4 hgnc:19165 relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:25043022 SUPPORT Human Clinical

"we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%"

Names the variant and its 17% allele frequency in the study population. No case_fractions record is kept for this gene: an allele frequency is a different quantity from the share of disease cases a gene explains, and the source reports no per-gene share.

PMID:25043022 SUPPORT Human Clinical

"their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24))"

Quantifies the type 2 diabetes risk carried by homozygotes, which is the relationship this record names.

PMID:25043022 SUPPORT Human Clinical

"Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers"

Supports the recessive dose pattern this record states: heterozygotes are affected only marginally, so the effect is essentially homozygote-restricted.

CAPN10 (Reported susceptibility locus, not replicated)

Gene: CAPN10 hgnc:1477 relationship_type: DISPUTED

Show evidence (3 references)

PMID:11017071 SUPPORT Human Clinical

"Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland."

The original report this MONDO class rests on, recorded so the disputed claim is traceable to its source.

PMID:14730479 REFUTE Human Clinical

"Under either an additive or a dominant effect model, we found no statistically significant relation between CAPN10 genotypes in the UCSNP-43 locus and T2D risk."

The meta-analytic result that makes this relationship disputed rather than established.

PMID:14730479 REFUTE Human Clinical

"After we removed these initial studies, this association became nonsignificant (OR 1.11; 95% CI 0.91-1.35)."

Shows the haplotype association was driven by the initial small positive studies, which is the second ground for the DISPUTED grade.

💊

Medical Actions

6

Metformin

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: metformin CHEBI:6801

First-line oral medication that reduces hepatic glucose production and improves insulin sensitivity.

Mechanism Target:

INHIBITS Hepatic Glucose Overproduction — Metformin's primary action is suppression of excessive hepatic gluconeogenesis, so it targets the hepatic-glucose-overproduction node directly (with a secondary insulin-sensitizing effect), lowering fasting glucose upstream of chronic hyperglycemia.

Show evidence (1 reference)

PMID:39266553 SUPPORT INDIRECT In Vitro

"However, only metformin and rosiglitazone decreased TNF and PCK1 gene expression in the iHEP-MPS and improved insulin response"

Human, non-animal support for the hepatic arm of this edge: in an interconnected adipose-liver chip metformin lowered expression of the gluconeogenic gene PCK1 in the hepatocyte compartment and restored its insulin response, while dexamethasone in the same panel did not. Graded INDIRECT because gluconeogenic gene expression in a chip is a step removed from the fasting glucose lowering the edge describes in patients.

Lifestyle Modification

Action: Lifestyle Therapy NCIT:C15900

Diet and exercise interventions to reduce weight and improve metabolic health.

Mechanism Target:

INHIBITS Insulin Resistance — Weight loss and exercise improve peripheral insulin sensitivity, acting on the insulin-resistance node that is the primary upstream driver of type 2 diabetes rather than merely lowering glucose downstream.

GLP-1 Receptor Agonists

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Injectable medications that enhance insulin secretion and promote weight loss.

Mechanism Target:

INHIBITS Incretin Axis Dysfunction — GLP-1 receptor agonists restore the deficient incretin signal, correcting the incretin-axis-dysfunction node to enhance glucose-dependent insulin secretion (with weight loss and appetite effects), upstream of chronic hyperglycemia.

INHIBITS White Adipose Tissue Inflammation — Beyond restoring the incretin signal, GLP-1 receptor agonism acts on the adipocyte itself to reduce adipose inflammation, and the reduction in cytokine output is what improves insulin action in the connected tissue. The edge is drawn from a human non-animal system rather than from clinical trial data, because the tissue-attribution question it answers is confounded in patients and in rodents by the drug's effects on appetite and body weight.

Show evidence (2 references)

PMID:39266553 SUPPORT INDIRECT In Vitro

"While selective semaglutide treatment of the M1-iADIPO-MPS component was as effective as treatment of the entire M1-iADIPO-iHEP-MPS, selective semaglutide treatment of the iHEP-MPS component was largely ineffective"

The compartment-selective result that localizes the drug's action to adipose tissue: dosing the adipocyte compartment alone reproduced the whole-system benefit, dosing the hepatocyte compartment alone did not. Graded INDIRECT because the tissue attribution is established in a human model system rather than in patients.

PMID:39266553 SUPPORT INDIRECT In Vitro

"Studying the specific role of the WAT-liver axis in the semaglutide response using mouse models has been difficult due to the strong effects on feeding behavior and body weight"

States why this claim rests on a non-animal human system: the tissue-specific question is confounded in rodents by the drug's central effects, which is the case for curating a New Approach Methodology result as the primary support for a mechanism edge.

Show evidence (1 reference)

PMID:38831203 SUPPORT

"Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge."

This establishes GLP-1/GIP receptor agonists as effective pharmacological strategies for T2D treatment.

SGLT2 Inhibitors

Action: Pharmacotherapy NCIT:C15986

Oral medications that increase urinary glucose excretion.

Mechanism Target:

INHIBITS Chronic Hyperglycemia — SGLT2 inhibitors act insulin-independently, increasing urinary glucose excretion to lower chronic hyperglycemia directly (with additional cardiorenal protection), targeting the shared hyperglycemia node that feeds the diabetic vascular-complication cascade.

Insulin Therapy

Action: insulin therapy Ontology label: Injected Insulin Diabetes Therapy NCIT:C179441

Required when beta cell function declines significantly.

Mechanism Target:

INHIBITS Chronic Hyperglycemia — When beta-cell secretory capacity has declined enough that endogenous insulin is inadequate, exogenous insulin replaces the shortfall and lowers chronic hyperglycemia directly — a later-line glucose-node intervention once upstream insulin-sensitizing and incretin approaches no longer suffice.

GLP-1/GIP Dual Agonists

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Tirzepatide and similar agents that activate both GLP-1 and GIP receptors for enhanced glycemic control and weight loss.

Mechanism Target:

INHIBITS Incretin Axis Dysfunction — Tirzepatide co-activates the GIP and GLP-1 receptors, correcting the incretin-axis-dysfunction node more completely than single GLP-1 agonism for enhanced glucose-dependent insulin secretion and weight loss.

Show evidence (1 reference)

PMID:38831203 SUPPORT

"Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity."

This confirms tirzepatide as an authorized dual GLP-1/GIP agonist for T2D and obesity treatment.

🌍

Environmental Factors

3

Sedentary Lifestyle

Major modifiable risk factor

Show evidence (1 reference)

PMID:22890825 SUPPORT Human Clinical

"The greatest sedentary time compared with the lowest was associated with a 112% increase in the RR of diabetes"

Systematic review and meta-analysis quantifies sedentary time's association with type 2 diabetes risk.

High-Calorie Diet

Contributes to obesity and insulin resistance

Show evidence (1 reference)

PMID:28065634 SUPPORT Human Clinical

"Risk of diabetes developing was 24% greater for women in the highest dietary energy density quintile compared with the lowest after adjusting for confounders (95% CI 1.17 to 1.32)"

Prospective cohort study (Women's Health Initiative) links higher dietary energy density to increased type 2 diabetes incidence.

Obesity

Primary risk factor for insulin resistance

Show evidence (1 reference)

PMID:20493574 SUPPORT Human Clinical

"The overall RR of diabetes for obese persons compared to those with normal weight was 7.19, 95% CI: 5.74, 9.00 and for overweight was 2.99, 95% CI: 2.42, 3.72"

Meta-analysis of prospective cohort studies quantifies obesity's association with type 2 diabetes risk.

🔬

Biochemical Markers

2

Myeloid Lineage Plasma Proteomic Age Gap (Elevated)

Context: Blood-based cell-type-specific aging clock. Plasma proteins are mapped to their putative cell of origin using Human Protein Atlas single-cell transcriptomic data, and a machine-learning model estimates myeloid lineage biological age; the age gap is the difference between that estimate and chronological age. "Extreme" agers are those in the upper tail of the age-gap distribution.

Pathograph Readouts

Predicts Beta Cell Dysfunction Positive Prognostic

An elevated myeloid lineage age gap predicts incident type 2 diabetes in still-normoglycemic individuals, and is read against beta cell dysfunction via the proposed route of myeloid-derived cytokines inflaming the islet microenvironment. The prognostic association is measured; the islet route is inference and should not be curated as an established causal edge.

Show evidence (1 reference)

PMID:42297981 SUPPORT Human Clinical

"consistent with a role of myeloid-derived cytokines in the initiation of an inflamed pancreatic islet microenvironment and increased susceptibility to type 2 diabetes"

The authors' stated mechanistic rationale linking the myeloid aging signature to the islet compartment, offered as consistency rather than as demonstrated causation.

Show evidence (2 references)

PMID:42297981 SUPPORT Human Clinical

"myeloid lineage extreme aging demonstrated the strongest prognostic value"

Establishes myeloid lineage aging as the leading cellular-aging predictor of incident type 2 diabetes among the cell types tested.

PMID:42297981 SUPPORT Human Clinical

"myeloid lineage aging identified normoglycemic individuals at higher type 2 diabetes risk"

States the clinically distinctive claim: risk stratification before glycemic criteria are met, which is what would make the marker useful for targeted surveillance.

NMR metabolomic risk score (MetRS)

Context: In the UK Biobank metabolome-phenome atlas, MetRS classified prevalent type 2 diabetes with an area under the curve of 0.941 and predicted incident diabetic complications, including diabetic maculopathy (0.921), diabetic kidney failure (0.919) and type 2 diabetes with peripheral circulatory complications (0.913). No presence value is recorded because MetRS is a derived multi-analyte score rather than a measured analyte. Two limits matter for interpretation: the score is trained and tested in a single, predominantly European-ancestry volunteer cohort, and a high classification area under the curve for prevalent disease partly reflects the metabolic consequences of established diabetes rather than antecedent risk.

Pathograph Readouts

Correlates With Chronic Hyperglycemia Positive Diagnostic

The lipid, amino-acid and glycolysis-related measures that dominate MetRS shift with sustained hyperglycemia and insulin resistance, so the score reads out the systemic metabolic state rather than any single mechanism.

Show evidence (3 references)

PMID:40973818 SUPPORT Computational

"MetRS offered favourable diagnostic and predictive performance, particularly in T2D"

Names type 2 diabetes as one of the conditions in which the machine-learning metabolomic risk score performed best, both for classification of prevalent disease and for prediction of incident disease.

PMID:40973818 SUPPORT Computational

"The MetRS witnessed excellent diagnosis for type 1 diabetes (T1D; AUC = 0.944), T2D (AUC = 0.941), diabetic maculopathy (AUC = 0.940) and chronic kidney disease (CKD; AUC = 0.933)."

Quotes the prevalent-disease classification figure of 0.941 for type 2 diabetes that the context field reports.

PMID:40973818 SUPPORT Computational

"the MetRS excellently predicted future diabetic complications, for example, diabetic maculopathy (AUC = 0.921 (95% CI, 0.914-0.928)), diabetic kidney failure (AUC = 0.919 (0.906-0.930)) and type 2 diabetes (T2D) with peripheral circulatory complications (AUC = 0.913 (0.898-0.926))."

Quotes all three incident-complication figures reported in the context field, so the predictive claim and its numbers both rest on source text.

🔬

Diagnosis

3

Hemoglobin A1C (Diagnostic)

Glycated hemoglobin is one of the three laboratory criteria by which the American Diabetes Association diagnoses diabetes, and the one that also defines the prediabetes band. The ADA criterion is an A1C of 6.5% or higher, measured by an NGSP-certified method traceable to the DCCT reference assay, with 5.7-6.4% identifying prediabetes. In the absence of unequivocal hyperglycemia the diagnosis requires a second abnormal result.

hemoglobin A1C measurement NCIT:C64849

hemoglobin A1C (NGSP, percent of total hemoglobin) LOINC:4548-4

Reference Ranges

Hemoglobin A1c/Hemoglobin.total in Blood (ADA Standards of Care in Diabetes, 2025 (nonpregnant individuals))

Normal (< 5.7 %) Prediabetes (5.7–6.5 %) Diabetes (≥ 6.5 %)

Prediabetes: ADA prediabetes band (5.7-6.4%); identifies individuals at high risk for diabetes and cardiovascular outcomes, not a diagnosis of diabetes.

Diabetes: Meets the ADA A1C criterion for diabetes; requires confirmation by a second abnormal test in the absence of unequivocal hyperglycemia.

Source phrasing: "A1C 5.7-6.4% (39-47 mmol/mol)" for prediabetes and "A1C (two results >=6.5% [>=48 mmol/mol])" for diabetes. The bands are half-open, so the prediabetes band runs [5.7, 6.5) rather than ending at 6.4; any value between 6.4 and 6.5 falls in the prediabetes band here, which is the one-point difference between the half-open convention and the source's "5.7-6.4%" wording. The source's lower limit of normal is not a separate cut-off; the Normal band is simply everything below 5.7%.

Show evidence (3 references)

PMID:39651986 SUPPORT REVIEW SYNTHESIS Other

"People with prediabetes are defined by the presence of IFG and/or IGT and/or A1C 5.7–6.4% (39–47 mmol/mol) (Table 2.2)."

Names the ADA prediabetes A1C band, 5.7-6.4%, which is the lower band recorded here.

PMID:39651986 SUPPORT REVIEW SYNTHESIS Other

"if an individual meets the diabetes criterion of A1C (two results ≥6.5%"

States the ADA A1C diabetes criterion of 6.5% or higher on two results; the sentence continues to say such a person is considered to have diabetes even when fasting glucose is below its own threshold.

PMID:20042775 SUPPORT REVIEW SYNTHESIS Other

"A1C ≥6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay."

The ADA position statement that first adopted the 6.5% A1C criterion in 2010, stating the threshold and the NGSP/DCCT standardization requirement that fixes the unit as percent.

This entry has no biochemical marker for A1C, so the code and its bands live on this diagnosis row rather than on a marker. LOINC:4548-4 is the method-less code whose property is a mass fraction reported in percent, which is the NGSP/DCCT unit the ADA thresholds are stated in. The IFCC-protocol code LOINC:59261-8 (Hemoglobin A1c/Hemoglobin.total in Blood by IFCC protocol) reports mmol/mol and is not bound because the cut-offs are percent values; the ADA text gives the mmol/mol equivalents in parentheses (48 mmol/mol for 6.5%, 39-47 mmol/mol for 5.7-6.4%). The LOINC Part is LOINC:LP16413-4 (Hemoglobin A1c). The ADA 2025 chapter is cached as full text, so the criteria quoted come from its prose; the chapter's Table 2.1 and Table 2.2 bodies are not in the cached text and are not quoted.

Show evidence (2 references)

PMID:39651986 SUPPORT REVIEW SYNTHESIS Other

"Diabetes may be diagnosed based on A1C or plasma glucose criteria. Plasma glucose criteria include either the fasting plasma glucose (FPG), 2-h plasma glucose (2-h PG) during a 75-g oral glucose tolerance test (OGTT), or random glucose accompanied by classic hyperglycemic symptoms"

Establishes A1C as one of the ADA diagnostic criteria for diabetes, alongside the two plasma glucose tests curated as separate rows.

PMID:39651986 SUPPORT REVIEW SYNTHESIS Other

"The A1C test should be performed using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) (ngsp.org) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay."

The standardization requirement that fixes the unit of the ADA thresholds as NGSP percent, which is why the percent-reporting LOINC code rather than the IFCC mmol/mol code is bound.

Fasting plasma glucose (Diagnostic)

Fasting plasma glucose is an ADA diagnostic criterion for diabetes at 126 mg/dL (7.0 mmol/L) or higher, with fasting defined as no caloric intake for at least 8 h. The ADA impaired fasting glucose band is 100-125 mg/dL (5.6-6.9 mmol/L); the ADA text notes that the World Health Organization and several diabetes organizations set the IFG lower limit at 110 mg/dL (6.1 mmol/L) instead.

fasting plasma glucose measurement NCIT:C92744

fasting plasma glucose (mg/dL) LOINC:1558-6

Reference Ranges

Fasting glucose [Mass/volume] in Serum or Plasma (ADA Standards of Care in Diabetes, 2025 (nonpregnant individuals))

Normal (< 100.0 mg/dL) Impaired fasting glucose (prediabetes) (100.0–126.0 mg/dL) Diabetes (≥ 126.0 mg/dL)

Impaired fasting glucose (prediabetes): ADA impaired fasting glucose, 100-125 mg/dL (5.6-6.9 mmol/L); a prediabetes category, not a diagnosis of diabetes.

Diabetes: Meets the ADA fasting plasma glucose criterion for diabetes; requires confirmation in the absence of unequivocal hyperglycemia.

Source phrasing: "IFG is defined as FPG levels from 100 to 125 mg/dL (from 5.6 to 6.9 mmol/L)" and "FPG ≥126 mg/dl (7.0 mmol/l)". Half-open bands: the IFG band is recorded as [100, 126) rather than ending at 125, which is the one-point difference between the convention and the source's "100 to 125" wording. The ADA text also records that the WHO and some other organizations use 110 mg/dL (6.1 mmol/L) as the IFG lower limit; that alternative is not recorded as a separate range because the WHO document itself is not cited here.

Show evidence (2 references)

PMID:39651986 SUPPORT REVIEW SYNTHESIS Other

"IFG is defined as FPG levels from 100 to 125 mg/dL (from 5.6 to 6.9 mmol/L) (78,84) and IGT as 2-h PG levels during 75-g OGTT from 140 to 199 mg/dL (from 7.8 to 11.0 mmol/L) (10). It should be noted that the World Health Organization and a number of diabetes organizations define the IFG lower..."

States the ADA impaired fasting glucose band, 100-125 mg/dL, and discloses the WHO alternative lower limit of 110 mg/dL.

PMID:20042775 SUPPORT REVIEW SYNTHESIS Other

"FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h."

States the fasting plasma glucose diabetes criterion of 126 mg/dL and the definition of fasting that the measurement presupposes.

LOINC:1558-6 is the method-less mass-concentration code, matching the mg/dL in which the ADA states its thresholds. The molar sibling, LOINC:14771-0 (Fasting glucose [Moles/volume] in Serum or Plasma), carries the same measurement in mmol/L and is the code bound on the Gestational_Diabetes_Mellitus entry for criteria stated in mmol/L. The LOINC Part is LOINC:LP14635-4 (Glucose).

Show evidence (1 reference)

PMID:39651986 SUPPORT REVIEW SYNTHESIS Other

"In nonpregnant individuals, FPG (or A1C) is typically preferred for routine screening due to the ease of administration"

Names fasting plasma glucose as the ADA's usual screening and diagnostic test in nonpregnant individuals.

75-g oral glucose tolerance test (Diagnostic)

The 2-h plasma glucose during a 75-g oral glucose tolerance test is the third ADA diagnostic criterion for diabetes, at 200 mg/dL (11.1 mmol/L) or higher, with 140-199 mg/dL (7.8-11.0 mmol/L) defining impaired glucose tolerance. The ADA notes that the 2-h value diagnoses more people with prediabetes and diabetes than the fasting glucose or A1C cut points do.

75-g oral glucose tolerance test NCIT:C45946

2-h plasma glucose after 75 g oral glucose (mg/dL) LOINC:1518-0

Reference Ranges

Glucose [Mass/volume] in Serum or Plasma --2 hours post 75 g glucose PO (ADA Standards of Care in Diabetes, 2025 (nonpregnant individuals))

Normal (< 140.0 mg/dL) Impaired glucose tolerance (prediabetes) (140.0–200.0 mg/dL) Diabetes (≥ 200.0 mg/dL)

Impaired glucose tolerance (prediabetes): ADA impaired glucose tolerance, 140-199 mg/dL (7.8-11.0 mmol/L); a prediabetes category, not a diagnosis of diabetes.

Diabetes: Meets the ADA 2-h plasma glucose criterion for diabetes; requires confirmation in the absence of unequivocal hyperglycemia.

Source phrasing: "IGT as 2-h PG levels during 75-g OGTT from 140 to 199 mg/dL (from 7.8 to 11.0 mmol/L)" and "2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT". Half-open bands: the IGT band is recorded as [140, 200) rather than ending at 199, which is the one-point difference between the convention and the source's "140 to 199" wording.

Show evidence (2 references)

PMID:39651986 SUPPORT REVIEW SYNTHESIS Other

"IGT as 2-h PG levels during 75-g OGTT from 140 to 199 mg/dL (from 7.8 to 11.0 mmol/L)"

States the ADA impaired glucose tolerance band on the 2-h post-load glucose, 140-199 mg/dL.

PMID:20042775 SUPPORT REVIEW SYNTHESIS Other

"2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water."

States the 2-h plasma glucose diabetes criterion of 200 mg/dL and the 75-g load that defines the test.

LOINC:1518-0 is the method-less mass-concentration code for the 2-h post-load sample, matching the mg/dL the ADA states its thresholds in. The molar sibling is LOINC:14995-5 (Glucose [Moles/volume] in Serum or Plasma --2 hours post 75 g glucose PO), bound on the Gestational_Diabetes_Mellitus entry for criteria stated in mmol/L. Only the 2-h sample is bound: the ADA criterion is on the 2-h value alone, and the fasting sample drawn at the start of the test is the measurement on the fasting plasma glucose row.

Show evidence (1 reference)

PMID:39651986 SUPPORT REVIEW SYNTHESIS Other

"Compared with FPG and A1C cut points, the 2-h PG value diagnoses more people with prediabetes and diabetes (4)."

Records the ADA's statement that the 2-h post-load glucose detects more cases than the fasting glucose or A1C criteria, which is the clinical reason the OGTT is kept as a diagnostic row alongside them.

📊

Related Datasets

4

Metformin treatment effects on gut microbiome in T2D bioproject:PRJNA361402

Shotgun metagenomics from 40 individuals in a randomized, placebo-controlled, double-blind type 2 diabetes study. Samples at baseline and after 4 months of metformin treatment to assess drug-microbiome interactions.

human gut metagenome WGS n=40

fecal sample UBERON:0001988

Conditions: type 2 diabetes metformin treatment type 2 diabetes placebo

Nature Communications 2022 - metformin-microbiome interactions

Gut microbiome in urban African type 2 diabetes bioproject:PRJNA607849

16S rRNA gene sequencing of gut microbiome profiles from type 2 diabetes patients and controls in urban African populations, examining geographic and dietary influences on diabetes-associated microbiome signatures.

human gut metagenome

fecal sample UBERON:0001988

Conditions: type 2 diabetes healthy controls

Frontiers Cellular Infection Microbiology 2020

Gut microbiota in obese T2DM patients - Pakistani cohort bioproject:PRJNA554535

16S rRNA sequencing of gut microbiota from 60 Pakistani adults comparing obese individuals with type 2 diabetes to healthy controls. V3-V4 hypervariable regions sequenced.

human gut metagenome n=60

fecal sample UBERON:0001988

Conditions: obese type 2 diabetes healthy controls

PMID:31809500

Chinese MGWAS of gut microbiome in type 2 diabetes bioproject:PRJNA422434

Landmark metagenome-wide association study (MGWAS) comparing gut microbial DNA from 345 Chinese individuals. Identified ~60,000 T2D-associated markers and established metagenomic linkage groups.

human gut metagenome WGS n=345

fecal sample UBERON:0001988

Conditions: type 2 diabetes healthy controls

PMID:23023125

Nature 2012 - first MGWAS of T2D, foundational study

🧫

Experimental Models

3

Metabolically competent iPSC white adipose tissue microphysiological system (iADIPO-MPS) ORGAN_ON_CHIP namo:OrganOnChip

A New Approach Methodology built specifically because animal models and murine preadipocyte lines were poor substrates for type 2 diabetes drug discovery. Human pluripotent stem cells are differentiated into three-dimensional adipose tissue in a microphysiological system, and — the finding that makes the platform usable — previously published differentiation protocols were shown to yield tissue that is already insulin resistant, which cannot report a further loss of insulin sensitivity. Revised conditions plus chip optimization gave hormonally responsive tissue with larger, more unilocular lipid droplets and a dynamic range the authors report as competent against in vivo and ex vivo comparators, wide enough to identify both insulin sensitizers and desensitizers.

Organism

human NCBITaxon:9606

Tissue

white adipose tissue UBERON:0001347

Cell source

Human pluripotent stem cell-derived white adipocytes

Culture

Three-dimensional adipose tissue in a microphysiological system, benchmarked against two-dimensional culture

Publication

PMID:34761526

Pathograph links

Insulin Resistance measures fidelity: moderate Provides a calibrated human, non-animal assay for the adipose limb of this node, with the dynamic range needed to score a compound as sensitizing or desensitizing rather than merely to observe a resistant state.

Limitations: Adipose tissue alone, with no muscle, liver, islet or immune compartment, so it addresses one of the three tissues this node names. It is a healthy-tissue platform rather than a disease model: what it characterizes is a defect in prior differentiation protocols, not a defect in patients.

Readouts

Insulin-stimulated glucose uptake, fatty acid uptake and lipolysis suppression

Insulin Receptor Signaling GO:0008286

Direction: INCREASED

Interpretation: Direction is relative to conventional two-dimensional culture, not to a disease state: the readouts record restored insulin responsiveness in the chip, which is the precondition for a later loss of responsiveness being interpretable as insulin resistance.

Show evidence (1 reference)

PMID:34761526 SUPPORT In Vitro

"Using three independent insulin sensitivity assays, i.e., glucose and fatty acid uptake and suppression of lipolysis, as the functional readouts new differentiation conditions yielding hormonally responsive iADIPO are derived."

Names the three functional readouts and records that the differentiation conditions were selected against them rather than assumed to satisfy them.

Show evidence (1 reference)

PMID:34761526 SUPPORT In Vitro

"Surprisingly, previously reported WAT differentiation approaches create insulin resistant WAT ill-suited for type-2 diabetes mellitus drug discovery."

The negative platform result that makes this model informative for the node, and a caution for any curator reading an adipose insulin-resistance claim out of a stem-cell adipose model that has not been characterized this way.

Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1 measures fidelity: moderate Insulin-stimulated fatty acid uptake is one of the three assays the platform is validated on, so the arm this node represents is directly measurable in human adipose tissue rather than only in mouse adipocytes.

Limitations: The assay measures net insulin-stimulated fatty acid uptake and does not attribute it to FATP1: no SLC27A1 knockdown, inhibition or expression measurement is reported in this system.

Readouts

Insulin responsiveness of fatty acid uptake

Insulin-Stimulated Long-Chain Fatty Acid Import GO:0044539

Direction: INCREASED

Interpretation: A roughly three- to sixfold insulin response in the optimized chip, which is the dynamic range a knockdown or cytokine experiment on this node would need in order to register.

Show evidence (1 reference)

PMID:34761526 SUPPORT In Vitro

"increased insulin responsiveness of glucose uptake (≈2-3 fold), fatty acid uptake (≈3-6 fold), and ≈40% suppressing of stimulated lipolysis giving a dynamic range that is competent to current in vivo and ex vivo models"

Quantifies the insulin response of fatty acid uptake specifically, and the dynamic range a knockdown or cytokine experiment on this node would need in order to register.

Show evidence (1 reference)

PMID:34761526 SUPPORT In Vitro

"Using three independent insulin sensitivity assays, i.e., glucose and fatty acid uptake and suppression of lipolysis, as the functional readouts new differentiation conditions yielding hormonally responsive iADIPO are derived."

Establishes fatty acid uptake as a first-class validated readout of the platform, which is why this model is linked to the fatty acid arm and not only to the glucose arm.

Isogenic iPSC macrophage-adipocyte microphysiological system (iMAC-iADIPO-MPS) ORGAN_ON_CHIP namo:OrganOnChip

Human adipose tissue inflammation reconstructed from isogenic induced pluripotent stem cells. Macrophages migrate into three-dimensional adipocyte clusters and form crown-like structures around damaged adipocytes, reproducing the defining histology of obese human adipose tissue, and the number of such structures increases with adipocyte age and with palmitic acid exposure so inflammatory severity is gradable. Polarization is the operative variable: M1 but not M2 macrophages induce adipocyte insulin resistance and dysregulated lipolysis, and transcriptomic and cytokine profiling identify a reciprocal proinflammatory loop between the two cell types.

Organism

human NCBITaxon:9606

Tissue

white adipose tissue UBERON:0001347

Cell source

Isogenic human induced pluripotent stem cell-derived macrophages and adipocytes

Culture

Microphysiological system supporting three-dimensional adipocyte clusters with macrophage infiltration

Publication

PMID:37104853

Pathograph links

White Adipose Tissue Inflammation recapitulates fidelity: moderate Reproduces this node in human cells down to its histologic signature, and supplies the polarization control the rodent literature reaches by cytokine neutralization: M2 macrophages present in the same numbers do not produce the phenotype.

Limitations: Inflammation is imposed by adding pre-polarized macrophages rather than arising from resident immune recruitment, so the model reproduces the inflamed state without reproducing how patients arrive at it. There is no vasculature, no lymphocyte compartment and no adipose expansion over time. Isogenic by design, so it cannot speak to donor variation in inflammatory susceptibility.

Readouts

Crown-like structure formation around damaged adipocytes

Direction: INCREASED

Interpretation: The histologic hallmark named in this node, reproduced in a non-animal human system and gradable with exposure severity rather than scored present or absent.

Show evidence (1 reference)

PMID:37104853 SUPPORT In Vitro

"iMACs migrate toward and infiltrate into the 3D iADIPOs cluster to form crown-like structures (CLSs)-like morphology around damaged iADIPOs, recreating classic histological features of WAT inflammation seen in obesity."

States the structural correspondence between the model and obese human adipose tissue.

Dysregulated adipocyte lipolysis under proinflammatory macrophage co-culture

Dysregulated Adipocyte Lipolysis GO:0019433

Direction: INCREASED

Interpretation: Dysregulated lipolysis is the step by which this node exports fatty acids to liver and muscle, and the M1-versus-M2 contrast shows it is specific to proinflammatory polarization.

Show evidence (1 reference)

PMID:37104853 SUPPORT In Vitro

"M1 (proinflammatory) but not M2 (tissue repair) iMACs induced insulin resistance and dysregulated lipolysis in iADIPOs."

The polarization-controlled comparison that grounds this readout.

Show evidence (1 reference)

PMID:37104853 SUPPORT In Vitro

"This iMAC-iADIPO-MPS thus successfully recreates pathological conditions of chronically inflamed human WAT"

The authors' summary of what the model reproduces, which is the content of this node.

Isogenic iPSC adipocyte-hepatocyte-macrophage microphysiological system (M1-iADIPO-iHEP-MPS) ORGAN_ON_CHIP namo:OrganOnChip

The adipose compartment above fluidically connected to an induced pluripotent stem cell-derived hepatocyte compartment by circulating media, with all three cell types from one donor line. Because adipose expansion (set by the adipocyte-to-hepatocyte ratio) and adipose inflammation (set by macrophage polarization) are varied independently, the system separates two variables that animal models confound, and finds inflammation rather than expansion to be the driver of hepatic insulin resistance. It also carries the drug panel: metformin and rosiglitazone improve the hepatic compartment, dexamethasone does not, and the GLP-1 receptor agonist semaglutide works through the adipocyte compartment alone.

Organism

human NCBITaxon:9606

Tissue

white adipose tissue UBERON:0001347

Cell source

Isogenic human induced pluripotent stem cell-derived white adipocytes, hepatocytes and macrophages from a single donor line

Culture

Interconnected two-chamber microphysiological system with circulating media at 20 microlitres per hour, and a non-circulating flow-through configuration for compartment-selective drug exposure

Publication

PMID:39266553

Pathograph links

Insulin Resistance recapitulates fidelity: moderate Produces insulin resistance across two connected human tissues from a single upstream manipulation, and adjudicates between adipose inflammation and adipose expansion as its cause. Expansion alone produced hepatic insulin resistance only at an extreme adipocyte-to-hepatocyte ratio; inflammation produced it readily.

Limitations: Two tissues only — no muscle and no islet, so neither the largest site of insulin-stimulated glucose disposal nor the beta-cell arm of this entry is represented. Insulin resistance is imposed over days by macrophage polarization rather than developing over years, and the iPSC-derived cells retain a fetal-like maturation state. There is no central control of feeding or body weight, which is precisely why the semaglutide result is interpretable here and confounded in rodents.

Readouts

Insulin suppression of hepatic glucose production under adipose inflammation

Insulin Receptor Signaling GO:0008286

Direction: DECREASED

Interpretation: Measured in the hepatocyte compartment after manipulating only the adipose compartment, so it reads the transfer of insulin resistance between tissues rather than a cell-autonomous defect.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"Analysis of insulin regulation of HGP after 48 h of iADIPO-iHEP-MPS interconnection showed insulin resistance only at the highest iADIPO-iHEP ratio of 30:1"

The expansion arm, recorded as the weaker of the two: mass alone produced hepatic insulin resistance only at an extreme ratio, which is the comparison that makes inflammation the primary driver.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"macrophage-induced adipocyte inflammation causes lipid accumulation in hepatocytes and MPS-wide insulin resistance, corresponding to initiation of metabolic dysfunction-associated steatotic liver disease."

States that the manipulation produces system-wide insulin resistance, which is the node this link asserts the model is informative for.

White Adipose Tissue Inflammation recapitulates fidelity: moderate Carries the same inflamed adipose compartment as the two-cell system, now with a downstream tissue attached, so the consequences of this node can be measured outside the tissue in which it occurs.

Limitations: Same limitation as the two-cell configuration: inflammation is imposed by adding pre-polarized macrophages rather than arising from recruitment, and the system is isogenic so donor variation is excluded by design.

Readouts

Adipose tumor necrosis factor alpha secretion into shared circulation

Tumor Necrosis Factor Production GO:0032640

Direction: INCREASED

Interpretation: The cytokine this node produces, measured in the circulating media that reaches the second tissue, which is the mechanism by which a local adipose lesion becomes systemic.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"As expected, inflammation markers were increased in the M1-iADIPO-MPS, including gene expression of the proinflammatory cytokine TNF."

Confirms the cytokine content of the inflamed adipose compartment in this configuration.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"Consistent with our previous results8,34 and human studies44, our model shows that M1-iMAC-mediated inflammation readily induces metabolic dysfunction, including increased WAT lipolysis and induction of systemic insulin resistance."

The authors' own statement that the inflamed adipose compartment drives lipolysis and systemic insulin resistance, which is what this node asserts.

Hepatic Glucose Overproduction measures fidelity: moderate Hepatic glucose production and its suppression by insulin are primary endpoints of the chip, alongside PCK1 expression, so this node has a direct human non-animal assay. The chip also shows the node responding to metformin.

Limitations: Hepatocyte compartment only, with no pancreatic alpha cell and no counterregulatory hormone axis, so glucagon-driven hepatic glucose production is absent. Absolute production rates in an iPSC-derived hepatocyte compartment are not calibrated against human liver.

Readouts

PCK1 expression and hepatic glucose production

Insulin Receptor Signaling GO:0008286

Direction: INCREASED

Interpretation: Rising gluconeogenic gene expression alongside loss of insulin suppression is the molecular and functional pair this node describes.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"whereas PCK1 gene expression was increased in the iHEP-MPS, suggesting activation of gluconeogenesis and development of insulin resistance"

The gluconeogenic readout in the hepatocyte compartment, which is the content of this node.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"We found that inclusion of iADIPOs worsened the metabolic alterations in iHEP-MPS, including higher HGP, earlier onset of insulin resistance, higher lipid levels and higher expression of genes reflecting inflammation, gluconeogenesis, lipogenesis and lipid transport"

Names hepatic glucose production as a measured endpoint that responds to the adipose manipulation, which is why this model is linked to the hepatic node.

Fully curated for its MASLD arm in the Metabolic_Dysfunction-Associated_Steatotic_Liver_Disease entry, where the same chip is linked to hepatocyte lipid overload and hepatic fatty acid uptake. The links here are the type 2 diabetes arm of the same system, and the two entries should be kept consistent if either is revised.

🐁

Animal Models

1

FATP1 (Slc27a1) knockout mouse on high-fat diet

Germline loss of the insulin-responsive fatty acid transporter. Insulin-stimulated long-chain fatty acid uptake is abolished in adipocytes and greatly reduced in skeletal muscle while basal uptake is untouched, postprandial fatty acids are redistributed from adipose and muscle to the liver, and the animals are completely protected from diet-induced obesity and insulin desensitization. The protection is the reason this model is curated: it is the result that prevents the adipocyte fatty acid uptake node from being drawn as a straightforward driver of insulin resistance.

Species

Mouse

Genotype

Slc27a1 (FATP1) targeted deletion, homozygous null

Background

Diet-induced obesity

Genes

SLC27A1 hgnc:10995

Publication

PMID:16611988

Pathograph links

Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1 perturbs fidelity: moderate Removes the hormone-responsive arm of adipocyte fatty acid uptake genetically, and shows the loss is specific to the insulin-stimulated component rather than to fatty acid handling generally.

Limitations: A germline null cannot separate lifelong adaptation from the acute consequence of losing the transporter, which matters here because the whole-animal outcome is protection rather than harm. Lipid is redistributed to the liver rather than simply not absorbed, so adipose and muscle are spared at a hepatic cost this entry does not model. Murine, and no human SLC27A1 variant evidence is curated here.

Readouts

Insulin-stimulated versus basal long-chain fatty acid uptake

Insulin-Stimulated Long-Chain Fatty Acid Import GO:0044539

Direction: ABOLISHED

Interpretation: The basal-versus-stimulated contrast is the informative part: it shows the transporter carries the hormone-responsive arm specifically, which is what the node claims.

Show evidence (1 reference)

PMID:16611988 SUPPORT Model Organism

"insulin-stimulated fatty acid uptake is completely abolished in FATP1-null adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals while basal LCFA uptake by both tissues was unaffected."

The measurement that grounds this readout, including the unaffected basal arm that serves as the internal control.

Diet-induced obesity and insulin desensitization

Direction: ABOLISHED

Interpretation: The counterintuitive result. If loss of this arm were simply a pathogenic feature of the insulin-resistant adipocyte, animals lacking it should be worse; they are protected. This readout is what the attached knowledge-gap discussion turns on.

Show evidence (1 reference)

PMID:16611988 SUPPORT Model Organism

"led to a complete protection from diet-induced obesity and insulin desensitization."

Records the protective whole-animal outcome that bounds any causal reading of the adipocyte fatty acid uptake node.

Show evidence (1 reference)

PMID:16611988 SUPPORT Model Organism

"This is the first in vivo evidence that insulin can regulate the uptake of LCFA by tissues via FATP1 activation and that FATPs determine the tissue distribution of dietary lipids."

The authors' own statement of what the model establishes, which is the content of the node it is linked to.

🧮

Computational Models

6

Topp Beta-Cell Mass / Insulin / Glucose Model SBML COPASI KINETIC

Minimal three-ODE dynamical model of the glucose regulatory system (Topp et al. 2000): plasma glucose, plasma insulin, and beta-cell mass, with fast glucose/insulin dynamics on a slow beta-cell-mass manifold. For normal parameters the system is bistable - a physiological steady state (euglycemia) and a pathological, insulinopenic steady state (beta-cell-mass collapse and severe hyperglycemia) separated by a saddle. This makes it the reference dynamical substrate for type 2 diabetes: reduced insulin sensitivity, impaired secretion, or hepatic glucose overproduction decompensates the at-risk state to overt diabetes, and it is wired for perturbation analysis (see the model config sidecar) so that both risk genes and glucose-lowering treatments can be simulated as parameter changes.

Repository ↗ PMID:11013117 Model page: rules, runs →

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
Fasting_Plasma_Glucose Plasma glucose concentration at steady state.	`G`	mg/dL	glucose	Hyperglycemia above 126 mild 126 moderate 200 severe 400
Plasma_Insulin Plasma insulin concentration at steady state. Elevated in the compensated insulin-resistant regime and near-zero after glucotoxic beta-cell-mass collapse.	`I`	uU/mL		Hyperinsulinemia above 18 mild 18 moderate 30 severe 60
Beta_Cell_Mass Functional beta-cell mass (slow state variable). Expands under mild hyperglycemia (compensation) and collapses toward zero under sustained extreme hyperglycemia (glucotoxicity), the positive-feedback route to insulinopenic diabetes.	`B`	mg

Simulation results — 15 scenarios run with dismech-perturb (tellurium / libRoadRunner CVODE) over 4000 h; baseline si = 0.72

Interpretation caveat. This model is bistable and its baseline sits near the saddle separating the physiological and pathological fixed points, so every impairing lesion collapses to the same attractor (glucose 600 mg/dL, beta-cell mass 0) regardless of magnitude. Scenario outcomes are therefore NOT comparable in severity, and severity tiers are suppressed for this model. Two scenarios in particular must not be read as clinical claims: GCK loss-of-function is GCK-MODY (MODY2), which causes mild, non-progressive fasting hyperglycemia with no beta-cell mass loss and usually needs no pharmacotherapy; and the TCF7L2 risk allele is a modest susceptibility factor (per-allele odds ratio ~1.4), not a deterministic route to beta-cell failure.

Scenario	Beta_Cell_Mass (mg)	Fasting_Plasma_Glucose (mg/dL)	Plasma_Insulin (uU/mL)	Activated phenotypes
Healthy baseline si = 0.72	300.0	100.0	10.0	reference
Severe insulin resistance (si=0.30) drives Insulin Resistance	0.0 0.00× baseline	600.0 6.00× baseline	0.0 0.00× baseline	Hyperglycemia
Insulin resistance (si=0.45) drives Insulin Resistance	0.0 0.00× baseline	600.0 6.00× baseline	0.0 0.00× baseline	Hyperglycemia
PPARG loss-of-function (insulin resistance) drives Insulin Resistance	0.0 0.00× baseline	600.0 6.00× baseline	0.0 0.00× baseline	Hyperglycemia
TCF7L2 risk variant (impaired secretion) drives Beta Cell Dysfunction	0.0 0.00× baseline	600.0 6.00× baseline	0.0 0.00× baseline	Hyperglycemia
KCNJ11 K_ATP gain (impaired secretion) drives Beta Cell Dysfunction	0.0 0.00× baseline	600.0 6.00× baseline	0.0 0.00× baseline	Hyperglycemia
HNF1A loss-of-function (MODY3) drives Beta Cell Dysfunction	0.0 0.00× baseline	600.0 6.00× baseline	0.0 0.00× baseline	Hyperglycemia
GCK loss-of-function (glucose-sensing defect) drives Beta Cell Dysfunction	0.0 0.00× baseline	600.0 6.00× baseline	0.0 0.00× baseline	Hyperglycemia
SLC5A2 loss-of-function (renal glucosuria; protective) drives Hyperglycemia	210.0 0.70× baseline	100.0 1.00× baseline	7.0 0.70× baseline	none
Metformin (reduced hepatic glucose output) drives Hepatic Glucose Overproduction	307.2 1.02× baseline	100.0 1.00× baseline	10.24 1.02× baseline	none
Thiazolidinedione (insulin sensitizer) drives Insulin Resistance	300.0 1.00× baseline	100.0 1.00× baseline	10.0 1.00× baseline	none
SGLT2 inhibitor (insulin-independent glucose clearance) drives Hyperglycemia	504.0 1.68× baseline	100.0 1.00× baseline	16.8 1.68× baseline	none
Sulfonylurea (secretagogue) - fails once beta cells collapse drives Beta Cell Dysfunction	0.0 0.00× baseline	600.0 6.00× baseline	0.0 0.00× baseline	Hyperglycemia
GLP-1 receptor agonist (secretion + reduced hepatic output) drives Incretin Axis Dysfunction	260.571429 0.87× baseline	100.0 1.00× baseline	12.16 1.22× baseline	none
Insulin therapy (increased net insulin action) drives Hyperglycemia	240.0 0.80× baseline	100.0 1.00× baseline	8.0 0.80× baseline	none
Metformin + SGLT2 inhibitor (severe disease) drives Hyperglycemia	244.8 0.82× baseline	100.0 1.00× baseline	8.16 0.82× baseline	none

Derived artifact, regenerated by just gen-model-results — not curated evidence. Values rounded to 6 decimals. Config e8ecf0513c19, model.xml e86507d1dc05. Phenotypes activate per the curated variable thresholds.

Pathograph links

Insulin Resistance Reduced whole-body insulin sensitivity is the model parameter si; lowering si (or PPARG/thiazolidinedione perturbation of si) reproduces the insulin-resistance driver of type 2 diabetes.

Beta Cell Dysfunction Maximal per-beta-cell secretory capacity (sigma) and the beta-cell-mass state variable (B) capture secretory failure and glucotoxic beta-cell-mass loss; TCF7L2/KCNJ11/HNF1A perturbations act here.

Hepatic Glucose Overproduction Insulin-independent hepatic glucose output is the parameter R0, the target reduced by metformin in the simulated treatment scenarios.

Findings

For normal parameters the model is bistable, with a physiological (euglycemic) and a pathological (hyperglycemic, beta-cell-collapse) steady state separated by a saddle - the dynamical basis for decompensation to overt diabetes.

Show evidence (1 reference)

PMID:11013117 SUPPORT Computational

"For normal parameter values, the model has two stable fixed points (representing physiological and pathological steady states), separated on a slow manifold by a saddle point"

Confirms the bistable, saddle-separated structure that lets an impairing perturbation tip the at-risk state to overt diabetes while a corrective treatment restores euglycemia.

The model defines three routes to prolonged hyperglycemia (regulated hyperglycemia, saddle-node bifurcation, and dynamical hyperglycemia), mapping onto insulin-resistance, secretory-failure, and hepatic-output drivers of type 2 diabetes.

Show evidence (1 reference)

PMID:11013117 SUPPORT Computational

"The model predicts that there are three pathways in prolonged hyperglycemia"

Grounds the perturbation scenarios: each disease driver corresponds to one of the model's predicted pathways into sustained hyperglycemia.

Notes

Wired for dismech-perturb (models/BIOMD0000000341/config.yaml). The disease-severity dial is insulin sensitivity si (baseline_gfr 0.72 = healthy); the deposited initial state (G=250 mg/dL) sits on the model's unstable saddle, i.e. the metabolically at-risk / impaired-fasting tipping point. Glucose-lowering treatments are simulated as parameter changes: metformin (R0 down), thiazolidinedione (si up), SGLT2 inhibitor (Eg0 up, insulin-independent), sulfonylurea/GLP-1 (sigma up), insulin therapy (net insulin action up). Insulin-independent therapies (SGLT2 inhibition, metformin) and sensitizers (TZD) recompensate the model to euglycemia, whereas a pure secretagogue fails once beta-cell mass has collapsed - reproducing secondary secretagogue failure in advanced disease. Thresholds are calibrated to model steady-state values, not clinical reference ranges.

Show evidence (1 reference)

PMID:11013117 SUPPORT Computational

"which consists of a system of three nonlinear ordinary differential equations, where glucose and insulin dynamics are fast relative to beta-cell mass dynamics"

Establishes the Topp model as a three-ODE dynamical model of beta-cell mass, insulin, and glucose - the substrate used here for simulating type 2 diabetes mechanisms and treatments.

Pancreatic Beta Cell Genome-Scale Metabolic Model GENOME_SCALE_METABOLIC

First comprehensive genome-scale metabolic reconstruction of human pancreatic beta cells, integrating transcriptomic data from healthy and type 2 diabetic islets. The model captures beta cell-specific metabolic pathways and identifies metabolic alterations in T2D including impaired glucose-stimulated insulin secretion mechanisms.

PMID:35276551

PLOS Computational Biology 2022 - context-specific reconstruction using RNA-seq from healthy and T2D beta cells

Whole-Body Human Metabolic Model for Diabetes GENOME_SCALE_METABOLIC

Multi-organ metabolic model (Harvey/Harvetta) capturing inter-organ metabolic fluxes in diabetes. Models liver, muscle, adipose, and pancreas metabolism with tissue-specific constraints derived from omics data.

Repository ↗ PMID:32472720 Base model: Recon3D

Predicts diabetes biomarkers and drug effects across multiple organs

PBPK Model for GLP-1 Receptor Agonists PHYSIOLOGICAL

Physiologically-based pharmacokinetic model for GLP-1 receptor agonists (semaglutide, tirzepatide) in T2D patients. Incorporates drug absorption, distribution, and receptor binding kinetics to optimize dosing regimens.

Used in clinical trial design and dose optimization for incretin-based therapies

AGORA2 Gut Microbiome Metabolic Models GENOME_SCALE_METABOLIC

Collection of 7,302 strain-resolved genome-scale metabolic reconstructions of human gut microorganisms. Enables personalized microbiome-host metabolic modeling by integrating with human metabolic models (Recon3D). Captures strain-level variation in SCFA production, bile acid metabolism, and drug biotransformation relevant to T2D.

Repository ↗ PMID:36543475

Nature Biotechnology 2022 - includes drug metabolism capabilities for 98 drugs; enables community-level FBA with MICOM

MICOM Community Metabolic Model COBRApy GENOME_SCALE_METABOLIC

Metagenome-scale modeling framework for simulating metabolic interactions in the gut microbiota. Integrates dietary constraints and taxon abundances from metagenomic data to predict personalized SCFA production, cross-feeding networks, and metabolic fluxes. Applied to T2D to study dysbiosis effects on butyrate production and glucose-insulin signaling.

PMID:31964767

mSystems 2020 - enables personalized microbiome metabolic modeling from 16S/metagenomics data

{ }

Source YAML

click to show

name: Type 2 Diabetes Mellitus
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Type 2 diabetes mellitus is a common metabolic disease defined by chronic
  hyperglycemia arising from the combination of peripheral insulin resistance
  and progressive pancreatic beta-cell dysfunction. Excess adiposity, physical
  inactivity, and polygenic susceptibility drive impaired insulin signaling in
  muscle, liver, and adipose tissue, with compensatory hyperinsulinemia that
  eventually fails as beta-cell secretory capacity declines. Hepatic glucose
  overproduction and incretin axis dysfunction further worsen glycemic control,
  and sustained hyperglycemia leads to microvascular and macrovascular
  complications such as retinopathy, nephropathy, and peripheral neuropathy.
category: Complex
parents:
- Diabetes Mellitus
- Metabolic Disease
- Endocrine Disease
disease_term:
  preferred_term: type 2 diabetes mellitus
  term:
    id: MONDO:0005148
    label: type 2 diabetes mellitus
gene_sets:
- gene_set: MYGENESET:KEGG_TYPE_II_DIABETES_MELLITUS
  relationship: CANONICAL_PATHWAY
  note: >-
    KEGG type II diabetes mellitus pathway.
pathophysiology:
- name: White Adipose Tissue Inflammation
  biological_scale: TISSUE
  description: >
    With expanding adiposity, bone-marrow-derived macrophages accumulate in white
    adipose tissue, shift toward classical (M1) proinflammatory activation, and
    surround damaged adipocytes as crown-like structures. The resulting local and
    systemic tumor necrosis factor alpha, together with other proinflammatory
    cytokines, impairs adipocyte insulin signalling and releases lipolysis from
    insulin restraint, so non-esterified fatty acids and cytokines are exported to
    liver and muscle. This node is the adipose-tissue origin of the insulin
    resistance the entry otherwise begins with: the Insulin Resistance node names
    adipose as a resistant tissue but does not say what makes it resistant.
    The causal direction is anchored by an intervention rather than an
    association: neutralizing tumor necrosis factor alpha in obese rats restores
    insulin-stimulated peripheral glucose uptake.
  cell_types:
  - preferred_term: White Adipocyte
    term:
      id: CL:0000448
      label: white adipocyte
  - preferred_term: Proinflammatory (M1) Adipose Tissue Macrophage
    term:
      id: CL:0000863
      label: M1 macrophage
  genes:
  - preferred_term: TNF
    term:
      id: hgnc:11892
      label: TNF
  biological_processes:
  - preferred_term: Adipose Tissue Inflammation
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: Tumor Necrosis Factor Production
    term:
      id: GO:0032640
      label: tumor necrosis factor production
    modifier: INCREASED
  - preferred_term: Dysregulated Adipocyte Lipolysis
    term:
      id: GO:0019433
      label: triglyceride catabolic process
    modifier: INCREASED
  locations:
  - preferred_term: White Adipose Tissue
    term:
      id: UBERON:0001347
      label: white adipose tissue
  evidence:
  - reference: PMID:14679176
    reference_title: Obesity is associated with macrophage accumulation in adipose tissue.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was
      significantly and positively correlated with both adipocyte size and body
      mass
    explanation: >-
      Establishes the macrophage accumulation that defines this node, and scales
      it with adiposity rather than treating it as present or absent.
  - reference: PMID:14679176
    reference_title: Obesity is associated with macrophage accumulation in adipose tissue.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar relationships were found in human subcutaneous adipose tissue
      stained for the macrophage antigen CD68.
    explanation: >-
      The human arm of the same study, cited separately so the node does not rest
      on rodent adipose tissue alone.
  - reference: PMID:7678183
    reference_title: 'Adipose expression of tumor necrosis factor-alpha: direct role
      in obesity-linked insulin resistance.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      An induction of TNF-alpha messenger RNA expression was observed in adipose
      tissue from four different rodent models of obesity and diabetes.
    explanation: >-
      Supplies the cytokine content of the node across four independent obesity
      and diabetes models, which is what makes it a general feature rather than a
      property of one model.
  - reference: PMID:21633179
    reference_title: Inflammatory links between obesity and metabolic disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Adipose tissue insulin resistance and dysfunctional lipid storage in
      adipocytes are sentinel events in the progression toward metabolic
      dysregulation with obesity.
    explanation: >-
      A review placing adipose insulin resistance and disordered lipid storage
      early in the sequence, which is why this node is modeled upstream of the
      systemic Insulin Resistance node rather than as one of its consequences.
  downstream:
  - target: Insulin Resistance
    description: >-
      Macrophage-derived tumor necrosis factor alpha and the accompanying
      cytokines impair insulin action in adipose tissue and, through cytokine and
      fatty acid export, in muscle and liver. The edge is drawn causally because
      the cytokine can be removed and the insulin response recovers.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7678183
      reference_title: 'Adipose expression of tumor necrosis factor-alpha: direct role
        in obesity-linked insulin resistance.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Neutralization of TNF-alpha in obese fa/fa rats caused a significant
        increase in the peripheral uptake of glucose in response to insulin.
      explanation: >-
        An intervention, not an association: removing the cytokine restores
        insulin-stimulated glucose uptake, which is the direction this edge
        asserts.
    - reference: PMID:21633179
      reference_title: Inflammatory links between obesity and metabolic disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Over time, ectopic lipid accumulation in muscle, liver, and blood vessels
        activates tissue leukocytes, contributes to organ-specific disease, and
        exacerbates systemic insulin resistance.
      explanation: >-
        Names the route by which a local adipose lesion becomes systemic insulin
        resistance, which is the step this edge crosses.
  - target: Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
    description: >-
      Tumor necrosis factor alpha suppresses both basal and insulin-stimulated
      long-chain fatty acid uptake in adipocytes and lowers FATP1 and FATP4
      protein levels, so the inflamed adipocyte loses the fatty acid arm of the
      insulin response as well as the glucose arm.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11970897
      reference_title: Insulin causes fatty acid transport protein translocation and
        enhanced fatty acid uptake in adipocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In contrast, treatment with TNF-alpha inhibited basal and insulin-induced
        LCFA uptake and reduced FATP1 and -4 levels.
      explanation: >-
        The direct measurement behind this edge: the cytokine this node produces
        suppresses the transport step the target node represents, at both the
        activity and the protein level.
- name: Impaired GLUT4-Mediated Glucose Uptake
  description: >
    Dysregulation of GLUT4 trafficking in adipocytes and skeletal muscle reduces
    insulin-stimulated glucose uptake. GULP1 facilitates GLUT4 translocation to
    the plasma membrane by counteracting ACAP1 inhibition of ARF6 activity.
    Reduced GULP1 activity therefore decreases peripheral glucose disposal and
    contributes to systemic insulin resistance. TBC1D4 is bound here as the
    human-genetic entry point to the same step: muscle biopsies show TBC1D4 and
    GLUT4 protein falling with increasing count of the common Greenlandic
    p.Arg684Ter allele, alongside severely decreased insulin-stimulated glucose
    uptake in muscle.
  genes:
  - preferred_term: GULP1
    term:
      id: hgnc:18649
      label: GULP1
  - preferred_term: ACAP1
    term:
      id: hgnc:16467
      label: ACAP1
  - preferred_term: ARF6
    term:
      id: hgnc:659
      label: ARF6
  - preferred_term: TBC1D4
    term:
      id: hgnc:19165
      label: TBC1D4
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  - preferred_term: Skeletal Muscle Cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: Insulin Receptor Signaling
    term:
      id: GO:0008286
      label: insulin receptor signaling pathway
  - preferred_term: Protein Transport
    term:
      id: GO:0015031
      label: protein transport
  evidence:
  - reference: PMID:42436120
    reference_title: "GULP1 enhances GLUT4 translocation by counteracting ACAP1-ARF6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "GULP1 significantly enhanced glucose uptake in adipocytes and muscle cells by promoting GLUT4 translocation to the plasma membrane. In obese mice, GULP1 overexpression improved insulin sensitivity and glucose tolerance."
    explanation: >-
      Demonstrates GULP1-dependent GLUT4 trafficking and improved insulin
      sensitivity in metabolic tissues and obese mice.
  - reference: PMID:42436120
    reference_title: "GULP1 enhances GLUT4 translocation by counteracting ACAP1-ARF6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mechanistically, GULP1 counteracted ACAP1's inhibition of ARF6 activity, thereby facilitating insulin-stimulated GLUT4 trafficking."
    explanation: >-
      Establishes the GULP1-ACAP1-ARF6 regulatory mechanism.
  - reference: PMID:25043022
    reference_title: "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analyses of skeletal muscle biopsies showed lower messenger RNA and
      protein levels of the long isoform of TBC1D4, and lower muscle protein
      levels of the glucose transporter GLUT4, with increasing number of
      p.Arg684Ter alleles.
    explanation: >-
      Measures the GLUT4 protein loss this node asserts, in human muscle, as a
      function of TBC1D4 genotype.
  - reference: PMID:25043022
    reference_title: "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings are concomitant with a severely decreased
      insulin-stimulated glucose uptake in muscle, leading to postprandial
      hyperglycaemia, impaired glucose tolerance and T2D.
    explanation: >-
      States the impaired insulin-stimulated glucose uptake this node is named
      for, and carries it to the disease outcome.
  downstream:
  - target: Insulin Resistance
    description: >-
      Impaired GLUT4-mediated uptake reduces peripheral glucose disposal and
      contributes to systemic insulin resistance.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42436120
      reference_title: "GULP1 enhances GLUT4 translocation by counteracting ACAP1-ARF6 inhibition."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "GULP1 can bind to ACAP1 and ARF6, and alleviate the inhibitory effect of ACAP1 on ARF6 activity, thereby enhancing insulin-mediated glucose uptake and improving insulin sensitivity in obese mice."
      explanation: >-
        Directly links the trafficking axis to insulin-mediated glucose uptake
        and insulin sensitivity in the obesity model.
- name: Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
  biological_scale: MOLECULAR
  description: >
    Insulin acts on the adipocyte through two transporter arms, not one. Alongside
    GLUT4, insulin drives translocation of fatty acid transport proteins — FATP1
    (SLC27A1) and FATP4 (SLC27A4) — from an intracellular perinuclear compartment
    to the plasma membrane within minutes, and long-chain fatty acid uptake rises
    in parallel. In FATP1-null adipocytes the insulin-stimulated component of
    fatty acid uptake is entirely absent while basal uptake is unaffected, so
    FATP1 specifically carries the hormone-responsive arm. Tumor necrosis factor
    alpha from inflamed adipose tissue suppresses this arm and lowers FATP1 and
    FATP4 protein.
    This node is deliberately terminal. Whether losing the arm drives systemic
    insulin resistance is genuinely unsettled — FATP1-null mice, which lack it
    from birth, are completely protected from diet-induced insulin desensitization
    — so no edge is drawn into Insulin Resistance and the tension is carried by
    the kgap_t2d_fatp1_insulin_stimulated_fatty_acid_uptake discussion instead. The
    node is curated because it is a real, measurable arm of adipocyte insulin
    action that the entry otherwise omits, and because it is one of the three
    functional assays the human adipose microphysiological systems use to score
    insulin sensitivity.
  genes:
  - preferred_term: SLC27A1
    term:
      id: hgnc:10995
      label: SLC27A1
  - preferred_term: SLC27A4
    term:
      id: hgnc:10998
      label: SLC27A4
  cell_types:
  - preferred_term: White Adipocyte
    term:
      id: CL:0000448
      label: white adipocyte
  - preferred_term: Skeletal Muscle Cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: Insulin-Stimulated Long-Chain Fatty Acid Import
    term:
      id: GO:0044539
      label: long-chain fatty acid import into cell
    modifier: DECREASED
  - preferred_term: Insulin Receptor Signaling
    term:
      id: GO:0008286
      label: insulin receptor signaling pathway
  molecular_functions:
  - preferred_term: FATP1/FATP4 long-chain fatty acid transport activity
    term:
      id: GO:0005324
      label: long-chain fatty acid transmembrane transporter activity
  locations:
  - preferred_term: White Adipose Tissue
    term:
      id: UBERON:0001347
      label: white adipose tissue
  evidence:
  - reference: PMID:11970897
    reference_title: Insulin causes fatty acid transport protein translocation and
      enhanced fatty acid uptake in adipocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      in adipocytes, insulin induces plasma membrane translocation of FATPs from
      an intracellular perinuclear compartment to the plasma membrane.
    explanation: >-
      Establishes the regulated trafficking step this node represents, and its
      parallel to the GLUT4 translocation the entry already models.
  - reference: PMID:16611988
    reference_title: FATP1 is an insulin-sensitive fatty acid transporter involved
      in diet-induced obesity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      insulin-stimulated fatty acid uptake is completely abolished in FATP1-null
      adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals
      while basal LCFA uptake by both tissues was unaffected.
    explanation: >-
      Assigns the hormone-responsive component specifically to FATP1 — basal
      uptake is untouched — which is what makes this a distinct node rather than a
      restatement of fatty acid handling in general.
- name: Insulin Resistance
  description: >
    Peripheral tissues (muscle, liver, adipose) become resistant to insulin action,
    requiring higher insulin levels to maintain glucose homeostasis. This leads to
    compensatory hyperinsulinemia and eventually beta cell exhaustion.
  genes:
  - preferred_term: PPARG
    term:
      id: hgnc:9236
      label: PPARG
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Skeletal Muscle Cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: Insulin Signaling
    term:
      id: GO:0008286
      label: insulin receptor signaling pathway
  evidence:
  - reference: PMID:12231074
    reference_title: "Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus."
    supports: SUPPORT
    snippet: "Insulin resistance is caused by the decreased ability of peripheral target tissues (especially muscle) to respond properly to normal circulating concentrations of insulin."
    explanation: This establishes that skeletal muscle is a key site of insulin resistance in type 2 diabetes, with impaired response to normal insulin levels.
  - reference: PMID:12231074
    reference_title: "Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus."
    supports: SUPPORT
    snippet: "These alterations in glucose transport activity are likely the result of dysregulation of intramyocellular fatty acid metabolism, whereby fatty acids cause insulin resistance by activation of a serine kinase cascade, leading to decreased insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and decreased IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle."
    explanation: This describes the molecular mechanism of insulin resistance involving fatty acid-induced serine kinase activation that impairs insulin receptor signaling through IRS-1 and PI3K.
  - reference: PMID:29939616
    reference_title: "Insulin Resistance."
    supports: SUPPORT
    snippet: "Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta-cell insulin production and hyperinsulinemia."
    explanation: This confirms that insulin resistance leads to compensatory hyperinsulinemia as beta cells attempt to overcome impaired glucose disposal in peripheral tissues.
  - reference: PMID:17463248
    reference_title: "A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk"
    explanation: This genome-wide association study confirms PPARG (the insulin-sensitizing nuclear receptor and thiazolidinedione drug target) as a genetic susceptibility locus for type 2 diabetes, tying it to insulin-resistance biology.
  downstream:
  - target: Beta Cell Dysfunction
    description: Sustained insulin resistance increases compensatory beta-cell insulin demand, contributing to eventual beta-cell failure.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Compensatory hyperinsulinemia and beta-cell secretory stress
    evidence:
    - reference: PMID:29939616
      reference_title: "Insulin Resistance."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "This vicious cycle continues until pancreatic beta-cell activity can no longer adequately meet the insulin demand created by insulin resistance, resulting in hyperglycemia."
      explanation: Directly supports progression from insulin-resistance-driven insulin demand to beta-cell failure.
  - target: Hepatic Glucose Overproduction
    description: Hepatic insulin resistance reduces insulin-mediated suppression of liver glucose production.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32872570
      reference_title: "Pathophysiology of Type 2 Diabetes Mellitus."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "IR contributes to increased glucose production in the liver and decreased glucose uptake both in the muscle, liver and adipose tissue."
      explanation: Supports insulin resistance as a cause of increased hepatic glucose production.
- name: Beta Cell Dysfunction
  description: >
    Progressive loss of pancreatic beta cell function and mass leads to inadequate
    insulin secretion relative to insulin demand. Beta cell failure is the key
    determinant of disease progression.
  genes:
  - preferred_term: KCNJ11
    term:
      id: hgnc:6257
      label: KCNJ11
  - preferred_term: SLC30A8
    term:
      id: hgnc:20303
      label: SLC30A8
  cell_types:
  - preferred_term: Pancreatic Beta Cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  biological_processes:
  - preferred_term: Insulin Secretion
    term:
      id: GO:0030073
      label: insulin secretion
  evidence:
  - reference: PMID:37035220
    reference_title: "Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress."
    supports: SUPPORT
    snippet: "Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D)."
    explanation: This establishes beta cell dysfunction as a core pathological mechanism in type 2 diabetes development alongside insulin resistance.
  - reference: PMID:37035220
    reference_title: "Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress."
    supports: SUPPORT
    snippet: "Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with T2D."
    explanation: This demonstrates that inflammatory markers are associated with beta cell failure, indicating inflammation contributes to beta cell dysfunction.
  - reference: PMID:37035220
    reference_title: "Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress."
    supports: SUPPORT
    snippet: "Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D."
    explanation: This confirms that oxidative stress, characterized by increased ROS and depleted antioxidants, contributes to pancreatic beta cell damage in type 2 diabetes.
  - reference: PMID:29939616
    reference_title: "Insulin Resistance."
    supports: SUPPORT
    snippet: "This vicious cycle continues until pancreatic beta-cell activity can no longer adequately meet the insulin demand created by insulin resistance, resulting in hyperglycemia."
    explanation: This describes the progression from compensatory beta cell hyperfunction to beta cell exhaustion and failure, leading to hyperglycemia.
  - reference: PMID:17463248
    reference_title: "A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk"
    explanation: This genome-wide association study confirms two beta-cell genes as type 2 diabetes susceptibility loci — KCNJ11 (Kir6.2 subunit of the beta-cell KATP channel governing insulin secretion) and SLC30A8 (the beta-cell zinc transporter involved in insulin granule storage).
  downstream:
  - target: Hyperglycemia
    description: Insufficient beta-cell insulin secretion limits glucose control and drives hyperglycemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32872570
      reference_title: "Pathophysiology of Type 2 Diabetes Mellitus."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "In the case of β-cell dysfunction, insulin secretion is reduced, limiting the body’s capacity to maintain physiological glucose levels."
      explanation: Supports beta-cell dysfunction as a direct cause of impaired glucose homeostasis.
- name: Hepatic Glucose Overproduction
  description: >
    Impaired suppression of hepatic gluconeogenesis leads to elevated fasting
    glucose levels. The liver fails to respond appropriately to insulin signals.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: Gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
  evidence:
  - reference: PMID:30150719
    reference_title: "Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase."
    supports: SUPPORT
    snippet: "Diabetes is characterized by impaired glucose homeostasis partly due to abnormally elevated hepatic glucose production (HGP)."
    explanation: This establishes that elevated hepatic glucose production is a key feature of diabetes pathophysiology.
  - reference: PMID:30150719
    reference_title: "Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase."
    supports: SUPPORT
    snippet: "Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP)."
    explanation: This confirms that hepatic glucose overproduction is central to diabetes hyperglycemia, as metformin's primary mechanism targets HGP suppression.
  - reference: PMID:30150719
    reference_title: "Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase."
    supports: SUPPORT
    snippet: "FBP1 catalyzes the irreversible hydrolysis of fructose-1,6-bisphosphate (F-1,6-P2) to fructose-6-phosphate (F6P) and inorganic phosphate (Pi) in the presence of divalent cations. FBP1 is a key rate-controlling enzyme in the gluconeogenic pathway."
    explanation: This identifies fructose-1,6-bisphosphatase (FBP1) as a key rate-controlling enzyme in hepatic gluconeogenesis, the pathway responsible for glucose overproduction in diabetes.
  downstream:
  - target: Hyperglycemia
    description: Excess hepatic glucose production contributes directly to impaired glucose homeostasis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30150719
      reference_title: "Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Diabetes is characterized by impaired glucose homeostasis partly due to abnormally elevated hepatic glucose production (HGP)."
      explanation: Supports hepatic glucose overproduction as a contributor to diabetes-associated hyperglycemia.
- name: Mitochondrial Dysfunction and Oxidative Stress
  description: >
    Early-onset mitochondrial dysfunction and pathological reactive oxygen species
    (ROS) generation occur across multiple metabolic tissues including pancreatic
    beta cells, skeletal muscle, and adipose tissue. Impaired mitophagy and
    mitochondrial dynamics contribute to disease progression. Extracellular
    vesicle-mediated inter-organ miscommunication propagates oxidative damage.
  cell_types:
  - preferred_term: Pancreatic Beta Cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  - preferred_term: Skeletal Muscle Cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: Oxidative Stress Response
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: Mitophagy
    term:
      id: GO:0000422
      label: autophagy of mitochondrion
  evidence:
  - reference: PMID:38338783
    reference_title: "Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression."
    supports: SUPPORT
    snippet: "New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression."
    explanation: This establishes that mitochondrial dysfunction and oxidative damage occur early and may drive T2D progression regardless of whether insulin resistance or beta cell dysfunction is the primary event.
  - reference: PMID:38338783
    reference_title: "Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression."
    supports: SUPPORT
    snippet: "Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs."
    explanation: This describes the novel mechanism of extracellular vesicle-mediated oxidative stress propagation between tissues in T2D pathogenesis.
  - reference: PMID:37035220
    reference_title: "Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress."
    supports: SUPPORT
    snippet: "Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D."
    explanation: This confirms that oxidative stress characterized by increased ROS and depleted antioxidants contributes to beta cell damage.
- name: Ceramide Accumulation
  description: >
    Ectopic accumulation of ceramides, sphingolipids formed from saturated fatty
    acids such as palmitate, in skeletal muscle, liver, and pancreatic beta cells.
    Ceramides impair insulin signaling through PP2A-mediated dephosphorylation of Akt,
    and within the beta cell they induce ER stress, mitochondrial dysfunction, and
    mitochondrial-mediated apoptosis.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Skeletal Muscle Cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  - preferred_term: Pancreatic Beta Cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  biological_processes:
  - preferred_term: ceramide formation from saturated fatty acids
    modifier: INCREASED
    term:
      id: GO:0046513
      label: ceramide biosynthetic process
  downstream:
  - target: Insulin Resistance
    description: >-
      Intramyocellular ceramide impairs insulin signaling in skeletal muscle, in part
      through PP2A-mediated dephosphorylation of Akt.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42549109
      reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Intramyocellular lipid, specifically in the form of DAG and ceramide, is a key mediator of this defect"
      explanation: Review synthesis placing intramyocellular ceramide upstream of skeletal-muscle insulin resistance.
  - target: Beta Cell Dysfunction
    description: >-
      Ceramide accumulation in beta cells induces ER stress, mitochondrial dysfunction,
      and mitochondrial-mediated apoptosis, reducing functional beta-cell mass.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42549109
      reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Within the β-cell, chronic exposure to saturated fatty acids like palmitate promotes the formation of ceramides, which induce ERS and mitochondrial dysfunction, ultimately triggering apoptosis"
      explanation: Review synthesis linking palmitate-driven ceramide formation in beta cells to ER stress, mitochondrial dysfunction, and apoptosis.
  evidence:
  - reference: PMID:42549109
    reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Among the most potent lipotoxic molecules are ceramides, sphingolipids that act as central mediators of both IR and β-cell apoptosis."
    explanation: Review synthesis identifying ceramides as central lipotoxic mediators of insulin resistance and beta-cell apoptosis in T2D.
  - reference: PMID:42549109
    reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Beyond insulin signaling, ceramides are powerful inducers of mitochondrial-mediated apoptosis."
    explanation: Review synthesis describing the apoptotic action of ceramides beyond their effect on insulin signaling.
- name: Diacylglycerol Accumulation
  description: >
    Ectopic accumulation of diacylglycerols (DAG) in liver and skeletal muscle. DAG
    acts as a second messenger that activates novel PKC isoforms (PKC-theta in muscle,
    PKC-epsilon in liver), which phosphorylate insulin receptor substrate proteins on
    inhibitory serine residues and so blunt insulin signaling.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Skeletal Muscle Cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  molecular_functions:
  - preferred_term: DAG-activated novel PKC (PKC-theta/epsilon) activity
    modifier: INCREASED
    term:
      id: GO:0004697
      label: diacylglycerol-dependent serine/threonine kinase activity
  downstream:
  - target: Insulin Resistance
    description: >-
      DAG-activated PKC-theta phosphorylates IRS-1 on inhibitory serine residues,
      impairing insulin signaling in skeletal muscle.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42549109
      reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "DAG accumulation activates novel PKCθ, which phosphorylates IRS-1 on inhibitory serine residues"
      explanation: Review synthesis describing the DAG to PKC-theta to inhibitory IRS-1 phosphorylation route to insulin resistance.
    - reference: PMID:42549109
      reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Intramyocellular lipid, specifically in the form of DAG and ceramide, is a key mediator of this defect"
      explanation: Review synthesis placing intramyocellular DAG upstream of skeletal-muscle insulin resistance.
  evidence:
  - reference: PMID:42549109
    reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The accumulation of DAGs in nonadipose tissues like liver, skeletal muscle, and pancreatic islets is another major driver of lipotoxicity."
    explanation: Review synthesis identifying ectopic DAG accumulation as a lipotoxic driver in T2D.
  - reference: PMID:42549109
    reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Thus, DAG serves as a key lipid intermediate that disrupts insulin sensitivity in metabolic tissues, primarily through PKC signaling cascades."
    explanation: Review synthesis stating that DAG acts on insulin sensitivity through PKC signaling.
- name: Islet Amyloid Polypeptide Oligomer Proteotoxicity
  description: >
    Human IAPP (amylin), co-secreted with insulin, misfolds into soluble toxic
    oligomers under the insulin hypersecretion of the compensatory phase of T2D.
    These oligomers, rather than the inert extracellular amyloid fibrils of late-stage
    disease, are the cytotoxic species: they impair beta-cell mitochondrial function,
    overwhelm ER folding capacity, and activate the NLRP3 inflammasome. Declining
    autophagic clearance lets them persist.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Pancreatic Beta Cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  biological_processes:
  - preferred_term: hIAPP toxic oligomer formation
    modifier: INCREASED
    term:
      id: GO:0051260
      label: protein homooligomerization
  notes: >-
    Bound to GO:0051260 protein homooligomerization rather than GO:1990000 amyloid
    fibril formation, because the cited review identifies soluble hIAPP oligomers, not
    fibrils, as the cytotoxic species. An OLS search of GO for "protein aggregation"
    returned no biological-process term for aggregation or toxic oligomer formation
    as such.
  downstream:
  - target: Beta Cell Dysfunction
    description: >-
      Soluble hIAPP oligomers impair beta-cell mitochondrial function, trigger chronic
      ER stress, and activate the NLRP3 inflammasome, adding proteotoxic stress to
      beta cells that already carry lipotoxic and inflammatory load.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42549109
      reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Beyond the direct impact of lipotoxicity, β-cell failure in T2D is profoundly exacerbated by the toxic misfolding of islet amyloid polypeptide (IAPP)"
      explanation: Review synthesis placing IAPP misfolding upstream of beta-cell failure.
    - reference: PMID:42549109
      reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Intracellularly, hIAPP oligomers impair mitochondrial function, reducing ATP production and increasing ROS"
      explanation: Review synthesis describing one intracellular route by which hIAPP oligomers damage beta cells.
  evidence:
  - reference: PMID:42549109
    reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cosecreted with insulin, hIAPP is prone to misfolding and forming toxic oligomers, particularly under the demanding conditions of insulin hypersecretion that characterize the compensatory phase of T2D"
    explanation: Review synthesis describing hIAPP oligomer formation under compensatory insulin hypersecretion.
  - reference: PMID:42549109
    reference_title: "Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Unlike the inert, extracellular amyloid fibrils found in late-stage disease, these soluble oligomers are the primary cytotoxic species"
    explanation: Review synthesis identifying soluble oligomers, not fibrils, as the cytotoxic hIAPP species, which is why this node is bound to oligomerization.
- name: Incretin Axis Dysfunction
  description: >
    Impaired incretin hormone signaling, particularly blunted glucose-dependent
    insulinotropic peptide (GIP) action in beta cells. GLP-1 action is relatively
    preserved. The incretin effect amplifies insulin secretion in response to
    oral glucose via cAMP-PKA signaling pathways.
  genes:
  - preferred_term: TCF7L2
    term:
      id: hgnc:11641
      label: TCF7L2
  cell_types:
  - preferred_term: Pancreatic Beta Cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  - preferred_term: Enteroendocrine Cell
    term:
      id: CL:0000164
      label: enteroendocrine cell
  biological_processes:
  - preferred_term: cAMP Signaling
    term:
      id: GO:0141156
      label: cAMP/PKA signal transduction
  - preferred_term: Insulin Secretion Regulation
    term:
      id: GO:0050796
      label: regulation of insulin secretion
  evidence:
  - reference: PMID:38831203
    reference_title: "GLP1-GIP receptor co-agonists: a promising evolution in the treatment of type 2 diabetes."
    supports: SUPPORT
    snippet: "Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge."
    explanation: This establishes the importance of the GLP-1/GIP incretin axis in T2D pathophysiology and its targeting by dual agonist therapies.
  - reference: PMID:38831203
    reference_title: "GLP1-GIP receptor co-agonists: a promising evolution in the treatment of type 2 diabetes."
    supports: SUPPORT
    snippet: "Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity."
    explanation: This demonstrates the clinical relevance of incretin axis dysfunction by showing dual GLP-1/GIP agonism is effective for T2D treatment.
  - reference: PMID:19934000
    reference_title: "TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The TCF7L2 variant rs7903146 appears to affect risk of type 2 diabetes, at least in part, by modifying the effect of incretins on insulin secretion."
    explanation: Supports TCF7L2 as a genetic contributor to incretin-axis effects on insulin secretion in humans.
  downstream:
  - target: Beta Cell Dysfunction
    description: Reduced beta-cell sensitivity to incretins impairs oral-glucose-stimulated insulin secretion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19934000
      reference_title: "TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This is not due to reduced secretion of GLP-1 and GIP but rather due to the effect of TCF7L2 on the sensitivity of the beta-cell to incretins."
      explanation: Directly supports a TCF7L2-associated incretin-sensitivity defect at the beta cell.
- name: Chronic Hyperglycemia
  description: >-
    Sustained hyperglycemia arising from the combined insulin resistance,
    beta-cell secretory failure, and hepatic glucose overproduction is the shared
    driver of long-term diabetic tissue injury and the entry point to the
    conserved diabetic vascular-complication cascade captured by the
    diabetic_vascular_complications module (chronic hyperglycemia -> oxidative
    and AGE-RAGE stress -> endothelial dysfunction and vascular inflammation ->
    micro- and macrovascular injury -> end-organ complications). In type 2
    diabetes this cascade manifests clinically as diabetic retinopathy,
    neuropathy, nephropathy, and atherosclerotic cardiovascular disease.
  conforms_to: "diabetic_vascular_complications#Chronic Hyperglycemia"
  biological_processes:
  - preferred_term: glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
    modifier: ABNORMAL
  downstream:
  - target: Diabetic Retinopathy
    description: >-
      Sustained hyperglycemia drives the microvascular injury that produces
      diabetic retinopathy, one of the shared end-organ complications captured by
      the diabetic_vascular_complications module this node conforms to.
    evidence:
    - reference: PMID:39158206
      reference_title: "Serum biomarkers for predicting microvascular complications of diabetes mellitus."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diabetic microvascular complications such as retinopathy, nephropathy, and neuropathy are primary causes of blindness, terminal renal failure, and neuropathic disorders in type 2 diabetes mellitus patients."
      explanation: >-
        Supports chronic hyperglycemia driving retinopathy as a microvascular
        end-organ complication in type 2 diabetes.
  - target: Peripheral Neuropathy
    description: >-
      Sustained hyperglycemia drives the microvascular and metabolic nerve injury
      that produces diabetic peripheral neuropathy, another shared end-organ
      complication of the conserved vascular-complication cascade.
    evidence:
    - reference: PMID:39158206
      reference_title: "Serum biomarkers for predicting microvascular complications of diabetes mellitus."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diabetic microvascular complications such as retinopathy, nephropathy, and neuropathy are primary causes of blindness, terminal renal failure, and neuropathic disorders in type 2 diabetes mellitus patients."
      explanation: >-
        Supports chronic hyperglycemia driving neuropathy as a microvascular
        end-organ complication in type 2 diabetes.
  evidence:
  - reference: PMID:29939616
    reference_title: "Insulin Resistance."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This vicious cycle continues until pancreatic beta-cell activity can no longer adequately meet the insulin demand created by insulin resistance, resulting in hyperglycemia."
    explanation: >-
      Supports sustained hyperglycemia arising from beta-cell failure to
      compensate for insulin resistance, the shared trigger that feeds the
      diabetic vascular-complication cascade.
mechanistic_hypotheses:
- hypothesis_group_id: pgs_context_amplification
  hypothesis_label: Amplification of polygenic T2D risk in adverse metabolic contexts via shared insulin-resistance convergence
  status: EMERGING
  description: >-
    Polygenic-score-by-context (PGS×C) interactions reported for type 2 diabetes
    in the UK Biobank appear to reflect amplification rather than
    context-specific causal variants: the same susceptibility loci (e.g. TCF7L2,
    PPARG, KCNJ11, SLC30A8) exert systematically larger effects in
    disease-promoting metabolic contexts. This entry proposes that the
    amplification arises because polygenic liability and adverse exposures
    converge on the shared Insulin Resistance node (with Beta Cell Dysfunction as
    a parallel target), so their joint effect on the liability-threshold scale is
    super-additive rather than additive. Nagpal & Gibson (Nat Genet 2026,
    PMID:42443528) highlight the interaction between reduced
    polyunsaturated fatty acids (low omega-6) and high glucose, which elevates
    T2D risk increasingly as the PGS rises, and identify sex and sex-adjusted
    testosterone as further amplifying contexts.
  evidence:
  - reference: PMID:42443528
    reference_title: "Pervasive interactions between exposures and polygenic risk can inform more effective clinical and behavioral interventions."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: The predominant mechanism for PGS×C is the amplification of genetic effects in adverse contexts, such as low polyunsaturated fatty acids or social determinants of ill health
    explanation: >-
      Direct source (Nagpal & Gibson 2026): across seven UK Biobank diseases and
      75 contexts, amplification of genetic effects in adverse contexts is
      identified as the predominant mechanism of PGS×context interaction — the
      mechanism applied in this hypothesis.
  - reference: PMID:37228747
    reference_title: "Amplification is the primary mode of gene-by-sex interaction in complex human traits."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: GxSex is pervasive but acts primarily through systematic sex differences in the magnitude of many genetic effects
    explanation: >-
      Establishes amplification — systematic differences in the magnitude of
      polygenic effects rather than in the identity of causal variants — as the
      primary mode of gene-by-sex interaction across physiological traits, and
      notes that testosterone may mediate this amplification. Cited as general
      support for amplification as a mode of PGS×context interaction; the paper
      is not T2D-specific.
  notes: >-
    EMERGING hypothesis motivated by population-scale PGS×context analyses
    (primary source PMID:42443528; general amplification mechanism corroborated
    by PMID:37228747, which documents testosterone-mediated amplification). The
    convergence claim (polygenic liability + adverse metabolic context → Insulin
    Resistance) is a mechanistic interpretation and is not itself established as
    causal — see the reverse-causation knowledge gap under discussions.
phenotypes:
- name: Hyperglycemia
  category: Metabolic
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Hyperglycemia
    term:
      id: HP:0003074
      label: Hyperglycemia
  evidence:
  - reference: PMID:29939616
    reference_title: "Insulin Resistance."
    supports: SUPPORT
    snippet: "This vicious cycle continues until pancreatic beta-cell activity can no longer adequately meet the insulin demand created by insulin resistance, resulting in hyperglycemia."
    explanation: This describes how the failure of beta cells to compensate for insulin resistance results in hyperglycemia, the hallmark of type 2 diabetes.
  - reference: PMID:30150719
    reference_title: "Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase."
    supports: SUPPORT
    snippet: "Diabetes is characterized by impaired glucose homeostasis partly due to abnormally elevated hepatic glucose production (HGP)."
    explanation: This confirms that hyperglycemia in diabetes results from elevated hepatic glucose production and impaired glucose homeostasis.
- name: Polydipsia
  category: Systemic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Polydipsia
    term:
      id: HP:0001959
      label: Polydipsia
  evidence:
  - reference: PMID:9398128
    reference_title: "Factors contributing to the degree of polyuria in a patient with poorly controlled diabetes mellitus."
    supports: SUPPORT
    snippet: "Polyuria due to a glucose-induced osmotic diuresis is common in patients with hyperglycemia."
    explanation: This establishes that polyuria results from glucose-induced osmotic diuresis in hyperglycemia, which in turn leads to polydipsia as a compensatory response to fluid loss.
- name: Polyuria
  category: Renal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Polyuria
    term:
      id: HP:0000103
      label: Polyuria
  evidence:
  - reference: PMID:9398128
    reference_title: "Factors contributing to the degree of polyuria in a patient with poorly controlled diabetes mellitus."
    supports: SUPPORT
    snippet: "Polyuria due to a glucose-induced osmotic diuresis is common in patients with hyperglycemia. This diuresis usually abates when the plasma glucose level approaches its renal threshold."
    explanation: This describes the mechanism of polyuria in diabetes as glucose-induced osmotic diuresis when plasma glucose exceeds the renal threshold.
- name: Obesity
  category: Metabolic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
- name: Fatigue
  category: Systemic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- name: Insulin Resistance
  category: Metabolic
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Insulin Resistance
    term:
      id: HP:0000855
      label: Insulin resistance
  evidence:
  - reference: PMID:12231074
    reference_title: "Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus."
    supports: SUPPORT
    snippet: "Insulin resistance is caused by the decreased ability of peripheral target tissues (especially muscle) to respond properly to normal circulating concentrations of insulin."
    explanation: This establishes insulin resistance as a hallmark feature of T2D pathophysiology.
- name: Impaired Glucose Tolerance
  category: Metabolic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Impaired Glucose Tolerance
    term:
      id: HP:0001952
      label: Glucose intolerance
- name: Hyperinsulinemia
  category: Metabolic
  frequency: FREQUENT
  notes: Compensatory response to insulin resistance
  phenotype_term:
    preferred_term: Hyperinsulinemia
    term:
      id: HP:0000842
      label: Hyperinsulinemia
  evidence:
  - reference: PMID:29939616
    reference_title: "Insulin Resistance."
    supports: SUPPORT
    snippet: "Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta-cell insulin production and hyperinsulinemia."
    explanation: This establishes hyperinsulinemia as a compensatory response to insulin resistance in T2D.
- name: Diabetic Retinopathy
  category: Ophthalmologic
  frequency: OCCASIONAL
  notes: Long-term microvascular complication
  phenotype_term:
    preferred_term: Retinopathy
    term:
      id: HP:0000488
      label: Retinopathy
- name: Peripheral Neuropathy
  category: Neurological
  frequency: OCCASIONAL
  notes: Long-term microvascular complication
  phenotype_term:
    preferred_term: Peripheral Neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
biochemical:
- name: Myeloid Lineage Plasma Proteomic Age Gap
  biomarker_term:
    preferred_term: myeloid lineage plasma proteomic aging clock (age gap)
    term:
      id: NCIT:C97139
      label: Proteomic Profile
  presence: Elevated
  context: >-
    Blood-based cell-type-specific aging clock. Plasma proteins are mapped to
    their putative cell of origin using Human Protein Atlas single-cell
    transcriptomic data, and a machine-learning model estimates myeloid lineage
    biological age; the age gap is the difference between that estimate and
    chronological age. "Extreme" agers are those in the upper tail of the age-gap
    distribution.
  cell_types:
  - preferred_term: Myeloid lineage cell
    term:
      id: CL:0000763
      label: myeloid cell
  notes: >-
    Myeloid lineage aging was the strongest cellular-aging predictor of incident
    type 2 diabetes in UK Biobank (HR 3.88, 95% CI 3.33-4.52) and remained
    significant after adjustment for established risk factors including HbA1c,
    BMI, smoking and renal function. Its distinctive value is that it stratified
    risk among people who were still normoglycemic, so it identifies future cases
    before the glycemic measures used to diagnose them move. Type 1 diabetes and
    other specified diabetes were excluded from the incidence analysis. This is
    an observational prognostic association; the islet-inflammation reading below
    is the authors' mechanistic interpretation, not something the clock measures.
  evidence:
  - reference: PMID:42297981
    reference_title: "Plasma proteomic signatures of cellular aging predict human disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: myeloid lineage extreme aging demonstrated the strongest prognostic value
    explanation: >-
      Establishes myeloid lineage aging as the leading cellular-aging predictor
      of incident type 2 diabetes among the cell types tested.
  - reference: PMID:42297981
    reference_title: "Plasma proteomic signatures of cellular aging predict human disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: myeloid lineage aging identified normoglycemic individuals at higher type 2 diabetes risk
    explanation: >-
      States the clinically distinctive claim: risk stratification before
      glycemic criteria are met, which is what would make the marker useful for
      targeted surveillance.
  readouts:
  - target: Beta Cell Dysfunction
    relationship: PREDICTS
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      An elevated myeloid lineage age gap predicts incident type 2 diabetes in
      still-normoglycemic individuals, and is read against beta cell dysfunction
      via the proposed route of myeloid-derived cytokines inflaming the islet
      microenvironment. The prognostic association is measured; the islet route
      is inference and should not be curated as an established causal edge.
    evidence:
    - reference: PMID:42297981
      reference_title: "Plasma proteomic signatures of cellular aging predict human disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: consistent with a role of myeloid-derived cytokines in the initiation of an inflamed pancreatic islet microenvironment and increased susceptibility to type 2 diabetes
      explanation: >-
        The authors' stated mechanistic rationale linking the myeloid aging
        signature to the islet compartment, offered as consistency rather than
        as demonstrated causation.
- name: NMR metabolomic risk score (MetRS)
  specificity: >
    A research composite, not a clinical assay. MetRS is a machine-learning
    score built from the top 30 of 313 Nightingale Health NMR plasma measures,
    derived and replicated in UK Biobank. It is not validated for clinical use
    and does not replace fasting glucose or HbA1c.
  context: >
    In the UK Biobank metabolome-phenome atlas, MetRS classified prevalent type
    2 diabetes with an area under the curve of 0.941 and predicted incident
    diabetic complications, including diabetic maculopathy (0.921), diabetic
    kidney failure (0.919) and type 2 diabetes with peripheral circulatory
    complications (0.913). No presence value is recorded because MetRS is a
    derived multi-analyte score rather than a measured analyte. Two limits
    matter for interpretation: the score is trained and tested in a single,
    predominantly European-ancestry volunteer cohort, and a high classification
    area under the curve for prevalent disease partly reflects the metabolic
    consequences of established diabetes rather than antecedent risk.
  readouts:
  - target: Chronic Hyperglycemia
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      The lipid, amino-acid and glycolysis-related measures that dominate MetRS
      shift with sustained hyperglycemia and insulin resistance, so the score
      reads out the systemic metabolic state rather than any single mechanism.
  evidence:
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "MetRS offered favourable diagnostic and predictive performance, particularly in T2D"
    explanation: >
      Names type 2 diabetes as one of the conditions in which the
      machine-learning metabolomic risk score performed best, both for
      classification of prevalent disease and for prediction of incident
      disease.
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The MetRS witnessed excellent diagnosis for type 1 diabetes (T1D; AUC = 0.944), T2D (AUC = 0.941), diabetic maculopathy (AUC = 0.940) and chronic kidney disease (CKD; AUC = 0.933)."
    explanation: >
      Quotes the prevalent-disease classification figure of 0.941 for type 2
      diabetes that the context field reports.
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "the MetRS excellently predicted future diabetic complications, for example, diabetic maculopathy (AUC = 0.921 (95% CI, 0.914-0.928)), diabetic kidney failure (AUC = 0.919 (0.906-0.930)) and type 2 diabetes (T2D) with peripheral circulatory complications (AUC = 0.913 (0.898-0.926))."
    explanation: >
      Quotes all three incident-complication figures reported in the context
      field, so the predictive claim and its numbers both rest on source text.
genetic:
- name: TCF7L2
  gene_term:
    preferred_term: TCF7L2
    term:
      id: hgnc:11641
      label: TCF7L2
  association: Risk Factor
- name: PPARG
  gene_term:
    preferred_term: PPARG
    term:
      id: hgnc:9236
      label: PPARG
  association: Risk Factor
- name: KCNJ11
  gene_term:
    preferred_term: KCNJ11
    term:
      id: hgnc:6257
      label: KCNJ11
  association: Risk Factor
- name: SLC30A8
  gene_term:
    preferred_term: SLC30A8
    term:
      id: hgnc:20303
      label: SLC30A8
  association: Risk Factor
- name: TBC1D4
  gene_term:
    preferred_term: TBC1D4
    term:
      id: hgnc:19165
      label: TBC1D4
  association: Founder nonsense variant, recessive effect
  relationship_type: SUSCEPTIBILITY
  notes: >-
    The gene behind MONDO:0014488 "diabetes mellitus, noninsulin-dependent, 5",
    which MONDO defines as a type 2 diabetes in which the cause is a TBC1D4
    mutation. It is recorded here rather than as a subtype of the diabetes
    mellitus umbrella because the phenotype is type 2 diabetes with a defined
    muscle mechanism, not a separate clinical entity: the p.Arg684Ter allele is
    common in the Greenlandic population (17% allele frequency in the study
    population), acts overwhelmingly in homozygotes -
    heterozygotes show only a moderately higher 2-hour glucose - and raises risk
    rather than being fully penetrant, so SUSCEPTIBILITY rather than CAUSATIVE.
    The committed ClinGen Gene-Disease Validity snapshot
    (data/clingen/gene_validity.csv) carries no TBC1D4 row for any disease.
  evidence:
  - reference: PMID:25043022
    reference_title: "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we discovered a nonsense p.Arg684Ter variant (in which arginine is
      replaced by a termination codon) in the gene TBC1D4 with an allele
      frequency of 17%
    explanation: >-
      Names the variant and its 17% allele frequency in the study population.
      No case_fractions record is kept for this gene: an allele frequency is a
      different quantity from the share of disease cases a gene explains, and
      the source reports no per-gene share.
  - reference: PMID:25043022
    reference_title: "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24))
    explanation: >-
      Quantifies the type 2 diabetes risk carried by homozygotes, which is the
      relationship this record names.
  - reference: PMID:25043022
    reference_title: "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous carriers have a moderately higher plasma glucose
      concentration 2 hours after an oral glucose load than non-carriers
    explanation: >-
      Supports the recessive dose pattern this record states: heterozygotes are
      affected only marginally, so the effect is essentially homozygote-restricted.
- name: CAPN10
  gene_term:
    preferred_term: CAPN10
    term:
      id: hgnc:1477
      label: CAPN10
  association: Reported susceptibility locus, not replicated
  relationship_type: DISPUTED
  notes: >-
    The gene behind MONDO:0011027 "diabetes mellitus, noninsulin-dependent, 1"
    (OMIM:601283), the first type 2 diabetes gene found by positional cloning.
    It is recorded as DISPUTED rather than as a susceptibility locus because the
    2004 meta-analysis cited below found no significant association under
    additive or dominant models, and found that the haplotype association became
    nonsignificant once the initial small positive studies were removed. The
    committed ClinGen Gene-Disease Validity snapshot
    (data/clingen/gene_validity.csv) carries no CAPN10 row for any disease, so
    no expert-panel classification is available either way.
  evidence:
  - reference: PMID:11017071
    reference_title: "Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe the positional cloning of a gene located in the NIDDM1
      region that shows association with type 2 diabetes in Mexican Americans
      and a Northern European population from the Botnia region of Finland.
    explanation: The original report this MONDO class rests on, recorded so the disputed claim is traceable to its source.
  - reference: PMID:14730479
    reference_title: "Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Under either an additive or a dominant effect model, we found no
      statistically significant relation between CAPN10 genotypes in the
      UCSNP-43 locus and T2D risk.
    explanation: The meta-analytic result that makes this relationship disputed rather than established.
  - reference: PMID:14730479
    reference_title: "Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After we removed these initial studies, this association became
      nonsignificant (OR 1.11; 95% CI 0.91-1.35).
    explanation: Shows the haplotype association was driven by the initial small positive studies, which is the second ground for the DISPUTED grade.
environmental:
- name: Sedentary Lifestyle
  exposure_term:
    preferred_term: sedentary lifestyle
    term:
      id: ECTO:6000004
      label: exposure to sedentary lifestyle
  notes: Major modifiable risk factor
  evidence:
  - reference: PMID:22890825
    reference_title: "Sedentary time in adults and the association with diabetes, cardiovascular disease and death: systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The greatest sedentary time compared with the lowest was associated with a 112% increase in the RR of diabetes"
    explanation: Systematic review and meta-analysis quantifies sedentary time's association with type 2 diabetes risk.
- name: High-Calorie Diet
  exposure_term:
    preferred_term: high-calorie dietary pattern
    modifier: INCREASED
    term:
      id: XCO:0000013
      label: diet
  notes: Contributes to obesity and insulin resistance
  evidence:
  - reference: PMID:28065634
    reference_title: "Association between Dietary Energy Density and Incident Type 2 Diabetes in the Women's Health Initiative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Risk of diabetes developing was 24% greater for women in the highest dietary energy density quintile compared with the lowest after adjusting for confounders (95% CI 1.17 to 1.32)"
    explanation: Prospective cohort study (Women's Health Initiative) links higher dietary energy density to increased type 2 diabetes incidence.
- name: Obesity
  notes: Primary risk factor for insulin resistance
  evidence:
  - reference: PMID:20493574
    reference_title: "The magnitude of association between overweight and obesity and the risk of diabetes: a meta-analysis of prospective cohort studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall RR of diabetes for obese persons compared to those with normal weight was 7.19, 95% CI: 5.74, 9.00 and for overweight was 2.99, 95% CI: 2.42, 3.72"
    explanation: Meta-analysis of prospective cohort studies quantifies obesity's association with type 2 diabetes risk.
diagnosis:
- name: Hemoglobin A1C
  description: >-
    Glycated hemoglobin is one of the three laboratory criteria by which the
    American Diabetes Association diagnoses diabetes, and the one that also
    defines the prediabetes band. The ADA criterion is an A1C of 6.5% or
    higher, measured by an NGSP-certified method traceable to the DCCT
    reference assay, with 5.7-6.4% identifying prediabetes. In the absence of
    unequivocal hyperglycemia the diagnosis requires a second abnormal result.
  diagnosis_term:
    preferred_term: hemoglobin A1C measurement
    term:
      id: NCIT:C64849
      label: Hemoglobin A1C Measurement
  presence: Diagnostic
  measurements:
  - preferred_term: hemoglobin A1C (NGSP, percent of total hemoglobin)
    term:
      id: LOINC:4548-4
      label: Hemoglobin A1c/Hemoglobin.total in Blood
  reference_ranges:
  - loinc_term:
      id: LOINC:4548-4
      label: Hemoglobin A1c/Hemoglobin.total in Blood
    unit: '%'
    population: ADA Standards of Care in Diabetes, 2025 (nonpregnant individuals)
    notes: >-
      Source phrasing: "A1C 5.7-6.4% (39-47 mmol/mol)" for prediabetes and
      "A1C (two results >=6.5% [>=48 mmol/mol])" for diabetes. The bands are
      half-open, so the prediabetes band runs [5.7, 6.5) rather than ending at
      6.4; any value between 6.4 and 6.5 falls in the prediabetes band here,
      which is the one-point difference between the half-open convention and
      the source's "5.7-6.4%" wording. The source's lower limit of normal is
      not a separate cut-off; the Normal band is simply everything below 5.7%.
    evidence:
    - reference: PMID:39651986
      reference_title: "2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2025."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "People with prediabetes are defined by the presence of IFG and/or IGT and/or A1C 5.7–6.4% (39–47 mmol/mol) (Table 2.2)."
      explanation: >-
        Names the ADA prediabetes A1C band, 5.7-6.4%, which is the lower band
        recorded here.
    - reference: PMID:39651986
      reference_title: "2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2025."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "if an individual meets the diabetes criterion of A1C (two results ≥6.5%"
      explanation: >-
        States the ADA A1C diabetes criterion of 6.5% or higher on two
        results; the sentence continues to say such a person is considered to
        have diabetes even when fasting glucose is below its own threshold.
    - reference: PMID:20042775
      reference_title: Diagnosis and classification of diabetes mellitus.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "A1C ≥6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay."
      explanation: >-
        The ADA position statement that first adopted the 6.5% A1C criterion
        in 2010, stating the threshold and the NGSP/DCCT standardization
        requirement that fixes the unit as percent.
    interpretation_bands:
    - name: Normal
      upper_bound: 5.7
      unit: '%'
      abnormal_flag: NORMAL
    - name: Prediabetes
      lower_bound: 5.7
      upper_bound: 6.5
      unit: '%'
      abnormal_flag: HIGH
      interpretation: >-
        ADA prediabetes band (5.7-6.4%); identifies individuals at high risk
        for diabetes and cardiovascular outcomes, not a diagnosis of diabetes.
    - name: Diabetes
      lower_bound: 6.5
      unit: '%'
      abnormal_flag: HIGH
      interpretation: >-
        Meets the ADA A1C criterion for diabetes; requires confirmation by a
        second abnormal test in the absence of unequivocal hyperglycemia.
  evidence:
  - reference: PMID:39651986
    reference_title: "2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2025."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Diabetes may be diagnosed based on A1C or plasma glucose criteria. Plasma glucose criteria include either the fasting plasma glucose (FPG), 2-h plasma glucose (2-h PG) during a 75-g oral glucose tolerance test (OGTT), or random glucose accompanied by classic hyperglycemic symptoms"
    explanation: >-
      Establishes A1C as one of the ADA diagnostic criteria for diabetes,
      alongside the two plasma glucose tests curated as separate rows.
  - reference: PMID:39651986
    reference_title: "2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2025."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The A1C test should be performed using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) (ngsp.org) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay."
    explanation: >-
      The standardization requirement that fixes the unit of the ADA
      thresholds as NGSP percent, which is why the percent-reporting LOINC code
      rather than the IFCC mmol/mol code is bound.
  notes: >-
    This entry has no biochemical marker for A1C, so the code and its bands
    live on this diagnosis row rather than on a marker. LOINC:4548-4 is the
    method-less code whose property is a mass fraction reported in percent,
    which is the NGSP/DCCT unit the ADA thresholds are stated in. The
    IFCC-protocol code LOINC:59261-8 (Hemoglobin A1c/Hemoglobin.total in Blood
    by IFCC protocol) reports mmol/mol and is not bound because the cut-offs
    are percent values; the ADA text gives the mmol/mol equivalents in
    parentheses (48 mmol/mol for 6.5%, 39-47 mmol/mol for 5.7-6.4%). The LOINC
    Part is LOINC:LP16413-4 (Hemoglobin A1c). The ADA 2025 chapter is cached
    as full text, so the criteria quoted come from its prose; the chapter's
    Table 2.1 and Table 2.2 bodies are not in the cached text and are not
    quoted.
- name: Fasting plasma glucose
  description: >-
    Fasting plasma glucose is an ADA diagnostic criterion for diabetes at 126
    mg/dL (7.0 mmol/L) or higher, with fasting defined as no caloric intake
    for at least 8 h. The ADA impaired fasting glucose band is 100-125 mg/dL
    (5.6-6.9 mmol/L); the ADA text notes that the World Health Organization
    and several diabetes organizations set the IFG lower limit at 110 mg/dL
    (6.1 mmol/L) instead.
  diagnosis_term:
    preferred_term: fasting plasma glucose measurement
    term:
      id: NCIT:C92744
      label: Blood Glucose Measurement
  presence: Diagnostic
  measurements:
  - preferred_term: fasting plasma glucose (mg/dL)
    term:
      id: LOINC:1558-6
      label: Fasting glucose [Mass/volume] in Serum or Plasma
  reference_ranges:
  - loinc_term:
      id: LOINC:1558-6
      label: Fasting glucose [Mass/volume] in Serum or Plasma
    unit: mg/dL
    population: ADA Standards of Care in Diabetes, 2025 (nonpregnant individuals)
    notes: >-
      Source phrasing: "IFG is defined as FPG levels from 100 to 125 mg/dL
      (from 5.6 to 6.9 mmol/L)" and "FPG ≥126 mg/dl (7.0 mmol/l)". Half-open
      bands: the IFG band is recorded as [100, 126) rather than ending at 125,
      which is the one-point difference between the convention and the
      source's "100 to 125" wording. The ADA text also records that the WHO
      and some other organizations use 110 mg/dL (6.1 mmol/L) as the IFG lower
      limit; that alternative is not recorded as a separate range because the
      WHO document itself is not cited here.
    evidence:
    - reference: PMID:39651986
      reference_title: "2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2025."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "IFG is defined as FPG levels from 100 to 125 mg/dL (from 5.6 to 6.9 mmol/L) (78,84) and IGT as 2-h PG levels during 75-g OGTT from 140 to 199 mg/dL (from 7.8 to 11.0 mmol/L) (10). It should be noted that the World Health Organization and a number of diabetes organizations define the IFG lower limit at 110 mg/dL (6.1 mmol/L)."
      explanation: >-
        States the ADA impaired fasting glucose band, 100-125 mg/dL, and
        discloses the WHO alternative lower limit of 110 mg/dL.
    - reference: PMID:20042775
      reference_title: Diagnosis and classification of diabetes mellitus.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h."
      explanation: >-
        States the fasting plasma glucose diabetes criterion of 126 mg/dL and
        the definition of fasting that the measurement presupposes.
    interpretation_bands:
    - name: Normal
      upper_bound: 100.0
      unit: mg/dL
      abnormal_flag: NORMAL
    - name: Impaired fasting glucose (prediabetes)
      lower_bound: 100.0
      upper_bound: 126.0
      unit: mg/dL
      abnormal_flag: HIGH
      interpretation: >-
        ADA impaired fasting glucose, 100-125 mg/dL (5.6-6.9 mmol/L); a
        prediabetes category, not a diagnosis of diabetes.
    - name: Diabetes
      lower_bound: 126.0
      unit: mg/dL
      abnormal_flag: HIGH
      interpretation: >-
        Meets the ADA fasting plasma glucose criterion for diabetes; requires
        confirmation in the absence of unequivocal hyperglycemia.
  evidence:
  - reference: PMID:39651986
    reference_title: "2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2025."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In nonpregnant individuals, FPG (or A1C) is typically preferred for routine screening due to the ease of administration"
    explanation: >-
      Names fasting plasma glucose as the ADA's usual screening and
      diagnostic test in nonpregnant individuals.
  notes: >-
    LOINC:1558-6 is the method-less mass-concentration code, matching the
    mg/dL in which the ADA states its thresholds. The molar sibling,
    LOINC:14771-0 (Fasting glucose [Moles/volume] in Serum or Plasma), carries
    the same measurement in mmol/L and is the code bound on the
    Gestational_Diabetes_Mellitus entry for criteria stated in mmol/L. The
    LOINC Part is LOINC:LP14635-4 (Glucose).
- name: 75-g oral glucose tolerance test
  description: >-
    The 2-h plasma glucose during a 75-g oral glucose tolerance test is the
    third ADA diagnostic criterion for diabetes, at 200 mg/dL (11.1 mmol/L) or
    higher, with 140-199 mg/dL (7.8-11.0 mmol/L) defining impaired glucose
    tolerance. The ADA notes that the 2-h value diagnoses more people with
    prediabetes and diabetes than the fasting glucose or A1C cut points do.
  diagnosis_term:
    preferred_term: 75-g oral glucose tolerance test
    term:
      id: NCIT:C45946
      label: Glucose Tolerance Test
  presence: Diagnostic
  measurements:
  - preferred_term: 2-h plasma glucose after 75 g oral glucose (mg/dL)
    term:
      id: LOINC:1518-0
      label: Glucose [Mass/volume] in Serum or Plasma --2 hours post 75 g glucose PO
  reference_ranges:
  - loinc_term:
      id: LOINC:1518-0
      label: Glucose [Mass/volume] in Serum or Plasma --2 hours post 75 g glucose PO
    unit: mg/dL
    population: ADA Standards of Care in Diabetes, 2025 (nonpregnant individuals)
    notes: >-
      Source phrasing: "IGT as 2-h PG levels during 75-g OGTT from 140 to 199
      mg/dL (from 7.8 to 11.0 mmol/L)" and "2-h plasma glucose ≥200 mg/dl
      (11.1 mmol/l) during an OGTT". Half-open bands: the IGT band is recorded
      as [140, 200) rather than ending at 199, which is the one-point
      difference between the convention and the source's "140 to 199"
      wording.
    evidence:
    - reference: PMID:39651986
      reference_title: "2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2025."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "IGT as 2-h PG levels during 75-g OGTT from 140 to 199 mg/dL (from 7.8 to 11.0 mmol/L)"
      explanation: >-
        States the ADA impaired glucose tolerance band on the 2-h post-load
        glucose, 140-199 mg/dL.
    - reference: PMID:20042775
      reference_title: Diagnosis and classification of diabetes mellitus.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water."
      explanation: >-
        States the 2-h plasma glucose diabetes criterion of 200 mg/dL and the
        75-g load that defines the test.
    interpretation_bands:
    - name: Normal
      upper_bound: 140.0
      unit: mg/dL
      abnormal_flag: NORMAL
    - name: Impaired glucose tolerance (prediabetes)
      lower_bound: 140.0
      upper_bound: 200.0
      unit: mg/dL
      abnormal_flag: HIGH
      interpretation: >-
        ADA impaired glucose tolerance, 140-199 mg/dL (7.8-11.0 mmol/L); a
        prediabetes category, not a diagnosis of diabetes.
    - name: Diabetes
      lower_bound: 200.0
      unit: mg/dL
      abnormal_flag: HIGH
      interpretation: >-
        Meets the ADA 2-h plasma glucose criterion for diabetes; requires
        confirmation in the absence of unequivocal hyperglycemia.
  evidence:
  - reference: PMID:39651986
    reference_title: "2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2025."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Compared with FPG and A1C cut points, the 2-h PG value diagnoses more people with prediabetes and diabetes (4)."
    explanation: >-
      Records the ADA's statement that the 2-h post-load glucose detects more
      cases than the fasting glucose or A1C criteria, which is the clinical
      reason the OGTT is kept as a diagnostic row alongside them.
  notes: >-
    LOINC:1518-0 is the method-less mass-concentration code for the 2-h
    post-load sample, matching the mg/dL the ADA states its thresholds in. The
    molar sibling is LOINC:14995-5 (Glucose [Moles/volume] in Serum or Plasma
    --2 hours post 75 g glucose PO), bound on the Gestational_Diabetes_Mellitus
    entry for criteria stated in mmol/L. Only the 2-h sample is bound: the ADA
    criterion is on the 2-h value alone, and the fasting sample drawn at the
    start of the test is the measurement on the fasting plasma glucose row.
treatments:
- name: Metformin
  description: First-line oral medication that reduces hepatic glucose production and improves insulin sensitivity.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: metformin
      term:
        id: CHEBI:6801
        label: metformin
  target_mechanisms:
  - target: Hepatic Glucose Overproduction
    treatment_effect: INHIBITS
    description: >-
      Metformin's primary action is suppression of excessive hepatic
      gluconeogenesis, so it targets the hepatic-glucose-overproduction node
      directly (with a secondary insulin-sensitizing effect), lowering fasting
      glucose upstream of chronic hyperglycemia.
    evidence:
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        However, only metformin and rosiglitazone decreased TNF and PCK1 gene
        expression in the iHEP-MPS and improved insulin response
      explanation: >-
        Human, non-animal support for the hepatic arm of this edge: in an
        interconnected adipose-liver chip metformin lowered expression of the
        gluconeogenic gene PCK1 in the hepatocyte compartment and restored its
        insulin response, while dexamethasone in the same panel did not. Graded
        INDIRECT because gluconeogenic gene expression in a chip is a step removed
        from the fasting glucose lowering the edge describes in patients.
- name: Lifestyle Modification
  description: Diet and exercise interventions to reduce weight and improve metabolic health.
  treatment_term:
    preferred_term: Lifestyle Therapy
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  target_mechanisms:
  - target: Insulin Resistance
    treatment_effect: INHIBITS
    description: >-
      Weight loss and exercise improve peripheral insulin sensitivity, acting on
      the insulin-resistance node that is the primary upstream driver of type 2
      diabetes rather than merely lowering glucose downstream.
- name: GLP-1 Receptor Agonists
  description: Injectable medications that enhance insulin secretion and promote weight loss.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
  target_mechanisms:
  - target: Incretin Axis Dysfunction
    treatment_effect: INHIBITS
    description: >-
      GLP-1 receptor agonists restore the deficient incretin signal, correcting
      the incretin-axis-dysfunction node to enhance glucose-dependent insulin
      secretion (with weight loss and appetite effects), upstream of chronic
      hyperglycemia.
  - target: White Adipose Tissue Inflammation
    treatment_effect: INHIBITS
    description: >-
      Beyond restoring the incretin signal, GLP-1 receptor agonism acts on the
      adipocyte itself to reduce adipose inflammation, and the reduction in
      cytokine output is what improves insulin action in the connected tissue. The
      edge is drawn from a human non-animal system rather than from clinical trial
      data, because the tissue-attribution question it answers is confounded in
      patients and in rodents by the drug's effects on appetite and body weight.
    evidence:
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        While selective semaglutide treatment of the M1-iADIPO-MPS component was as
        effective as treatment of the entire M1-iADIPO-iHEP-MPS, selective
        semaglutide treatment of the iHEP-MPS component was largely ineffective
      explanation: >-
        The compartment-selective result that localizes the drug's action to adipose
        tissue: dosing the adipocyte compartment alone reproduced the whole-system
        benefit, dosing the hepatocyte compartment alone did not. Graded INDIRECT
        because the tissue attribution is established in a human model system rather
        than in patients.
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Studying the specific role of the WAT-liver axis in the semaglutide response
        using mouse models has been difficult due to the strong effects on feeding
        behavior and body weight
      explanation: >-
        States why this claim rests on a non-animal human system: the tissue-specific
        question is confounded in rodents by the drug's central effects, which is the
        case for curating a New Approach Methodology result as the primary support
        for a mechanism edge.
  evidence:
  - reference: PMID:38831203
    reference_title: "GLP1-GIP receptor co-agonists: a promising evolution in the treatment of type 2 diabetes."
    supports: SUPPORT
    snippet: "Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge."
    explanation: This establishes GLP-1/GIP receptor agonists as effective pharmacological strategies for T2D treatment.
- name: SGLT2 Inhibitors
  description: Oral medications that increase urinary glucose excretion.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Chronic Hyperglycemia
    treatment_effect: INHIBITS
    description: >-
      SGLT2 inhibitors act insulin-independently, increasing urinary glucose
      excretion to lower chronic hyperglycemia directly (with additional
      cardiorenal protection), targeting the shared hyperglycemia node that feeds
      the diabetic vascular-complication cascade.
- name: Insulin Therapy
  description: Required when beta cell function declines significantly.
  treatment_term:
    preferred_term: insulin therapy
    term:
      id: NCIT:C179441
      label: Injected Insulin Diabetes Therapy
  target_mechanisms:
  - target: Chronic Hyperglycemia
    treatment_effect: INHIBITS
    description: >-
      When beta-cell secretory capacity has declined enough that endogenous
      insulin is inadequate, exogenous insulin replaces the shortfall and lowers
      chronic hyperglycemia directly — a later-line glucose-node intervention
      once upstream insulin-sensitizing and incretin approaches no longer suffice.
- name: GLP-1/GIP Dual Agonists
  description: Tirzepatide and similar agents that activate both GLP-1 and GIP receptors for enhanced glycemic control and weight loss.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
  target_mechanisms:
  - target: Incretin Axis Dysfunction
    treatment_effect: INHIBITS
    description: >-
      Tirzepatide co-activates the GIP and GLP-1 receptors, correcting the
      incretin-axis-dysfunction node more completely than single GLP-1 agonism
      for enhanced glucose-dependent insulin secretion and weight loss.
  evidence:
  - reference: PMID:38831203
    reference_title: "GLP1-GIP receptor co-agonists: a promising evolution in the treatment of type 2 diabetes."
    supports: SUPPORT
    snippet: "Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity."
    explanation: This confirms tirzepatide as an authorized dual GLP-1/GIP agonist for T2D and obesity treatment.
discussions:
- discussion_id: t2d_pgsxc_reverse_causation
  prompt: >-
    Are the T2D PGS×context interactions driven by adverse exposures causally
    amplifying genetic risk, or are some "contexts" (notably circulating glucose)
    actually downstream readouts of incipient disease (reverse causation)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Insulin Resistance
  - environmental#Sedentary Lifestyle
  - environmental#High-Calorie Diet
  rationale: >-
    Population PGS×context analyses (Nagpal & Gibson 2026,
    PMID:42443528) are largely unable to establish the
    causality of specific contexts. For T2D this is especially acute for
    circulating glucose, a major amplifying "context" in the paper that is also
    nearly definitional of the disease and therefore substantially downstream of
    incipient hyperglycemia rather than a purely upstream driver. Behavioural
    contexts such as reduced physical activity and higher-calorie diet may also
    be partly responses to early metabolic decline. Distinguishing genuine
    amplification from reverse causation determines whether the modelled
    lifestyle interventions would actually reduce risk.
  proposed_experiments:
  - experiment_id: t2d_pgsxc_mr_direction
    name: Mendelian randomization of exposure-to-T2D direction across PGS strata
    description: >-
      Use bidirectional / multivariable Mendelian randomization to test whether
      each candidate context (glucose, omega-6 fatty acids, sex-adjusted
      testosterone, physical activity) causally affects T2D versus being a
      consequence of subclinical disease, and whether the causal effect estimate
      scales with polygenic liability as the amplification model predicts.
    decision_criterion: >-
      A context is retained as a causal amplifier if MR supports
      exposure-to-disease directionality and the exposure-attributable risk
      difference increases across increasing PGS strata; it is flagged as a
      reverse-causation suspect otherwise.
  - experiment_id: t2d_pgsxc_prospective_temporal
    name: Prospective incident-T2D analysis restricted to pre-diagnosis exposure windows
    description: >-
      Restrict exposures to measurements taken well before diagnosis and repeat
      the PGS×context liability-threshold modelling on incident cases only, to
      reduce the chance that exposure values (particularly glucose) reflect early
      disease rather than antecedent risk.
    decision_criterion: >-
      Amplification is supported if the PGS×context deviation from additivity
      persists when only pre-diagnosis exposure windows and incident cases are
      used.
- discussion_id: gap_t2d_beta_cell_dedifferentiation_reversibility
  prompt: >-
    Is beta-cell dedifferentiation and beta-to-alpha-like trajectory switching
    in type 2 diabetes a reversible driver of beta-cell failure, or mostly a
    late marker of intrapancreatic adiposity, inflammation, and metabolic stress?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Beta Cell Dysfunction
  - pathophysiology#Insulin Resistance
  - pathophysiology#Incretin Axis Dysfunction
  rationale: >-
    The entry links insulin resistance to beta-cell dysfunction, but recent
    human-islet work points to a specific beta-cell identity-loss axis involving
    intrapancreatic adipocytes, immune recruitment, alpha-like trajectories, and
    SMOC1. Resolving whether this state is causally reversible would determine
    whether beta-cell recovery should be modeled as a targetable mechanism
    rather than only as clinical glycemic improvement.
  proposed_experiments:
  - experiment_id: exp_t2d_islet_adipocyte_beta_dedifferentiation_rescue
    name: Human islet-adipocyte beta-cell dedifferentiation rescue assay
    description: >-
      Co-culture human pancreatic islets with intrapancreatic adipocytes and
      autologous immune cells in a microphysiological system; impose
      glucolipotoxic stress; perturb SMOC1 and incretin signaling; and test
      whether beta-cell identity, insulin secretion, and beta-to-alpha-like
      trajectory markers recover when the adipocyte-inflammatory niche is
      removed or therapeutically modulated.
    experiment_type:
      preferred_term: human islet microphysiological perturbation experiment
    model_systems:
    - name: Human islet-adipocyte-immune microphysiological system
      description: >-
        Human islet organ-on-chip or perifusion coculture pairing islets with
        adipocytes and immune cells to model the pancreatic fat-associated
        microenvironment implicated in beta-cell identity loss.
      experimental_model_type: ORGAN_ON_CHIP
      namo_type: namo:OrganOnChip
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      tissue_term:
        preferred_term: pancreas
        term:
          id: UBERON:0001264
          label: pancreas
      cell_types:
      - preferred_term: pancreatic beta cell
        term:
          id: CL:0000169
          label: type B pancreatic cell
      - preferred_term: pancreatic alpha cell
        term:
          id: CL:0000171
          label: pancreatic A cell
      - preferred_term: adipocyte
        term:
          id: CL:0000136
          label: adipocyte
      - preferred_term: T cell
        term:
          id: CL:0000084
          label: T cell
      cell_source: donor human islets with matched or donor-compatible pancreatic adipocytes and immune cells
      culture_system: perfused islet-on-chip or dynamic perifusion coculture
    perturbations:
    - name: Pancreatic adipocyte inflammatory niche
      target: pathophysiology#Beta Cell Dysfunction
      description: >-
        Adipocyte proximity plus inflammatory immune-cell recruitment used to
        model intrapancreatic fat-associated beta-cell stress.
      biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
    - name: SMOC1 gain and loss of function
      target: pathophysiology#Beta Cell Dysfunction
      description: >-
        Beta-cell SMOC1 overexpression and knockdown used to test whether the
        alpha-cell-associated trajectory gene is sufficient and necessary for
        beta-cell dedifferentiation.
      gene:
        preferred_term: SMOC1
        term:
          id: hgnc:20318
          label: SMOC1
    - name: GLP-1/GIP receptor agonist rescue
      target: pathophysiology#Incretin Axis Dysfunction
      description: >-
        Incretin receptor agonist exposure used to test whether clinically
        relevant treatment restores beta-cell function and identity under an
        adipocyte-inflammatory niche.
      treatment_term:
        preferred_term: targeted therapy
        term:
          id: NCIT:C93352
          label: Targeted Therapy
    readouts:
    - name: Glucose-stimulated insulin secretion
      target: pathophysiology#Beta Cell Dysfunction
      description: Dynamic insulin secretion normalized to beta-cell abundance.
      biological_processes:
      - preferred_term: insulin secretion
        term:
          id: GO:0030073
          label: insulin secretion
      assays:
      - preferred_term: glucose-stimulated insulin secretion assay
      direction: NEGATIVE
    - name: Beta-cell identity and alpha-like trajectory markers
      target: pathophysiology#Beta Cell Dysfunction
      description: >-
        Single-cell expression of INS, MAFA, INSM1, NPY, ALDH1A3, GCG, and
        SMOC1 interpreted as mature beta-cell identity versus dedifferentiated
        or alpha-like trajectory state.
      assays:
      - preferred_term: single-cell transcriptomic profiling
      - preferred_term: immunofluorescence assay
      direction: POSITIVE
    - name: Adipocyte-associated immune recruitment
      target: pathophysiology#Insulin Resistance
      description: T-cell proximity and inflammatory-cytokine readouts around adipocyte-islet interfaces.
      biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
      assays:
      - preferred_term: multiplex cytokine profiling
      - preferred_term: spatial transcriptomic profiling
      direction: POSITIVE
    controls:
    - name: Islet-only culture
      description: Donor-matched islets cultured without adipocytes or immune cells.
    - name: Non-diabetic donor islet-adipocyte coculture
      description: Parallel coculture built from non-diabetic donor material.
    - name: Vehicle-treated stressed coculture
      description: Stressed coculture receiving vehicle instead of incretin or SMOC1 perturbation.
    decision_criterion: >-
      Dedifferentiation is supported as a reversible causal mechanism if
      adipocyte-inflammatory challenge induces beta-cell identity loss and
      impaired insulin secretion, and if SMOC1 suppression or incretin rescue
      restores mature beta-cell markers and insulin secretion before cell-loss
      dominates.
    would_support:
    - pathophysiology#Beta Cell Dysfunction
    - pathophysiology#Incretin Axis Dysfunction
    evidence:
    - reference: PMID:40072535
      reference_title: "Intrapancreatic adipocytes and beta cell dedifferentiation in human type 2 diabetes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Higher pancreatic fat content was accompanied by increased beta cell dedifferentiation in the individuals with diabetes."
      explanation: >-
        Supports the human association between pancreatic adiposity and
        beta-cell dedifferentiation that this experiment tries to make causal
        and reversible.
    - reference: PMID:40072535
      reference_title: "Intrapancreatic adipocytes and beta cell dedifferentiation in human type 2 diabetes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the interactions among adipocytes, immune cells and beta cells in the pancreas microenvironment might contribute to beta cell failure and dedifferentiation"
      explanation: >-
        Motivates modeling the islet-adipocyte-immune microenvironment rather
        than studying isolated beta cells alone.
    - reference: PMID:41057332
      reference_title: "Human pancreatic α-cell heterogeneity and trajectory inference analyses reveal SMOC1 as a β-cell dedifferentiation gene."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Enhanced SMOC1 expression in β-cells decreased insulin expression and secretion and increased β-cell dedifferentiation markers."
      explanation: >-
        Provides a perturbational handle for testing whether the alpha-like
        trajectory is mechanistically upstream of beta-cell dysfunction.
- discussion_id: kgap_t2d_fatp1_insulin_stimulated_fatty_acid_uptake
  prompt: >-
    Inflamed adipose tissue loses the insulin-stimulated fatty acid uptake arm —
    tumor necrosis factor alpha suppresses it and lowers FATP1 protein — yet mice
    that lack that arm from birth are completely protected from diet-induced
    obesity and insulin desensitization. Is losing it a pathogenic feature of the
    insulin-resistant adipocyte, a protective adaptation, or an epiphenomenon?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
  - pathophysiology#White Adipose Tissue Inflammation
  rationale: >-
    The two curated results point in opposite directions and the entry does not
    resolve them, which is why no causal edge is drawn from the fatty acid uptake
    node into Insulin Resistance. On one side, tumor necrosis factor alpha — the
    cytokine the adipose inflammation node produces — inhibits both basal and
    insulin-stimulated long-chain fatty acid uptake in adipocytes and reduces FATP1
    and FATP4 protein, so the inflamed adipocyte demonstrably loses this arm
    alongside the GLUT4 arm. Read straightforwardly, that makes the loss part of
    the insulin-resistant phenotype. On the other side, FATP1-null mice, in which
    insulin-stimulated adipocyte fatty acid uptake is abolished outright, are
    completely protected from diet-induced obesity and insulin desensitization, and
    the authors propose FATP1 as an antidiabetic target. If the loss were simply
    pathogenic, that experiment should have gone the other way.
    Three readings survive the curated evidence and it does not discriminate
    between them. The loss may be a compensatory brake that limits adipocyte lipid
    loading, in which case it is protective and the cytokine effect is not the
    lesion. It may be pathogenic acutely but confounded in the knockout by lifelong
    adaptation and by the redistribution of postprandial lipid to the liver that
    the same paper reports — a redistribution that spares adipose at a hepatic cost
    this entry does not model. Or the timing may matter: a transient suppression
    during an established inflammatory state is not the same intervention as
    congenital absence.
    The discriminating experiment is unusually close to hand. Human adipose
    microphysiological systems already use insulin-stimulated fatty acid uptake as
    one of their three validated insulin-sensitivity assays, so the readout exists
    in a human non-animal system; what has not been reported is that assay run
    against an acute FATP1 knockdown, with and without the inflammatory stimulus.
  evidence:
  - reference: PMID:11970897
    reference_title: Insulin causes fatty acid transport protein translocation and
      enhanced fatty acid uptake in adipocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast, treatment with TNF-alpha inhibited basal and insulin-induced
      LCFA uptake and reduced FATP1 and -4 levels.
    explanation: >-
      The arm of the tension that makes loss of this transport step look like part
      of the inflamed, insulin-resistant adipocyte phenotype.
  - reference: PMID:16611988
    reference_title: FATP1 is an insulin-sensitive fatty acid transporter involved in
      diet-induced obesity.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      led to a complete protection from diet-induced obesity and insulin
      desensitization.
    explanation: >-
      Graded REFUTE against the reading that losing this arm drives insulin
      resistance: animals lacking it entirely are protected, not harmed. This is the
      result that keeps the node terminal rather than wired into Insulin Resistance.
  - reference: PMID:16611988
    reference_title: FATP1 is an insulin-sensitive fatty acid transporter involved in
      diet-induced obesity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      causing a redistribution of lipids from adipocyte tissue and muscle to the
      liver
    explanation: >-
      Names the confound in the knockout that a whole-animal protection result
      cannot separate from the adipocyte effect, and the hepatic cost that this
      entry, having no steatosis node, would otherwise not record at all.
  - reference: PMID:34761526
    reference_title: Probing Insulin Sensitivity with Metabolically Competent Human
      Stem Cell-Derived White Adipose Tissue Microphysiological Systems.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using three independent insulin sensitivity assays, i.e., glucose and fatty
      acid uptake and suppression of lipolysis, as the functional readouts new
      differentiation conditions yielding hormonally responsive iADIPO are derived.
    explanation: >-
      Establishes that the required human readout already exists and is validated,
      which is what makes this a reachable experiment rather than an open-ended call
      for human data.
  proposed_experiments:
  - experiment_id: exp_t2d_fatp1_knockdown_human_adipose_mps
    name: Acute FATP1 knockdown in the human iPSC adipose microphysiological system
      with and without proinflammatory macrophages
    description: >-
      Silence SLC27A1 in the iPSC-derived adipocyte compartment of the metabolically
      competent adipose microphysiological system, after the tissue has been shown
      insulin-responsive on all three validated assays, and run the same assays in
      four arms: knockdown or control, each with and without co-cultured M1
      macrophages. Because the knockdown is acute and applied to already-mature
      tissue, it separates the consequence of losing the transport arm from the
      lifelong adaptation that confounds the germline knockout, and because the chip
      has no liver compartment, the hepatic lipid redistribution seen in the mouse
      cannot rescue or mask the adipose readout.
    experiment_type:
      preferred_term: transporter knockdown in a human adipose microphysiological system
    perturbations:
    - name: Adipocyte SLC27A1 knockdown
      target: pathophysiology#Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
      description: >-
        RNA-interference or CRISPR-interference silencing of SLC27A1 in mature
        iPSC-derived adipocytes, applied after insulin responsiveness has been
        confirmed.
      genes:
      - preferred_term: SLC27A1
        term:
          id: hgnc:10995
          label: SLC27A1
    - name: Proinflammatory macrophage co-culture
      target: pathophysiology#White Adipose Tissue Inflammation
      description: >-
        Addition of M1-polarized iPSC-derived macrophages to impose the inflammatory
        state, with M0 macrophages as the polarization control.
    readouts:
    - name: Insulin-stimulated fatty acid uptake after knockdown
      target: pathophysiology#Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
      direction: DECREASED
      biological_processes:
      - preferred_term: Insulin-Stimulated Long-Chain Fatty Acid Import
        term:
          id: GO:0044539
          label: long-chain fatty acid import into cell
      interpretation: >-
        On-target confirmation, and the test of whether human FATP1 carries the
        hormone-responsive arm as mouse FATP1 does.
    - name: Insulin-stimulated glucose uptake and lipolysis suppression
      target: pathophysiology#Insulin Resistance
      direction: UNCHANGED
      biological_processes:
      - preferred_term: Insulin Receptor Signaling
        term:
          id: GO:0008286
          label: insulin receptor signaling pathway
      interpretation: >-
        The discriminating measurement. Direction is written as the compensatory
        reading — if losing the fatty acid arm is a brake rather than a lesion, the
        other two insulin-sensitivity assays should not deteriorate and may improve
        under inflammation.
    controls:
    - name: Non-targeting knockdown construct
      description: >-
        Scrambled construct on the same delivery schedule, controlling for the
        procedure rather than for the transporter.
    - name: M0 macrophage arm
      description: >-
        Non-activated macrophages in matched numbers, the polarization control that
        distinguishes an inflammatory effect from the presence of a second cell type.
    - name: Uninflamed knockdown arm
      description: >-
        Knockdown without macrophages, so the effect of losing the transport arm is
        measured against a healthy background as well as an inflamed one.
    decision_criterion: >-
      If knockdown worsens insulin-stimulated glucose uptake and lipolysis
      suppression, the loss of this arm is pathogenic and an edge into Insulin
      Resistance should be drawn. If knockdown leaves them unchanged or improves them
      under inflammation, the loss is a brake or an epiphenomenon, the node stays
      terminal, and the FATP1-null protection is explained without appealing to
      lifelong adaptation. A result that depends on whether macrophages are present
      supports the timing reading and neither of the other two.
    would_support:
    - pathophysiology#Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
    would_refute:
    - pathophysiology#Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
    supporting_outcome:
    - >-
      Confirmed SLC27A1 knockdown reduces insulin-stimulated fatty acid uptake and is
      accompanied by deterioration of insulin-stimulated glucose uptake and loss of
      lipolysis suppression, most markedly in the inflamed arm.
    refuting_outcome:
    - >-
      Confirmed knockdown reduces insulin-stimulated fatty acid uptake while glucose
      uptake and lipolysis suppression are unchanged or improved, reproducing in
      human tissue the protection seen in FATP1-null mice.
    - >-
      Knockdown fails to reduce insulin-stimulated fatty acid uptake in human
      adipocytes despite confirmed loss of transcript, which would mean the human
      hormone-responsive arm is not carried by FATP1 and the node needs rewriting
      rather than rewiring.
animal_models:
- name: FATP1 (Slc27a1) knockout mouse on high-fat diet
  species: Mouse
  genotype: Slc27a1 (FATP1) targeted deletion, homozygous null
  background: Diet-induced obesity
  publication: PMID:16611988
  genes:
  - preferred_term: SLC27A1
    term:
      id: hgnc:10995
      label: SLC27A1
  description: >-
    Germline loss of the insulin-responsive fatty acid transporter. Insulin-stimulated
    long-chain fatty acid uptake is abolished in adipocytes and greatly reduced in
    skeletal muscle while basal uptake is untouched, postprandial fatty acids are
    redistributed from adipose and muscle to the liver, and the animals are
    completely protected from diet-induced obesity and insulin desensitization. The
    protection is the reason this model is curated: it is the result that prevents
    the adipocyte fatty acid uptake node from being drawn as a straightforward
    driver of insulin resistance.
  modeled_mechanisms:
  - target: Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Removes the hormone-responsive arm of adipocyte fatty acid uptake
      genetically, and shows the loss is specific to the insulin-stimulated
      component rather than to fatty acid handling generally.
    limitations: >-
      A germline null cannot separate lifelong adaptation from the acute
      consequence of losing the transporter, which matters here because the
      whole-animal outcome is protection rather than harm. Lipid is redistributed
      to the liver rather than simply not absorbed, so adipose and muscle are
      spared at a hepatic cost this entry does not model. Murine, and no human
      SLC27A1 variant evidence is curated here.
    readouts:
    - name: Insulin-stimulated versus basal long-chain fatty acid uptake
      target: Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
      direction: ABOLISHED
      biological_processes:
      - preferred_term: Insulin-Stimulated Long-Chain Fatty Acid Import
        term:
          id: GO:0044539
          label: long-chain fatty acid import into cell
      interpretation: >-
        The basal-versus-stimulated contrast is the informative part: it shows the
        transporter carries the hormone-responsive arm specifically, which is what
        the node claims.
      evidence:
      - reference: PMID:16611988
        reference_title: FATP1 is an insulin-sensitive fatty acid transporter involved
          in diet-induced obesity.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          insulin-stimulated fatty acid uptake is completely abolished in FATP1-null
          adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals
          while basal LCFA uptake by both tissues was unaffected.
        explanation: >-
          The measurement that grounds this readout, including the unaffected basal
          arm that serves as the internal control.
    - name: Diet-induced obesity and insulin desensitization
      target: Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
      direction: ABOLISHED
      interpretation: >-
        The counterintuitive result. If loss of this arm were simply a pathogenic
        feature of the insulin-resistant adipocyte, animals lacking it should be
        worse; they are protected. This readout is what the attached knowledge-gap
        discussion turns on.
      evidence:
      - reference: PMID:16611988
        reference_title: FATP1 is an insulin-sensitive fatty acid transporter involved
          in diet-induced obesity.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          led to a complete protection from diet-induced obesity and insulin
          desensitization.
        explanation: >-
          Records the protective whole-animal outcome that bounds any causal reading
          of the adipocyte fatty acid uptake node.
    evidence:
    - reference: PMID:16611988
      reference_title: FATP1 is an insulin-sensitive fatty acid transporter involved
        in diet-induced obesity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This is the first in vivo evidence that insulin can regulate the uptake of
        LCFA by tissues via FATP1 activation and that FATPs determine the tissue
        distribution of dietary lipids.
      explanation: >-
        The authors' own statement of what the model establishes, which is the
        content of the node it is linked to.
experimental_models:
- name: Metabolically competent iPSC white adipose tissue microphysiological system (iADIPO-MPS)
  description: >-
    A New Approach Methodology built specifically because animal models and murine
    preadipocyte lines were poor substrates for type 2 diabetes drug discovery.
    Human pluripotent stem cells are differentiated into three-dimensional adipose
    tissue in a microphysiological system, and — the finding that makes the platform
    usable — previously published differentiation protocols were shown to yield
    tissue that is already insulin resistant, which cannot report a further loss of
    insulin sensitivity. Revised conditions plus chip optimization gave hormonally
    responsive tissue with larger, more unilocular lipid droplets and a dynamic range
    the authors report as competent against in vivo and ex vivo comparators, wide
    enough to identify both insulin sensitizers and desensitizers.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: white adipose tissue
    term:
      id: UBERON:0001347
      label: white adipose tissue
  cell_types:
  - preferred_term: iPSC-derived white adipocyte (iADIPO)
    term:
      id: CL:0000448
      label: white adipocyte
  conditions:
  - insulin-sensitive versus insulin-resistant human adipose tissue
  - insulin sensitizer and desensitizer pharmacology
  cell_source: Human pluripotent stem cell-derived white adipocytes
  culture_system: >-
    Three-dimensional adipose tissue in a microphysiological system, benchmarked
    against two-dimensional culture
  publication: PMID:34761526
  modeled_mechanisms:
  - target: Insulin Resistance
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Provides a calibrated human, non-animal assay for the adipose limb of this
      node, with the dynamic range needed to score a compound as sensitizing or
      desensitizing rather than merely to observe a resistant state.
    limitations: >-
      Adipose tissue alone, with no muscle, liver, islet or immune compartment, so
      it addresses one of the three tissues this node names. It is a healthy-tissue
      platform rather than a disease model: what it characterizes is a defect in
      prior differentiation protocols, not a defect in patients.
    readouts:
    - name: Insulin-stimulated glucose uptake, fatty acid uptake and lipolysis suppression
      target: Insulin Resistance
      direction: INCREASED
      biological_processes:
      - preferred_term: Insulin Receptor Signaling
        term:
          id: GO:0008286
          label: insulin receptor signaling pathway
      interpretation: >-
        Direction is relative to conventional two-dimensional culture, not to a
        disease state: the readouts record restored insulin responsiveness in the
        chip, which is the precondition for a later loss of responsiveness being
        interpretable as insulin resistance.
      evidence:
      - reference: PMID:34761526
        reference_title: Probing Insulin Sensitivity with Metabolically Competent Human
          Stem Cell-Derived White Adipose Tissue Microphysiological Systems.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Using three independent insulin sensitivity assays, i.e., glucose and fatty
          acid uptake and suppression of lipolysis, as the functional readouts new
          differentiation conditions yielding hormonally responsive iADIPO are
          derived.
        explanation: >-
          Names the three functional readouts and records that the differentiation
          conditions were selected against them rather than assumed to satisfy them.
    evidence:
    - reference: PMID:34761526
      reference_title: Probing Insulin Sensitivity with Metabolically Competent Human
        Stem Cell-Derived White Adipose Tissue Microphysiological Systems.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Surprisingly, previously reported WAT differentiation approaches create
        insulin resistant WAT ill-suited for type-2 diabetes mellitus drug discovery.
      explanation: >-
        The negative platform result that makes this model informative for the node,
        and a caution for any curator reading an adipose insulin-resistance claim out
        of a stem-cell adipose model that has not been characterized this way.
  - target: Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Insulin-stimulated fatty acid uptake is one of the three assays the platform
      is validated on, so the arm this node represents is directly measurable in
      human adipose tissue rather than only in mouse adipocytes.
    limitations: >-
      The assay measures net insulin-stimulated fatty acid uptake and does not
      attribute it to FATP1: no SLC27A1 knockdown, inhibition or expression
      measurement is reported in this system.
    readouts:
    - name: Insulin responsiveness of fatty acid uptake
      target: Insulin-Stimulated Adipocyte Fatty Acid Uptake via FATP1
      direction: INCREASED
      biological_processes:
      - preferred_term: Insulin-Stimulated Long-Chain Fatty Acid Import
        term:
          id: GO:0044539
          label: long-chain fatty acid import into cell
      interpretation: >-
        A roughly three- to sixfold insulin response in the optimized chip, which is
        the dynamic range a knockdown or cytokine experiment on this node would need
        in order to register.
      evidence:
      - reference: PMID:34761526
        reference_title: Probing Insulin Sensitivity with Metabolically Competent Human
          Stem Cell-Derived White Adipose Tissue Microphysiological Systems.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          increased insulin responsiveness of glucose uptake (≈2-3 fold), fatty acid
          uptake (≈3-6 fold), and ≈40% suppressing of stimulated lipolysis giving a
          dynamic range that is competent to current in vivo and ex vivo models
        explanation: >-
          Quantifies the insulin response of fatty acid uptake specifically, and the
          dynamic range a knockdown or cytokine experiment on this node would need in
          order to register.
    evidence:
    - reference: PMID:34761526
      reference_title: Probing Insulin Sensitivity with Metabolically Competent Human
        Stem Cell-Derived White Adipose Tissue Microphysiological Systems.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using three independent insulin sensitivity assays, i.e., glucose and fatty
        acid uptake and suppression of lipolysis, as the functional readouts new
        differentiation conditions yielding hormonally responsive iADIPO are derived.
      explanation: >-
        Establishes fatty acid uptake as a first-class validated readout of the
        platform, which is why this model is linked to the fatty acid arm and not
        only to the glucose arm.
- name: Isogenic iPSC macrophage-adipocyte microphysiological system (iMAC-iADIPO-MPS)
  description: >-
    Human adipose tissue inflammation reconstructed from isogenic induced
    pluripotent stem cells. Macrophages migrate into three-dimensional adipocyte
    clusters and form crown-like structures around damaged adipocytes, reproducing
    the defining histology of obese human adipose tissue, and the number of such
    structures increases with adipocyte age and with palmitic acid exposure so
    inflammatory severity is gradable. Polarization is the operative variable: M1
    but not M2 macrophages induce adipocyte insulin resistance and dysregulated
    lipolysis, and transcriptomic and cytokine profiling identify a reciprocal
    proinflammatory loop between the two cell types.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: white adipose tissue
    term:
      id: UBERON:0001347
      label: white adipose tissue
  cell_types:
  - preferred_term: iPSC-derived white adipocyte (iADIPO)
    term:
      id: CL:0000448
      label: white adipocyte
  - preferred_term: iPSC-derived macrophage (iMAC), M1 and M2 polarized
    term:
      id: CL:0000235
      label: macrophage
  conditions:
  - chronic white adipose tissue inflammation
  - M1 versus M2 macrophage polarization
  - palmitic acid lipotoxic exposure
  - adipocyte aging in culture
  cell_source: >-
    Isogenic human induced pluripotent stem cell-derived macrophages and adipocytes
  culture_system: >-
    Microphysiological system supporting three-dimensional adipocyte clusters with
    macrophage infiltration
  publication: PMID:37104853
  modeled_mechanisms:
  - target: White Adipose Tissue Inflammation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces this node in human cells down to its histologic signature, and
      supplies the polarization control the rodent literature reaches by cytokine
      neutralization: M2 macrophages present in the same numbers do not produce the
      phenotype.
    limitations: >-
      Inflammation is imposed by adding pre-polarized macrophages rather than
      arising from resident immune recruitment, so the model reproduces the inflamed
      state without reproducing how patients arrive at it. There is no vasculature,
      no lymphocyte compartment and no adipose expansion over time. Isogenic by
      design, so it cannot speak to donor variation in inflammatory susceptibility.
    readouts:
    - name: Crown-like structure formation around damaged adipocytes
      target: White Adipose Tissue Inflammation
      direction: INCREASED
      interpretation: >-
        The histologic hallmark named in this node, reproduced in a non-animal human
        system and gradable with exposure severity rather than scored present or
        absent.
      evidence:
      - reference: PMID:37104853
        reference_title: Human iPSC-Derived Proinflammatory Macrophages cause Insulin
          Resistance in an Isogenic White Adipose Tissue Microphysiological System.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          iMACs migrate toward and infiltrate into the 3D iADIPOs cluster to form
          crown-like structures (CLSs)-like morphology around damaged iADIPOs,
          recreating classic histological features of WAT inflammation seen in
          obesity.
        explanation: >-
          States the structural correspondence between the model and obese human
          adipose tissue.
    - name: Dysregulated adipocyte lipolysis under proinflammatory macrophage co-culture
      target: White Adipose Tissue Inflammation
      direction: INCREASED
      biological_processes:
      - preferred_term: Dysregulated Adipocyte Lipolysis
        term:
          id: GO:0019433
          label: triglyceride catabolic process
      interpretation: >-
        Dysregulated lipolysis is the step by which this node exports fatty acids to
        liver and muscle, and the M1-versus-M2 contrast shows it is specific to
        proinflammatory polarization.
      evidence:
      - reference: PMID:37104853
        reference_title: Human iPSC-Derived Proinflammatory Macrophages cause Insulin
          Resistance in an Isogenic White Adipose Tissue Microphysiological System.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          M1 (proinflammatory) but not M2 (tissue repair) iMACs induced insulin
          resistance and dysregulated lipolysis in iADIPOs.
        explanation: >-
          The polarization-controlled comparison that grounds this readout.
    evidence:
    - reference: PMID:37104853
      reference_title: Human iPSC-Derived Proinflammatory Macrophages cause Insulin
        Resistance in an Isogenic White Adipose Tissue Microphysiological System.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This iMAC-iADIPO-MPS thus successfully recreates pathological conditions of
        chronically inflamed human WAT
      explanation: >-
        The authors' summary of what the model reproduces, which is the content of
        this node.
- name: Isogenic iPSC adipocyte-hepatocyte-macrophage microphysiological system (M1-iADIPO-iHEP-MPS)
  description: >-
    The adipose compartment above fluidically connected to an induced pluripotent
    stem cell-derived hepatocyte compartment by circulating media, with all three
    cell types from one donor line. Because adipose expansion (set by the
    adipocyte-to-hepatocyte ratio) and adipose inflammation (set by macrophage
    polarization) are varied independently, the system separates two variables that
    animal models confound, and finds inflammation rather than expansion to be the
    driver of hepatic insulin resistance. It also carries the drug panel: metformin
    and rosiglitazone improve the hepatic compartment, dexamethasone does not, and
    the GLP-1 receptor agonist semaglutide works through the adipocyte compartment
    alone.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: white adipose tissue
    term:
      id: UBERON:0001347
      label: white adipose tissue
  cell_types:
  - preferred_term: iPSC-derived white adipocyte (iADIPO)
    term:
      id: CL:0000448
      label: white adipocyte
  - preferred_term: iPSC-derived hepatocyte (iHEP)
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: iPSC-derived proinflammatory (M1) macrophage (iMAC)
    term:
      id: CL:0000863
      label: M1 macrophage
  conditions:
  - white adipose tissue inflammation imposed by proinflammatory macrophages
  - graded adipose expansion set by adipocyte-to-hepatocyte ratio
  - hepatic insulin resistance and hepatic glucose production
  - pharmacological intervention with metformin, rosiglitazone, dexamethasone and semaglutide
  cell_source: >-
    Isogenic human induced pluripotent stem cell-derived white adipocytes,
    hepatocytes and macrophages from a single donor line
  culture_system: >-
    Interconnected two-chamber microphysiological system with circulating media at
    20 microlitres per hour, and a non-circulating flow-through configuration for
    compartment-selective drug exposure
  publication: PMID:39266553
  modeled_mechanisms:
  - target: Insulin Resistance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Produces insulin resistance across two connected human tissues from a single
      upstream manipulation, and adjudicates between adipose inflammation and
      adipose expansion as its cause. Expansion alone produced hepatic insulin
      resistance only at an extreme adipocyte-to-hepatocyte ratio; inflammation
      produced it readily.
    limitations: >-
      Two tissues only — no muscle and no islet, so neither the largest site of
      insulin-stimulated glucose disposal nor the beta-cell arm of this entry is
      represented. Insulin resistance is imposed over days by macrophage
      polarization rather than developing over years, and the iPSC-derived cells
      retain a fetal-like maturation state. There is no central control of feeding
      or body weight, which is precisely why the semaglutide result is interpretable
      here and confounded in rodents.
    readouts:
    - name: Insulin suppression of hepatic glucose production under adipose inflammation
      target: Insulin Resistance
      direction: DECREASED
      biological_processes:
      - preferred_term: Insulin Receptor Signaling
        term:
          id: GO:0008286
          label: insulin receptor signaling pathway
      interpretation: >-
        Measured in the hepatocyte compartment after manipulating only the adipose
        compartment, so it reads the transfer of insulin resistance between tissues
        rather than a cell-autonomous defect.
      evidence:
      - reference: PMID:39266553
        reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
          resistance in a human iPSC-based microphysiological system.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Analysis of insulin regulation of HGP after 48 h of iADIPO-iHEP-MPS
          interconnection showed insulin resistance only at the highest
          iADIPO-iHEP ratio of 30:1
        explanation: >-
          The expansion arm, recorded as the weaker of the two: mass alone produced
          hepatic insulin resistance only at an extreme ratio, which is the
          comparison that makes inflammation the primary driver.
    evidence:
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        macrophage-induced adipocyte inflammation causes lipid accumulation in
        hepatocytes and MPS-wide insulin resistance, corresponding to initiation of
        metabolic dysfunction-associated steatotic liver disease.
      explanation: >-
        States that the manipulation produces system-wide insulin resistance, which
        is the node this link asserts the model is informative for.
  - target: White Adipose Tissue Inflammation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Carries the same inflamed adipose compartment as the two-cell system, now with
      a downstream tissue attached, so the consequences of this node can be measured
      outside the tissue in which it occurs.
    limitations: >-
      Same limitation as the two-cell configuration: inflammation is imposed by
      adding pre-polarized macrophages rather than arising from recruitment, and the
      system is isogenic so donor variation is excluded by design.
    readouts:
    - name: Adipose tumor necrosis factor alpha secretion into shared circulation
      target: White Adipose Tissue Inflammation
      direction: INCREASED
      biological_processes:
      - preferred_term: Tumor Necrosis Factor Production
        term:
          id: GO:0032640
          label: tumor necrosis factor production
      interpretation: >-
        The cytokine this node produces, measured in the circulating media that
        reaches the second tissue, which is the mechanism by which a local adipose
        lesion becomes systemic.
      evidence:
      - reference: PMID:39266553
        reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
          resistance in a human iPSC-based microphysiological system.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          As expected, inflammation markers were increased in the M1-iADIPO-MPS,
          including gene expression of the proinflammatory cytokine TNF.
        explanation: >-
          Confirms the cytokine content of the inflamed adipose compartment in this
          configuration.
    evidence:
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Consistent with our previous results8,34 and human studies44, our model shows
        that M1-iMAC-mediated inflammation readily induces metabolic dysfunction,
        including increased WAT lipolysis and induction of systemic insulin
        resistance.
      explanation: >-
        The authors' own statement that the inflamed adipose compartment drives
        lipolysis and systemic insulin resistance, which is what this node asserts.
  - target: Hepatic Glucose Overproduction
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Hepatic glucose production and its suppression by insulin are primary endpoints
      of the chip, alongside PCK1 expression, so this node has a direct human
      non-animal assay. The chip also shows the node responding to metformin.
    limitations: >-
      Hepatocyte compartment only, with no pancreatic alpha cell and no counterregulatory
      hormone axis, so glucagon-driven hepatic glucose production is absent. Absolute
      production rates in an iPSC-derived hepatocyte compartment are not calibrated
      against human liver.
    readouts:
    - name: PCK1 expression and hepatic glucose production
      target: Hepatic Glucose Overproduction
      direction: INCREASED
      biological_processes:
      - preferred_term: Insulin Receptor Signaling
        term:
          id: GO:0008286
          label: insulin receptor signaling pathway
      interpretation: >-
        Rising gluconeogenic gene expression alongside loss of insulin suppression is
        the molecular and functional pair this node describes.
      evidence:
      - reference: PMID:39266553
        reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
          resistance in a human iPSC-based microphysiological system.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          whereas PCK1 gene expression was increased in the iHEP-MPS, suggesting
          activation of gluconeogenesis and development of insulin resistance
        explanation: >-
          The gluconeogenic readout in the hepatocyte compartment, which is the
          content of this node.
    evidence:
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We found that inclusion of iADIPOs worsened the metabolic alterations in
        iHEP-MPS, including higher HGP, earlier onset of insulin resistance, higher
        lipid levels and higher expression of genes reflecting inflammation,
        gluconeogenesis, lipogenesis and lipid transport
      explanation: >-
        Names hepatic glucose production as a measured endpoint that responds to the
        adipose manipulation, which is why this model is linked to the hepatic node.
  notes: >-
    Fully curated for its MASLD arm in the
    Metabolic_Dysfunction-Associated_Steatotic_Liver_Disease entry, where the same
    chip is linked to hepatocyte lipid overload and hepatic fatty acid uptake. The
    links here are the type 2 diabetes arm of the same system, and the two entries
    should be kept consistent if either is revised.
datasets:
# Type 2 Diabetes Gut Microbiome Studies

- accession: bioproject:PRJNA361402
  title: Metformin treatment effects on gut microbiome in T2D
  description: >-
    Shotgun metagenomics from 40 individuals in a randomized, placebo-controlled,
    double-blind type 2 diabetes study. Samples at baseline and after 4 months
    of metformin treatment to assess drug-microbiome interactions.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  data_type: WGS
  sample_types:
  - preferred_term: fecal sample
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  sample_count: 40
  conditions:
  - type 2 diabetes metformin treatment
  - type 2 diabetes placebo
  notes: Nature Communications 2022 - metformin-microbiome interactions

- accession: bioproject:PRJNA607849
  title: Gut microbiome in urban African type 2 diabetes
  description: >-
    16S rRNA gene sequencing of gut microbiome profiles from type 2 diabetes
    patients and controls in urban African populations, examining geographic
    and dietary influences on diabetes-associated microbiome signatures.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  sample_types:
  - preferred_term: fecal sample
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  conditions:
  - type 2 diabetes
  - healthy controls
  notes: Frontiers Cellular Infection Microbiology 2020

- accession: bioproject:PRJNA554535
  title: Gut microbiota in obese T2DM patients - Pakistani cohort
  description: >-
    16S rRNA sequencing of gut microbiota from 60 Pakistani adults comparing
    obese individuals with type 2 diabetes to healthy controls. V3-V4
    hypervariable regions sequenced.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  sample_types:
  - preferred_term: fecal sample
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  sample_count: 60
  conditions:
  - obese type 2 diabetes
  - healthy controls
  publication: PMID:31809500

- accession: bioproject:PRJNA422434
  title: Chinese MGWAS of gut microbiome in type 2 diabetes
  description: >-
    Landmark metagenome-wide association study (MGWAS) comparing gut microbial
    DNA from 345 Chinese individuals. Identified ~60,000 T2D-associated markers
    and established metagenomic linkage groups.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  data_type: WGS
  sample_types:
  - preferred_term: fecal sample
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  sample_count: 345
  conditions:
  - type 2 diabetes
  - healthy controls
  publication: PMID:23023125
  notes: Nature 2012 - first MGWAS of T2D, foundational study
computational_models:
- name: Topp Beta-Cell Mass / Insulin / Glucose Model
  description: >-
    Minimal three-ODE dynamical model of the glucose regulatory system (Topp et
    al. 2000): plasma glucose, plasma insulin, and beta-cell mass, with fast
    glucose/insulin dynamics on a slow beta-cell-mass manifold. For normal
    parameters the system is bistable - a physiological steady state (euglycemia)
    and a pathological, insulinopenic steady state (beta-cell-mass collapse and
    severe hyperglycemia) separated by a saddle. This makes it the reference
    dynamical substrate for type 2 diabetes: reduced insulin sensitivity,
    impaired secretion, or hepatic glucose overproduction decompensates the
    at-risk state to overt diabetes, and it is wired for perturbation analysis
    (see the model config sidecar) so that both risk genes and glucose-lowering
    treatments can be simulated as parameter changes.
  model_type: KINETIC
  repository_url: https://www.ebi.ac.uk/biomodels/BIOMD0000000341
  model_id: BIOMD0000000341
  model_software: COPASI
  model_format: SBML
  publication: PMID:11013117
  perturbations:
  - preferred_term: PPARG
    term:
      id: hgnc:9236
      label: PPARG
  - preferred_term: TCF7L2
    term:
      id: hgnc:11641
      label: TCF7L2
  - preferred_term: KCNJ11
    term:
      id: hgnc:6257
      label: KCNJ11
  - preferred_term: HNF1A
    term:
      id: hgnc:11621
      label: HNF1A
  - preferred_term: GCK
    term:
      id: hgnc:4195
      label: GCK
  - preferred_term: SLC5A2
    term:
      id: hgnc:11037
      label: SLC5A2
  modeled_mechanisms:
  - target: Insulin Resistance
    description: >-
      Reduced whole-body insulin sensitivity is the model parameter si; lowering
      si (or PPARG/thiazolidinedione perturbation of si) reproduces the
      insulin-resistance driver of type 2 diabetes.
  - target: Beta Cell Dysfunction
    description: >-
      Maximal per-beta-cell secretory capacity (sigma) and the beta-cell-mass
      state variable (B) capture secretory failure and glucotoxic beta-cell-mass
      loss; TCF7L2/KCNJ11/HNF1A perturbations act here.
  - target: Hepatic Glucose Overproduction
    description: >-
      Insulin-independent hepatic glucose output is the parameter R0, the target
      reduced by metformin in the simulated treatment scenarios.
  evidence:
  - reference: PMID:11013117
    reference_title: "A model of beta-cell mass, insulin, and glucose kinetics: pathways to diabetes."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      which consists of a system of three nonlinear ordinary differential
      equations, where glucose and insulin dynamics are fast relative to
      beta-cell mass dynamics
    explanation: >-
      Establishes the Topp model as a three-ODE dynamical model of beta-cell
      mass, insulin, and glucose - the substrate used here for simulating type 2
      diabetes mechanisms and treatments.
  findings:
  - statement: >-
      For normal parameters the model is bistable, with a physiological
      (euglycemic) and a pathological (hyperglycemic, beta-cell-collapse) steady
      state separated by a saddle - the dynamical basis for decompensation to
      overt diabetes.
    evidence:
    - reference: PMID:11013117
      reference_title: "A model of beta-cell mass, insulin, and glucose kinetics: pathways to diabetes."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        For normal parameter values, the model has two stable fixed points
        (representing physiological and pathological steady states), separated on
        a slow manifold by a saddle point
      explanation: >-
        Confirms the bistable, saddle-separated structure that lets an impairing
        perturbation tip the at-risk state to overt diabetes while a corrective
        treatment restores euglycemia.
  - statement: >-
      The model defines three routes to prolonged hyperglycemia (regulated
      hyperglycemia, saddle-node bifurcation, and dynamical hyperglycemia),
      mapping onto insulin-resistance, secretory-failure, and hepatic-output
      drivers of type 2 diabetes.
    evidence:
    - reference: PMID:11013117
      reference_title: "A model of beta-cell mass, insulin, and glucose kinetics: pathways to diabetes."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        The model predicts that there are three pathways in prolonged
        hyperglycemia
      explanation: >-
        Grounds the perturbation scenarios: each disease driver corresponds to
        one of the model's predicted pathways into sustained hyperglycemia.
  notes: >-
    Wired for dismech-perturb (models/BIOMD0000000341/config.yaml). The
    disease-severity dial is insulin sensitivity si (baseline_gfr 0.72 = healthy);
    the deposited initial state (G=250 mg/dL) sits on the model's unstable saddle,
    i.e. the metabolically at-risk / impaired-fasting tipping point.
    Glucose-lowering treatments are simulated as parameter changes: metformin
    (R0 down),
    thiazolidinedione (si up), SGLT2 inhibitor (Eg0 up, insulin-independent),
    sulfonylurea/GLP-1 (sigma up), insulin therapy (net insulin action up).
    Insulin-independent therapies (SGLT2 inhibition, metformin) and sensitizers
    (TZD) recompensate the model to euglycemia, whereas a pure secretagogue fails
    once beta-cell mass has collapsed - reproducing secondary secretagogue
    failure in advanced disease. Thresholds are calibrated to model steady-state
    values, not clinical reference ranges.
  variables:
  - name: Fasting_Plasma_Glucose
    dataset_identifier: G
    description: Plasma glucose concentration at steady state.
    unit: mg/dL
    mappings_list:
    - preferred_term: glucose
      term:
        id: CHEBI:17234
        label: glucose
    - preferred_term: Hyperglycemia
      description: >-
        Steady-state plasma glucose above the model's decompensation level. The
        pathological fixed point runs near 600 mg/dL; the physiological fixed
        point near 100 mg/dL. Bands are calibrated to model steady states, not
        clinical fasting-glucose cutoffs.
      term:
        id: HP:0003074
        label: Hyperglycemia
      threshold: 126
      threshold_direction: above
      severity_scale:
      - threshold: 126
        name: mild
      - threshold: 200
        name: moderate
      - threshold: 400
        name: severe
  - name: Plasma_Insulin
    dataset_identifier: I
    description: >-
      Plasma insulin concentration at steady state. Elevated in the compensated
      insulin-resistant regime and near-zero after glucotoxic beta-cell-mass
      collapse.
    unit: uU/mL
    mappings_list:
    - preferred_term: Hyperinsulinemia
      description: >-
        Compensatory hyperinsulinemia in the insulin-resistant regime before
        beta-cell-mass collapse. Threshold calibrated to model steady state
        (healthy ~10 uU/mL).
      term:
        id: HP:0000842
        label: Hyperinsulinemia
      threshold: 18
      threshold_direction: above
      severity_scale:
      - threshold: 18
        name: mild
      - threshold: 30
        name: moderate
      - threshold: 60
        name: severe
  - name: Beta_Cell_Mass
    dataset_identifier: B
    description: >-
      Functional beta-cell mass (slow state variable). Expands under mild
      hyperglycemia (compensation) and collapses toward zero under sustained
      extreme hyperglycemia (glucotoxicity), the positive-feedback route to
      insulinopenic diabetes.
    unit: mg
- name: Pancreatic Beta Cell Genome-Scale Metabolic Model
  description: >
    First comprehensive genome-scale metabolic reconstruction of human pancreatic
    beta cells,
    integrating transcriptomic data from healthy and type 2 diabetic islets. The model
    captures
    beta cell-specific metabolic pathways and identifies metabolic alterations in
    T2D including
    impaired glucose-stimulated insulin secretion mechanisms.
  model_type: GENOME_SCALE_METABOLIC
  publication: PMID:35276551
  notes: PLOS Computational Biology 2022 - context-specific reconstruction using RNA-seq from healthy and T2D beta cells
- name: Whole-Body Human Metabolic Model for Diabetes
  description: >
    Multi-organ metabolic model (Harvey/Harvetta) capturing inter-organ metabolic
    fluxes in
    diabetes. Models liver, muscle, adipose, and pancreas metabolism with tissue-specific
    constraints derived from omics data.
  model_type: GENOME_SCALE_METABOLIC
  base_model: Recon3D
  repository_url: https://www.vmh.life/
  publication: PMID:32472720
  notes: Predicts diabetes biomarkers and drug effects across multiple organs
- name: PBPK Model for GLP-1 Receptor Agonists
  description: >
    Physiologically-based pharmacokinetic model for GLP-1 receptor agonists (semaglutide,
    tirzepatide) in T2D patients. Incorporates drug absorption, distribution, and
    receptor
    binding kinetics to optimize dosing regimens.
  model_type: PHYSIOLOGICAL
  notes: Used in clinical trial design and dose optimization for incretin-based therapies
- name: AGORA2 Gut Microbiome Metabolic Models
  description: >
    Collection of 7,302 strain-resolved genome-scale metabolic reconstructions of
    human
    gut microorganisms. Enables personalized microbiome-host metabolic modeling by
    integrating with human metabolic models (Recon3D). Captures strain-level variation
    in SCFA production, bile acid metabolism, and drug biotransformation relevant
    to T2D.
  model_type: GENOME_SCALE_METABOLIC
  repository_url: https://www.vmh.life/
  publication: PMID:36543475
  notes: Nature Biotechnology 2022 - includes drug metabolism capabilities for 98 drugs; enables community-level FBA with MICOM
- name: MICOM Community Metabolic Model
  description: >
    Metagenome-scale modeling framework for simulating metabolic interactions in the
    gut microbiota. Integrates dietary constraints and taxon abundances from metagenomic
    data to predict personalized SCFA production, cross-feeding networks, and metabolic
    fluxes. Applied to T2D to study dysbiosis effects on butyrate production and
    glucose-insulin signaling.
  model_type: GENOME_SCALE_METABOLIC
  model_software: COBRApy
  publication: PMID:31964767
  notes: mSystems 2020 - enables personalized microbiome metabolic modeling from 16S/metagenomics data
references:
- reference: DOI:10.1007/s00592-024-02300-6
  title: 'GLP1-GIP receptor co-agonists: a promising evolution in the treatment of type 2 diabetes'
  findings: []
- reference: DOI:10.1007/s43152-024-00056-3
  title: Cellular and Molecular Mechanisms of Insulin Resistance
  findings: []
- reference: DOI:10.1038/s42255-024-01140-6
  title: Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology
  findings: []
- reference: DOI:10.3390/ijms25031504
  title: Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression
  findings: []
- reference: DOI:10.3390/ijms26031094
  title: 'Type 2 Diabetes Mellitus: New Pathogenetic Mechanisms, Treatment and the Most Important Complications'
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- reference: DOI:10.3390/nu17162708
  title: Type 2 Diabetes and the Multifaceted Gut-X Axes
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  title: 'Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.'
  findings: []
- reference: PMID:11970897
  title: Insulin causes fatty acid transport protein translocation and enhanced fatty acid uptake in adipocytes.
  findings: []
- reference: PMID:14679176
  title: Obesity is associated with macrophage accumulation in adipose tissue.
  findings: []
- reference: PMID:16611988
  title: FATP1 is an insulin-sensitive fatty acid transporter involved in diet-induced obesity.
  findings: []
- reference: PMID:21633179
  title: Inflammatory links between obesity and metabolic disease.
  findings: []
- reference: PMID:34761526
  title: Probing Insulin Sensitivity with Metabolically Competent Human Stem Cell-Derived White Adipose Tissue Microphysiological Systems.
  findings: []
- reference: PMID:37104853
  title: Human iPSC-Derived Proinflammatory Macrophages cause Insulin Resistance in an Isogenic White Adipose Tissue Microphysiological System.
  findings: []
- reference: PMID:39266553
  title: Adipocyte inflammation is the primary driver of hepatic insulin resistance in a human iPSC-based microphysiological system.
  findings: []

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References & Deep Research