graph LR
PDX1["PDX1"]
Exogenous_triggers_of_islet_autoimmunity_in_type_1_diabetes_pathways["Exogenous triggers of islet autoimmunity in type 1 diabetes pathways"]
Monogenic_Beta_Cell_Dysfunction["Monogenic Beta-Cell Dysfunction"]
SLC19A2["SLC19A2"]
HNF4A["HNF4A"]
Diabetogenic_pharmacotherapy_exposure["Diabetogenic pharmacotherapy exposure"]
Environmental_determinants_of_diabetes_susceptibility_and_progression["Environmental determinants of diabetes susceptibility and progression"]
HNF1B["HNF1B"]
ABCC8["ABCC8"]
Chronic_Hyperglycemia_shared_diabetic_complication_cascade["Chronic Hyperglycemia (shared diabetic complication cascade)"]
EIF2AK3["EIF2AK3"]
Early_dietary_exposures["Early dietary exposures"]
Immune_checkpoint_inhibitor_exposure["Immune checkpoint inhibitor exposure"]
NEUROD1["NEUROD1"]
Sedentary_lifestyle["Sedentary lifestyle"]
GCK["GCK"]
HNF1A["HNF1A"]
CEL["CEL"]
ALMS1["ALMS1"]
KCNJ11["KCNJ11"]
Obesogenic_environment["Obesogenic environment"]
WFS1["WFS1"]
RFX6["RFX6"]
CISD2["CISD2"]
High_calorie_diet["High-calorie diet"]
Viral_infection_exposure["Viral infection exposure"]
Monogenic_Beta_Cell_Dysfunction --> Chronic_Hyperglycemia_shared_diabetic_complication_cascade
Environmental_determinants_of_diabetes_susceptibility_and_progression --> Chronic_Hyperglycemia_shared_diabetic_complication_cascade
Exogenous_triggers_of_islet_autoimmunity_in_type_1_diabetes_pathways --> Chronic_Hyperglycemia_shared_diabetic_complication_cascade
Diabetogenic_pharmacotherapy_exposure --> Chronic_Hyperglycemia_shared_diabetic_complication_cascade
Immune_checkpoint_inhibitor_exposure --> Chronic_Hyperglycemia_shared_diabetic_complication_cascade
Viral_infection_exposure --> Chronic_Hyperglycemia_shared_diabetic_complication_cascade
Early_dietary_exposures --> Chronic_Hyperglycemia_shared_diabetic_complication_cascade
Sedentary_lifestyle --> Chronic_Hyperglycemia_shared_diabetic_complication_cascade
High_calorie_diet --> Chronic_Hyperglycemia_shared_diabetic_complication_cascade
Obesogenic_environment --> Chronic_Hyperglycemia_shared_diabetic_complication_cascade
KCNJ11 --> Monogenic_Beta_Cell_Dysfunction
HNF1A --> Monogenic_Beta_Cell_Dysfunction
HNF4A --> Monogenic_Beta_Cell_Dysfunction
HNF1B --> Monogenic_Beta_Cell_Dysfunction
ABCC8 --> Monogenic_Beta_Cell_Dysfunction
GCK --> Monogenic_Beta_Cell_Dysfunction
EIF2AK3 --> Monogenic_Beta_Cell_Dysfunction
WFS1 --> Monogenic_Beta_Cell_Dysfunction
ALMS1 --> Monogenic_Beta_Cell_Dysfunction
CISD2 --> Monogenic_Beta_Cell_Dysfunction
SLC19A2 --> Monogenic_Beta_Cell_Dysfunction
PDX1 --> Monogenic_Beta_Cell_Dysfunction
NEUROD1 --> Monogenic_Beta_Cell_Dysfunction
CEL --> Monogenic_Beta_Cell_Dysfunction
RFX6 --> Monogenic_Beta_Cell_Dysfunction
style PDX1 fill:#f3e8ff
style Exogenous_triggers_of_islet_autoimmunity_in_type_1_diabetes_pathways fill:#dcfce7
style Monogenic_Beta_Cell_Dysfunction fill:#dbeafe
style SLC19A2 fill:#f3e8ff
style HNF4A fill:#f3e8ff
style Diabetogenic_pharmacotherapy_exposure fill:#dcfce7
style Environmental_determinants_of_diabetes_susceptibility_and_progression fill:#dcfce7
style HNF1B fill:#f3e8ff
style ABCC8 fill:#f3e8ff
style Chronic_Hyperglycemia_shared_diabetic_complication_cascade fill:#dbeafe
style EIF2AK3 fill:#f3e8ff
style Early_dietary_exposures fill:#dcfce7
style Immune_checkpoint_inhibitor_exposure fill:#dcfce7
style NEUROD1 fill:#f3e8ff
style Sedentary_lifestyle fill:#dcfce7
style GCK fill:#f3e8ff
style HNF1A fill:#f3e8ff
style CEL fill:#f3e8ff
style ALMS1 fill:#f3e8ff
style KCNJ11 fill:#f3e8ff
style Obesogenic_environment fill:#dcfce7
style WFS1 fill:#f3e8ff
style RFX6 fill:#f3e8ff
style CISD2 fill:#f3e8ff
style High_calorie_diet fill:#dcfce7
style Viral_infection_exposure fill:#dcfce7
graph LR
Atherosclerosis["Atherosclerosis"]
Monocyte_Recruitment_and_Macrophage_Foam_Cell_Formation["Monocyte Recruitment and Macrophage Foam Cell Formation"]
Advanced_Atheroma_with_Necrotic_Core_and_Fibrous_Cap["Advanced Atheroma with Necrotic Core and Fibrous Cap"]
Thrombosis["Thrombosis"]
Endothelial_Dysfunction_and_Subendothelial_LDL_Retention["Endothelial Dysfunction and Subendothelial LDL Retention"]
Endothelial_Dysfunction_and_Subendothelial_LDL_Retention --> Monocyte_Recruitment_and_Macrophage_Foam_Cell_Formation
Monocyte_Recruitment_and_Macrophage_Foam_Cell_Formation --> Atherosclerosis
Atherosclerosis --> Advanced_Atheroma_with_Necrotic_Core_and_Fibrous_Cap
Advanced_Atheroma_with_Necrotic_Core_and_Fibrous_Cap --> Thrombosis
style Atherosclerosis fill:#dbeafe
style Monocyte_Recruitment_and_Macrophage_Foam_Cell_Formation fill:#dbeafe
style Advanced_Atheroma_with_Necrotic_Core_and_Fibrous_Cap fill:#dbeafe
style Thrombosis fill:#dbeafe
style Endothelial_Dysfunction_and_Subendothelial_LDL_Retention fill:#dbeafe
name: com_Diabetes_Mellitus__Peripheral_Artery_Disease
creation_date: "2026-08-19T00:00:00Z"
curation_status: CANDIDATE
notes: >-
Split out of `kb/disorders/Peripheral_Artery_Disease.yaml`'s `environmental:`
block (dismech#8551): that entry listed `Diabetes` as an "exposure" acting on
peripheral artery disease (PAD), but diabetes mellitus is a first-class
`Disease` entry in its own right (`kb/disorders/Diabetes_Mellitus.yaml`),
not something external to the organism the patient is exposed to. Modeling
the relationship here as a disease-disease comorbidity instead makes it
queryable and avoids a near-tautological "exposure" edge that ECTO/XCO can
never bind a term for. Directionality is A_BEFORE_B: diabetes is a
well-established antecedent risk state for atherosclerotic PAD via chronic
hyperglycemia-driven vascular injury (see the `diabetic_vascular_complications`
module), not the reverse. Evidence is carried over unchanged from the
original `environmental:` entry rather than dropped.
`disease_a` is deliberately the unstratified `Diabetes_Mellitus`
(MONDO:0005015) rather than `Type_2_Diabetes_Mellitus` (MONDO:0005148). In a
comorbidity entry `disease_a` is the claim, and the sole supporting citation
(PMID:23915883) pools "diabetes" across 34 community studies without
stratifying by type, so a T2DM-specific entry would be pitched above what its
evidence reaches. Retargeting rather than narrowing was chosen because no
T2DM-stratified PAD risk estimate was available to cite. If one is added
later, a separate `com_Type_2_Diabetes_Mellitus__Peripheral_Artery_Disease`
entry is the right home for it; this entry should stay at the level its
evidence supports.
disease_a:
slug: Diabetes_Mellitus
preferred_term: diabetes mellitus
term:
id: MONDO:0005015
label: diabetes mellitus
disease_b:
slug: Peripheral_Artery_Disease
preferred_term: peripheral arterial disease
term:
id: MONDO:0005386
label: peripheral arterial disease
directionality: A_BEFORE_B
effect_direction: RISK
hypotheses:
- description: >-
Chronic hyperglycemia in diabetes drives endothelial dysfunction, oxidative
stress, and accelerated atherosclerosis in peripheral arteries, making
diabetes a major risk factor for the development of peripheral artery
disease (the same final-common vascular-injury cascade captured by the
`diabetic_vascular_complications` module).
evidence:
- reference: PMID:23915883
reference_title: "Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "in LMIC, followed by diabetes (1·88"
explanation: >-
Meta-analysis across 34 community studies (112,027 participants) rating
15 risk factors for PAD; diabetes has the second-largest effect after
smoking. The quote begins mid-sentence and the fragment reads as though
it were about smoking in low- and middle-income countries: it is not.
`1·88` is the high-income meta-OR for diabetes, and the low/middle-income
estimate of 1.47 sits in the bracketed continuation that snippet
normalization strips, which is why the quote stops where it does. Carried
over unchanged from the original `Peripheral_Artery_Disease.yaml`
`environmental:` entry.
association_signals:
- source: LITERATURE
method: LITERATURE_ASSOCIATION
population: >-
Systematic review and meta-analysis of 34 community-based studies
(112,027 participants) estimating global peripheral artery disease
prevalence and its risk factors in 2000 and 2010, stratified into
high-income countries and low- and middle-income countries.
directionality: A_BEFORE_B
effect_direction: RISK
statistics:
metrics:
- metric_type: OR
metric_value: 1.88
metric_ci_lower: 1.66
metric_ci_upper: 2.14
notes: >-
Meta-OR for diabetes in high-income countries. The low- and
middle-income estimate from the same analysis is 1.47 (1.29-1.68); the
high-income value is recorded here because the two are not poolable and
a single metric slot cannot hold both. Diabetes ranks second of the 15
risk factors assessed, behind smoking.
evidence:
- reference: PMID:23915883
reference_title: "Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "in LMIC, followed by diabetes (1·88"
explanation: >-
The only exact-quotable fragment carrying the diabetes point estimate:
the effect sizes are printed inside a bracketed continuation that
snippet normalization strips, so the quote ends at `1·88`. That value is
the high-income meta-OR recorded in the metric above, not an LMIC
smoking figure, despite how the fragment reads in isolation.