Hyperinsulinemic Hypoglycemia: Disease-Characteristics Research Report

Scope. “Hyperinsulinemic hypoglycemia” (HH) is a biochemical-clinical state rather than one molecular disease. This report focuses on congenital hyperinsulinism (CHI)—the principal genetic category requested—while separating acquired perinatal-stress HI, syndromic HI, insulinoma, autoimmune HI, and drug-associated causes. Evidence is chiefly aggregated disease-level literature and registries, not individual EHR data. The leading authority is the international consensus published July 2023, DOI/URL: https://doi.org/10.1159/000531766. A major recent primary source is the Ukrainian national registry published 17 December 2024, DOI/URL: https://doi.org/10.3389/fendo.2024.1497579. PMIDs were not consistently exposed in the retrieved records; DOI links are therefore supplied rather than unverified PMID values.

1. Disease information

HH is inappropriate insulin action or failure to suppress insulin during hypoglycemia. Excess insulin simultaneously increases glucose utilization and prevents hepatic glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis; the resulting hypoketotic hypoglycemia deprives the brain of both glucose and alternative ketone fuel. CHI is the most common and most severe cause of persistent hypoglycemia in infancy and childhood. It is clinically, genetically, and histologically heterogeneous, encompassing focal, diffuse, and atypical/mosaic pancreatic disease. The 2024 Ukrainian study defines it directly as a condition “caused by inappropriate insulin secretion during hypoglycemia.” (globa2024congenitalhyperinsulinismin pages 1-2, leon2024internationalguidelinesfor pages 3-5)

Names: congenital hyperinsulinism; congenital hyperinsulinism of infancy; persistent hyperinsulinemic hypoglycemia of infancy; hyperinsulinemic hypoglycemia; familial hyperinsulinism; hyperinsulinism/hyperammonemia syndrome for the GLUD1 subtype. “Nesidioblastosis” is a historical/pathologic term and should not be used as a universal synonym.

Suggested identifiers: MONDO disease mapping should use the specific congenital hyperinsulinism/familial hyperinsulinism concept rather than generic hypoglycemia; OMIM uses separate phenotype entries by molecular subtype rather than one universal CHI entry. MeSH concepts include Hyperinsulinism and Hypoglycemia. ICD-10-CM commonly maps congenital hyperinsulinism to E16.1, Other hypoglycemia or E16.2, Hypoglycemia, unspecified, depending on local coding; ICD-11 should be mapped to the specific hyperinsulinism/hypoglycemia concept in the implementation used. Exact MONDO/Orphanet numeric identifiers should be database-validated before ingestion because HH and familial hyperinsulinism are represented at different granularity.

2. Etiology, risk, protective factors, and gene–environment interaction

Genetic causes

The most frequent causes are loss-of-function variants in ABCC8 and KCNJ11, encoding SUR1 and Kir6.2 of the pancreatic β-cell ATP-sensitive potassium channel. Other established or reported genes include GLUD1, GCK, HADH, HK1, SLC16A1, HNF4A, HNF1A, FOXA2, UCP2, PGM1, PMM2, ADK, CACNA1D, and additional rare/syndromic loci. The 2024 Ukrainian registry states that variants in more than 30 genes can cause CHI, although gene lists and strength of evidence vary across panels. (globa2024congenitalhyperinsulinismin pages 1-2, leon2024internationalguidelinesfor pages 5-6, maines2023anarrativereview pages 1-2)

Table: This table summarizes the main genetic and acquired etiologies of hyperinsulinemic hypoglycemia/congenital hyperinsulinism, highlighting distinguishing biomarkers, histologic patterns, inheritance, and immediate management implications. It is designed as a concise knowledge-base artifact for genotype-phenotype-treatment mapping.

Inheritance: biallelic recessive or monoallelic dominant ABCC8/KCNJ11 variants cause diffuse HI. Focal HI is a two-hit, parent-of-origin disorder: a paternally inherited recessive ABCC8/KCNJ11 variant is unmasked by somatic paternal isodisomy/loss of the maternal 11p15 region in a pancreatic clone. A single paternal KATP variant predicts focal disease with sensitivity around 97% and positive predictive value up to 94%. Somatic ABCC8 or GCK variants and inappropriate HK1 expression occur in LINE/mosaic disease. (leon2024internationalguidelinesfor pages 5-6)

Syndromic/chromosomal causes: Beckwith–Wiedemann spectrum/11p15 imprinting defects, Kabuki syndrome (KMT2D/KDM6A), Sotos syndrome, Turner syndrome, Costello syndrome, Simpson–Golabi–Behmel syndrome, trisomy 13, congenital disorders of glycosylation, and rare chromosomal deletions/duplications are reported. A December 2024 human case linked mosaic chromosome 7 duplication containing GCK to adult nesidioblastosis; this remains a novel case-level association rather than an established recurrent cause. (leon2024internationalguidelinesfor pages 19-20, leon2024internationalguidelinesfor pages 17-19, shoji2024casereportduplication pages 8-8, maines2023anarrativereview pages 1-2)

Acquired and environmental/perinatal causes

Maternal diabetes, birth asphyxia/hypoxia, intrauterine growth restriction, perinatal stress, maternal drugs, and high intrapartum maternal glucose infusion can produce perinatal-stress HI. The proposed interaction is hypoxia-mediated lowering of the β-cell glucose threshold for insulin suppression. PSHI usually presents in the first 24 hours and resolves in 10–14 days; a severe form persists beyond two weeks. These exposures are triggers for acquired HI, not established causes of germline CHI. (leon2024internationalguidelinesfor pages 3-5)

No reproducible lifestyle, toxin, smoking, alcohol, pollution, occupational, or infectious cause is established for genetic CHI. Rare autoimmune insulin syndromes or postinfectious associations belong in the broader HH differential, not the congenital genetic entry. No validated protective allele is known. Practical “protective factors” are therefore prevention of fasting, rapid glucose rescue, avoidance of genotype-specific triggers—protein/leucine in GLUD1/HADH disease and anaerobic exercise in SLC16A1 disease—and early specialist treatment. (leon2024internationalguidelinesfor pages 29-29, leon2024internationalguidelinesfor pages 5-6)

3. Phenotypes

• Biochemical hypoglycemia—usually neonatal or infantile, episodic/recurrent, and potentially severe; suggested HPO: Hypoglycemia (HP:0001943), Hyperinsulinemia (HP:0000842). Insulin action suppresses β-hydroxybutyrate and free fatty acids. Severity ranges from spontaneous remission to glucose requirements of 20–30 mg/kg/min. (leon2024internationalguidelinesfor pages 25-29, leon2024internationalguidelinesfor pages 6-8)
• Neuroglycopenic/autonomic manifestations—jitteriness, lethargy, poor feeding, apnea/cyanosis, altered consciousness, seizures, and coma; suggested HPO: neonatal hypoglycemia, seizures, lethargy, feeding difficulties, apnea, coma. Onset is commonly neonatal, but milder genetic disease can appear later. Frequency is cohort-dependent.
• Neurologic sequelae—epilepsy, infantile spasms, microcephaly, cerebral palsy, motor/speech delay, cognitive impairment, and attention, memory, visual, and sensorimotor deficits; suggested HPO: Seizure (HP:0001250), Global developmental delay (HP:0001263), Microcephaly (HP:0000252), Abnormality of movement, speech delay, intellectual disability. Transient HI still carries reported neurodevelopmental-deficit rates of 26–44%. In the 2024 Ukrainian persistent-CHI cohort, 11/22 (50%) had epilepsy and/or psychomotor retardation. GLUD1-HI has particularly high seizure/neurodevelopmental burden. (globa2024congenitalhyperinsulinismin pages 3-5, leon2024internationalguidelinesfor pages 13-15)
• Feeding dysfunction—vomiting, impaired suck/swallow, food aversion, tube dependence, and reflux; suggested HPO: feeding difficulties, dysphagia, vomiting. Feeding problems were reported in 68.6%, often reflecting disease plus medications, high-carbohydrate feeds, IV glucose, and tube feeding. (leon2024internationalguidelinesfor pages 13-15)
• Gene-specific phenotypes: moderate hyperammonemia and protein-induced hypoglycemia in GLUD1-HI; C4-OH acylcarnitine/urinary 3-hydroxyglutarate abnormalities in HADH-HI; exercise-induced episodes in SLC16A1-HI; occasionally ketotic fasting hypoglycemia in GCK-HI. (leon2024internationalguidelinesfor pages 5-6)

Quality of life is impaired by unpredictable episodes, sleep/feeding schedules, intensive glucose monitoring, medication toxicity, pump/tube failure, developmental disability, and caregiver anxiety. The guideline notes that caregiver worry affects physical and mental health and recommends psychological and patient-organization support. Disease-specific EQ-5D/SF-36 population norms were not identified. (leon2024internationalguidelinesfor pages 13-15)

4. Genetic and molecular information

Variant classes include missense, nonsense, frameshift, splice, exon-level copy-number, deep-intronic/regulatory, imprinting, and somatic variants. Germline variants predominate in inherited diffuse disease; focal lesions combine a germline paternal allele with a pancreatic somatic 11p15 event. LINE/mosaic disease can arise from somatic ABCC8/GCK variants. Variant classification must follow ACMG/AMP criteria with ClinVar/ClinGen review and segregation/functional evidence; a gene finding should not automatically be called pathogenic. Population allele frequency should be checked variant-by-variant in gnomAD, because no single useful “CHI allele frequency” exists.

The Ukrainian cohort provides current real-world data: a molecular diagnosis was obtained in 27/40 (67.5%); yield was 19/22 (86.4%) in persistent versus 8/18 (44.4%) in early-remission disease. Causes were ABCC8 (n=20), KCNJ11 (n=2), INSR (n=2), KMT2D (n=1), and 11p15 imprinting defects (n=2); one ABCC8 VUS was not counted as causal. (globa2024congenitalhyperinsulinismin pages 1-2, globa2024congenitalhyperinsulinismin pages 3-5)

No robust, generally accepted modifier-gene set, protective variant, anticipation phenomenon, or recurrent germline mosaicism rate is established. Consanguinity increases the probability of recessive diffuse CHI; founder variants explain high rates in some endogamous populations, but carrier frequencies are population- and variant-specific.

Epigenetics: 11p15 imprinting is causal in focal HI and BWS. In Kabuki syndrome, KMT2D and KDM6A alter H3K4/H3K27 chromatin regulation and may disturb β-cell differentiation and insulin-secretory gene expression, but the review explicitly concludes that the pathway “remains to be fully clarified.” Kabuki-associated HH occurs in approximately 0.3–4%, more strongly with KDM6A-Kabuki than KMT2D-Kabuki. (leon2024internationalguidelinesfor pages 11-13, maines2023anarrativereview pages 1-2)

5. Environmental information

Genetic CHI is not attributable to diet, obesity, smoking, alcohol, radiation, pollution, or infection. Feeding composition and physical activity can modify episode occurrence after disease exists: protein/leucine can trigger GLUD1, HADH, and sometimes KATP-HI; anaerobic exercise can trigger SLC16A1-HI; fasting is a general precipitant. Perinatal hypoxia, IUGR, maternal diabetes, and delivery-related glucose exposure cause acquired PSHI. Vaccines and antimicrobial measures are not etiologic or preventive interventions for CHI. (leon2024internationalguidelinesfor pages 3-5, leon2024internationalguidelinesfor pages 5-6)

6. Mechanism and pathophysiology

Canonical causal chain: glucose enters the β cell → metabolism raises ATP/ADP → KATP channels close → membrane depolarization → voltage-gated Ca²⁺ entry → insulin-granule exocytosis. ABCC8/KCNJ11 loss of function keeps the membrane depolarized despite low glucose, causing unsuppressed insulin. Diazoxide works upstream by opening functional KATP channels; it therefore often fails when the channel is severely defective. (leon2024internationalguidelinesfor pages 25-29, leon2024internationalguidelinesfor pages 8-10)

Downstream chain: excess insulin → increased peripheral glucose uptake plus suppressed hepatic glucose production, lipolysis, and ketogenesis → low glucose, free fatty acids, and β-hydroxybutyrate → cerebral fuel failure → seizures and hypoglycemic brain injury. Relevant GO suggestions include regulation of insulin secretion (GO:0050796), insulin secretion (GO:0030073), membrane depolarization during action potential, calcium-ion transmembrane transport, glucose homeostasis (GO:0042593), fatty-acid oxidation, and ketone-body biosynthesis.

Other upstream mechanisms include altered nutrient sensing (activating GCK), deregulated amino-acid oxidation (GLUD1), fatty-acid oxidation/SCHAD–GDH coupling (HADH), inappropriate low-Km hexokinase expression (HK1), pyruvate transport into β cells (SLC16A1), transcription-factor defects, and chromatin/imprinting abnormalities. Immune activation is not a core mechanism in genetic CHI. Tissue injury is secondary: repeated neuroglycopenia injures the developing brain, while near-total pancreatectomy can cause endocrine and exocrine insufficiency.

Cell types: pancreatic β cell—CL:0000169—is primary; α/δ cells and acinar/ductal structures are relevant to histology and surgery. Neurons, astrocytes, and oligodendroglial lineages are downstream targets of fuel deprivation. Subcellular terms: plasma membrane, KATP channel complex, voltage-gated calcium-channel complex, insulin secretory granule, cytosol, mitochondrion, and nucleus/chromatin.

Current single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, and multi-omic signatures are not sufficiently standardized for clinical annotation. No omics assay is currently a routine diagnostic replacement for biochemical and DNA testing.

7. Anatomical structures affected

The primary organ is the pancreas—suggested UBERON pancreas (UBERON:0001264)—specifically islets of Langerhans and β cells. Focal lesions are usually unencapsulated, approximately 0.5–1 cm, with increased endocrine-cell mass; diffuse disease displays β-cell nuclear enlargement throughout the pancreas; atypical disease has regional/mosaic abnormalities. There is no lateralization. (leon2024internationalguidelinesfor pages 10-11)

The main secondary organ is the brain, particularly the developing cerebral cortex, hippocampal/visual pathways, and white matter affected by recurrent hypoglycemia. Liver, skeletal muscle, and adipose tissue are metabolic effectors of insulin. After large pancreatic resection, both endocrine pancreas and exocrine acinar tissue are affected.

8. Temporal development

Severe KATP-CHI commonly begins in the first days of life, acutely or with recurrent episodes; genetic forms can occasionally present later. PSHI presents within 24 hours and usually resolves by days 10–14. “Early-remission” CHI in the Ukrainian study was defined by remission by age two years and no hypoglycemia for 24 months. Persistent CHI can remain lifelong, although ABCC8, KCNJ11, HNF1A, and HNF4A disease may attenuate with age. Later-onset HI after age two years requires insulinoma evaluation. (globa2024congenitalhyperinsulinismin pages 1-2, leon2024internationalguidelinesfor pages 13-15, leon2024internationalguidelinesfor pages 3-5)

The critical intervention window is immediate: the neonatal brain has high glucose requirements and limited alternative fuel because insulin suppresses ketogenesis. Prompt recognition, normal-range glucose restoration, and avoidance of recurrent episodes are more important than waiting for molecular confirmation.

9. Inheritance and population

Non-syndromic genetic HI is estimated at 1 per 25,000–45,000 births; a UK minimum estimate cited by recent literature is 1 per 28,389. PSHI is much more common, approximately 1 per 1,200–1,700 newborns, while prolonged severe PSHI occurs in about 1 per 12,000–13,600. (leon2024internationalguidelinesfor pages 3-5, globa2024congenitalhyperinsulinismin pages 10-11)

No consistent sex bias is established. In the Ukrainian registry, sex distributions differed numerically but not significantly: persistent CHI 36.4% male/63.6% female and early-remission CHI 55.6% male/44.4% female. Median diagnosis was 3.5 versus 17 days, respectively. (globa2024congenitalhyperinsulinismin pages 3-5)

Autosomal recessive, autosomal dominant, X-linked dominant syndromic, imprinting/parent-of-origin, and somatic mosaic mechanisms all occur. Penetrance and expressivity are gene- and variant-dependent; dominant KATP disease can be variably expressed. Genetic anticipation is not characteristic. Founder effects and consanguinity can markedly increase incidence in particular populations, but global carrier-frequency estimates are inappropriate.

10. Diagnostics

Biochemical diagnosis

Obtain a critical sample during plasma glucose <50 mg/dL (2.8 mmol/L). Evidence of excessive insulin action includes β-hydroxybutyrate <1.8 mmol/L, free fatty acids <1.7 mmol/L, glucose infusion requirement >8 mg/kg/min in neonates, and a glucagon-associated glucose rise ≥30 mg/dL. Inappropriately detectable insulin >1.25 μU/mL and C-peptide >0.5 ng/mL support diagnosis, but suppressed ketones/FFA and glucagon response are more sensitive than insulin concentration alone. Measure glucose, insulin, C-peptide, BOHB, FFA, cortisol, growth hormone, lactate, ammonia, acylcarnitines, and urine organic acids as clinically indicated. (leon2024internationalguidelinesfor pages 25-29, leon2024internationalguidelinesfor pages 3-5)

Infants tested before 72 hours during transitional hypoglycemia should be retested after 72 hours if hypoglycemia persists. Provocative glucose/leucine/protein tests are not needed to establish HI but can subtype selected disease. (leon2024internationalguidelinesfor pages 3-5)

Genetic and imaging algorithm

1. Exclude likely acquired PSHI and assess syndromic features.
2. In diazoxide-unresponsive disease, perform rapid ABCC8/KCNJ11 sequencing with parental testing.
3. If negative or disease persists beyond three months, use a comprehensive HI panel or WES/WGS with copy-number and non-coding coverage.
4. Add 11p15 methylation testing when BWS is suspected. WES can miss deep-intronic/regulatory variants; Sanger can miss CNVs. WGS is useful when panel/exome testing is negative but is not universally first-line. CMA is appropriate for syndromic/CNV suspicion; routine karyotype, FISH, mitochondrial DNA, and repeat-expansion testing are not indicated without phenotype-specific reasons. (leon2024internationalguidelinesfor pages 5-6)
5. For diazoxide-unresponsive cases without genetic proof of diffuse disease, perform 18F-DOPA PET/CT or PET/MRI. Across 286 histologically assessed cases, sensitivity was 75–100%, specificity 88–100%, and localization accuracy over 90% when a lesion was detected. Conventional ultrasound/CT/MRI does not reliably detect congenital focal lesions. (leon2024internationalguidelinesfor pages 6-8)

Differentials include transitional/PSHI, cortisol or growth-hormone deficiency, fatty-acid oxidation disorders, glycogen-storage disease, congenital glycosylation disorders, exogenous insulin or sulfonylurea exposure, insulinoma—especially after age two—insulin autoimmune syndrome, and non-insulin-mediated hypoglycemia. (leon2024internationalguidelinesfor pages 3-5)

No universal population newborn screen exists. Bedside glucose surveillance is indicated in high-risk newborns. Cascade testing, prenatal diagnosis, or preimplantation genetic testing is feasible once a familial pathogenic variant is known.

11. Outcome and prognosis

Survival is generally good with effective treatment; meaningful 5- or 10-year disease-specific survival statistics are not established because morbidity, not mortality, dominates. Untreated severe episodes can cause coma, death, epilepsy, cerebral palsy, and permanent cognitive/visual/motor disability.

Outcome depends on diagnostic delay, depth/duration and recurrence of hypoglycemia, genotype, diazoxide responsiveness, focal versus diffuse histology, and treatment access. More than 65.2% of patients required regimen adjustment in the first three months after discharge. Formal developmental surveillance and early intervention are strongly recommended. (leon2024internationalguidelinesfor pages 13-15)

Focal resection is curative in over 95% in expert series and generally avoids later diabetes if only the lesion is removed. After 95–98% pancreatectomy for diffuse disease, hypoglycemia recurs in 50–60%; approximately 25% have diabetes immediately after surgery and cumulative diabetes can reach 91% by age 14. Resection over 50% also risks exocrine pancreatic insufficiency. (leon2024internationalguidelinesfor pages 11-13)

The 2024 Ukrainian cohort provides contemporary implementation data: 14/19 operated patients had focal disease, and all 14 were cured; relapse occurred in three patients with diffuse or atypical disease. (globa2024congenitalhyperinsulinismin pages 1-2, globa2024congenitalhyperinsulinismin pages 3-5)

12. Treatment

Acute and chronic algorithm

• IV dextrose: 200 mg/kg—2 mL/kg of D10—then generally ≥8 mg/kg/min, escalating rapidly when necessary, to maintain plasma glucose 70–100 mg/dL. NCIt suggestions: dextrose, glucose infusion. (leon2024internationalguidelinesfor pages 6-8)
• Glucagon rescue: 0.5–1 mg or 20–30 μg/kg IM/SC when IV access is delayed. Continuous IV glucagon 2.5–20 μg/kg/h reduces dextrose/fluid requirements; vomiting 13%, rash 2%, respiratory distress 19%, and rare necrolytic migratory erythema are reported. (leon2024internationalguidelinesfor pages 6-8)
• Diazoxide: first-line established therapy, 5–15 mg/kg/day orally in children. Add chlorothiazide 10 mg/kg/day or hydrochlorothiazide 1–2 mg/kg/day to limit fluid retention. Confirm response by a safety fast showing BOHB >1.8 mmol/L before glucose falls below 50–60 mg/dL. Stop if maximal therapy fails after five days. Adverse effects include hypertrichosis 84.1%, facial coarsening 24%, pulmonary hypertension 2.4%, neutropenia 15.6%, thrombocytopenia 4.7%, hyperuricemia 5.0%, and serious events requiring discontinuation 9.7%. Obtain an echocardiogram about one week after initiation and periodic CBC/uric acid. NCIt: diazoxide. (leon2024internationalguidelinesfor pages 8-10)
• Somatostatin analogues: second-line off-label treatment. Octreotide starts at 5–10 μg/kg/day, maximum around 20 μg/kg/day; tachyphylaxis and necrotizing enterocolitis, especially in unstable premature infants, are major concerns. Lanreotide commonly starts at 30–60 mg monthly. Monitor growth, gallbladder ultrasound, liver enzymes, thyroid function, and growth factors. NCIt: octreotide; lanreotide. (leon2024internationalguidelinesfor pages 8-10, leon2024internationalguidelinesfor pages 10-11)
• Nutrition/support: frequent feeds, carbohydrate-enriched formula, and continuous gastric dextrose up to 20% via NG/gastrostomy when needed. Uncooked cornstarch 1–2 g/kg may help after nine months, but controlled evidence is lacking. Feeding, speech, occupational, physical, and neurodevelopmental therapy are integral. (leon2024internationalguidelinesfor pages 10-11)
• Avoid routine nifedipine, sirolimus, and glucocorticoids. The international panel found inadequate efficacy for nifedipine and serious infection, diabetes, hepatitis, and pancreatic-insufficiency concerns for sirolimus; use only in approved research protocols, apart from rare genotype-specific considerations such as CACNA1D. (leon2024internationalguidelinesfor pages 10-11)

Surgery

Resect localized focal disease in an expert center with intraoperative pathology. For medically uncontrollable diffuse disease, 90–98% pancreatectomy balances hypoglycemia control against diabetes risk. Monitor postoperative glucose, HbA1c every 6–12 months, fecal elastase, fat-soluble vitamins, and need for insulin or pancreatic enzymes. (leon2024internationalguidelinesfor pages 11-13, leon2024internationalguidelinesfor pages 10-11)

Real-world implementation and experimental therapy

A 2024 four-patient KATP-CHI series used IV glucagon, pump-delivered octreotide, later monthly long-acting somatostatin analogues, CGM, specialized feeds, and developmental follow-up. All octreotide-treated patients developed biliary debris, resolving with ursodeoxycholic acid; catheter obstruction and bloodstream infection complicated IV glucagon. This is useful implementation evidence but too small for response-rate inference. (takasawa2024clinicalmanagementof pages 10-13)

• RZ358/ersodetug, an allosteric insulin-receptor antibody, completed a 23-participant phase 2 study, NCT04538989; results were first posted 28 May 2025. A 56-participant phase 3 trial, NCT06208215, is active/not recruiting and uses CGM hypoglycemia endpoints. It remains investigational. (NCT04538989 chunk 1, NCT06208215 chunk 2)
• Dasiglucagon, a soluble glucagon analogue delivered by continuous SC infusion, completed a 32-participant phase 3 trial, NCT03777176; a 42-participant long-term extension, NCT03941236, is active/not recruiting through an estimated 2026 completion. It remains investigational for CHI. (NCT03941236 chunk 1, NCT03777176 chunk 1, NCT03777176 chunk 2)
• Efpegerglucagon/HM15136, weekly SC therapy, is in a 16-participant phase 2 study, NCT04732416, active/not recruiting with estimated completion in 2027. (NCT04732416 chunk 1)
• Continuous SC glucagon was tested in five infants in NCT02937558; the very small trial precludes broad conclusions. (NCT02937558 chunk 1)

No approved gene, RNA, or cell therapy is available. Genotype-guided focal-lesion surgery is currently the strongest precision-medicine implementation.

13. Prevention

Primary prevention of a de novo or inherited CHI phenotype is generally unavailable. Genetic counseling enables reproductive risk assessment, carrier/cascade testing, prenatal diagnosis, and PGT-M when a familial variant is known. Optimization of maternal diabetes and prevention of perinatal hypoxia/IUGR may reduce acquired PSHI risk but does not prevent genetic CHI.

Secondary prevention is rapid identification of at-risk neonates, critical-sample testing, early genetic diagnosis, and immediate maintenance of glucose above 70 mg/dL. Tertiary prevention includes home glucose monitoring, individualized fasting plans, rescue glucagon, CGM as an adjunct rather than sole diagnostic device, developmental and feeding surveillance, and diabetes/exocrine screening after surgery. No immunization or infectious prophylaxis is specific to CHI. (leon2024internationalguidelinesfor pages 11-13, leon2024internationalguidelinesfor pages 13-15, leon2024internationalguidelinesfor pages 6-8)

14. Other species and natural disease

The core β-cell KATP, glucokinase, glutamate-dehydrogenase, and insulin-signaling pathways are evolutionarily conserved. Naturally occurring hyperinsulinemic hypoglycemia/insulinoma is recognized in companion animals, especially dogs and ferrets, but it is usually tumor-associated rather than a validated orthologous congenital syndrome. No zoonotic transmission exists. Species-specific OMIA/VBO claims and breed associations were not sufficiently supported by the retrieved evidence and should not be populated without dedicated veterinary-database verification.

15. Model organisms

Available models include Abcc8/Kcnj11 knockout or channel-defective mice, activating-Gck mice, Glud1 hyperactivity models, isolated rodent/human islets, β-cell lines, and patient-derived pancreatic tissue. Genetic glucokinase activation causes hypoglycemia in mice, supporting GCK dosage/activity as causal, but mouse insulin-secretory thresholds and compensatory physiology do not fully reproduce neonatal human disease. (shoji2024casereportduplication pages 8-8)

Model applications include KATP electrophysiology, stimulus–secretion coupling, diazoxide response, amino-acid sensitivity, focal-lesion genetics, and candidate-drug testing. Important limitations are inability of simple germline models to recreate the human pancreatic somatic 11p15 focal lesion, species differences in islet architecture, and limited modeling of human neonatal brain injury. In-vitro calcium-channel and mTOR observations supplied rationale for nifedipine and sirolimus, but lack of reliable clinical effectiveness illustrates the translational limitation. (leon2024internationalguidelinesfor pages 10-11)

Robust CHI-specific single-cell atlases, spatial transcriptomics, mature patient-iPSC β-cell models, and CRISPR screens remain research opportunities rather than validated knowledge-base facts.

Overall assessment

Current expert consensus treats CHI as a time-critical, genotype-informed disorder of pancreatic β-cell insulin secretion. The strongest recent advance is not a newly approved drug but integration of rapid genetics, 18F-DOPA PET, expert pathology, and lesion-directed surgery. The 2024 Ukrainian national study demonstrates that international access to this pathway can produce molecular diagnoses in 67.5% overall and cure all identified focal cases. However, diffuse disease, feeding burden, medication toxicity, unequal access, and neurodevelopmental injury remain major unmet needs. (globa2024congenitalhyperinsulinismin pages 1-2, globa2024congenitalhyperinsulinismin pages 3-5, leon2024internationalguidelinesfor pages 13-15)

Selected exact source statements

• 2024 Ukrainian registry: “Pathogenic variants were identified in 19/22 (86.3%) individuals with persistent CHI … and 8/18 (44.4%) with early remission CHI.” (globa2024congenitalhyperinsulinismin pages 1-2)
• Same study: “After surgery, complete recovery was observed in all 14 with focal disease.” (globa2024congenitalhyperinsulinismin pages 1-2)
• 2023 international guideline: “We Recommend Diazoxide as the First-Line Treatment for Patients with an Established Diagnosis of Hyperinsulinism.” (leon2024internationalguidelinesfor pages 8-10)
• 2023 Kabuki review: “The impact of pathogenic variants in KDM6A and KMT2D genes on β-cell insulin release remains to be fully clarified.” (maines2023anarrativereview pages 1-2)

References

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2. (leon2024internationalguidelinesfor pages 3-5): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

3. (leon2024internationalguidelinesfor pages 5-6): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

4. (maines2023anarrativereview pages 1-2): Evelina Maines, Arianna Maiorana, Letizia Leonardi, Giovanni Piccoli, Massimo Soffiati, and Roberto Franceschi. A narrative review on pathogenetic mechanisms of hyperinsulinemic hypoglycemia in kabuki syndrome. Endocrine Regulations, 57:128-137, Jan 2023. URL: https://doi.org/10.2478/enr-2023-0016, doi:10.2478/enr-2023-0016. This article has 3 citations.

5. (globa2024congenitalhyperinsulinismin pages 3-5): Evgenia Globa, Henrik Thybo Christesen, Michael Bau Mortensen, Jayne A. L. Houghton, Anne Lerberg Nielsen, Sönke Detlefsen, and Sarah E. Flanagan. Congenital hyperinsulinism in the ukraine: a 10-year national study. Frontiers in Endocrinology, Dec 2024. URL: https://doi.org/10.3389/fendo.2024.1497579, doi:10.3389/fendo.2024.1497579. This article has 6 citations.

6. (leon2024internationalguidelinesfor pages 11-13): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

7. (leon2024internationalguidelinesfor pages 6-8): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

8. (leon2024internationalguidelinesfor pages 13-15): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

9. (mittal2024molecularmechanismsunderlying pages 7-9): Medha Mittal, Amit Kumar Gupta, and Seema Kapoor. Molecular mechanisms underlying congenital hyperinsulinemia of infancy and its relevance to management – a review. Journal of Pediatric Endocrinology and Diabetes, 4:9-20, Aug 2024. URL: https://doi.org/10.25259/jped_25_2024, doi:10.25259/jped_25_2024. This article has 1 citations.

10. (shoji2024casereportduplication pages 8-8): Takashi Shoji, Ichiro Yamauchi, Hidenori Kawasaki, Kogoro Iwanaga, Takuro Hakata, Daisuke Tanaka, Junji Fujikura, Toshihiko Masui, Hisato Suzuki, Mamiko Yamada, Kenjiro Kosaki, Yosuke Kasai, Etsuro Hatano, Akira Inaba, Takahito Wada, Shinji Kosugi, Yohei Ueda, Toshihito Fujii, Daisuke Taura, and Nobuya Inagaki. Case report: duplication of the gck gene is a novel cause of nesidioblastosis: evidence from a case with silver-russell syndrome-like phenotype related to chromosome 7. Frontiers in Endocrinology, Dec 2024. URL: https://doi.org/10.3389/fendo.2024.1431547, doi:10.3389/fendo.2024.1431547. This article has 0 citations.

11. (leon2024internationalguidelinesfor pages 8-10): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

12. (leon2024internationalguidelinesfor pages 19-20): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

13. (leon2024internationalguidelinesfor pages 17-19): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

14. (leon2024internationalguidelinesfor pages 29-29): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

15. (leon2024internationalguidelinesfor pages 25-29): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

16. (leon2024internationalguidelinesfor pages 10-11): Diva D. De Leon, Jean Baptiste Arnoux, Indraneel Banerjee, Ignacio Bergada, Tricia Bhatti, Louise S. Conwell, Junfen Fu, Sarah E. Flanagan, David Gillis, Thomas Meissner, Klaus Mohnike, Tai L.S. Pasquini, Pratik Shah, Charles A. Stanley, Adrian Vella, Tohru Yorifuji, and Paul S. Thornton. International guidelines for the diagnosis and management of hyperinsulinism. Jul 2023. URL: https://doi.org/10.1159/000531766, doi:10.1159/000531766. This article has 102 citations and is from a peer-reviewed journal.

17. (globa2024congenitalhyperinsulinismin pages 10-11): Evgenia Globa, Henrik Thybo Christesen, Michael Bau Mortensen, Jayne A. L. Houghton, Anne Lerberg Nielsen, Sönke Detlefsen, and Sarah E. Flanagan. Congenital hyperinsulinism in the ukraine: a 10-year national study. Frontiers in Endocrinology, Dec 2024. URL: https://doi.org/10.3389/fendo.2024.1497579, doi:10.3389/fendo.2024.1497579. This article has 6 citations.

18. (takasawa2024clinicalmanagementof pages 10-13): Kei Takasawa, Ryosei Iemura, Ryuta Orimoto, Haruki Yamano, Shizuka Kirino, Eriko Adachi, Yoko Saito, Kurara Yamamoto, Nozomi Matsuda, Shigeru Takishima, Kumi Shuno, Hanako Tajima, Manabu Sugie, Yuki Mizuno, Akito Sutani, Kentaro Okamoto, Michiya Masue, Tomohiro Morio, and Kenichi Kashimada. Clinical management of diazoxide-unresponsive congenital hyperinsulinism: a single-center experience. Clinical Pediatric Endocrinology, 33:187-194, Jun 2024. URL: https://doi.org/10.1297/cpe.2024-0004, doi:10.1297/cpe.2024-0004. This article has 4 citations and is from a peer-reviewed journal.

19. (NCT04538989 chunk 1): An Open-Label Multiple Dose Study of RZ358 in Patients With Congenital Hyperinsulinism. Rezolute. 2020. ClinicalTrials.gov Identifier: NCT04538989

20. (NCT06208215 chunk 2): RZ358 Treatment for Congenital Hyperinsulinism. Rezolute. 2024. ClinicalTrials.gov Identifier: NCT06208215

21. (NCT03941236 chunk 1): Extension Trial Evaluating the Long-term Safety and Efficacy of Dasiglucagon in Children With Congenital Hyperinsulinism. Zealand Pharma. 2019. ClinicalTrials.gov Identifier: NCT03941236

22. (NCT03777176 chunk 1): A Two-Period Open-label Trial Evaluating Efficacy and Safety of Dasiglucagon in Children With Congenital Hyperinsulinism. Zealand Pharma. 2019. ClinicalTrials.gov Identifier: NCT03777176

23. (NCT03777176 chunk 2): A Two-Period Open-label Trial Evaluating Efficacy and Safety of Dasiglucagon in Children With Congenital Hyperinsulinism. Zealand Pharma. 2019. ClinicalTrials.gov Identifier: NCT03777176

24. (NCT04732416 chunk 1): HM15136 (Efpegerglucagon) Treatment for 8 Weeks in Subjects Aged ≥2 Years With Congenital Hyperinsulinism (CHI). Hanmi Pharmaceutical Company Limited. 2022. ClinicalTrials.gov Identifier: NCT04732416

25. (NCT02937558 chunk 1): CSI-Glucagon for Prevention of Hypoglycemia in Children With Congenital Hyperinsulinism. Xeris Pharmaceuticals. 2016. ClinicalTrials.gov Identifier: NCT02937558

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