Hyperinsulinemic hypoglycemia

Summary

Hyperinsulinemic hypoglycemia (MONDO:0005803) is a disease (an umbrella term covering 5 Mondo subtypes) with 3 cohort genes and 10 clinical trials. Top therapeutic interventions include acarbose, exenatide, and pasireotide.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 72
• Clinical trials: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperinsulinemic hypoglycemia
Mondo ID	MONDO:0005803
EFO	EFO:0007318
OMIM	256450
Orphanet	443095
DOID	DOID:13317
SNOMED CT	42681006
UMLS	C1864903
MedGen	351247
GARD	0021849
Is cancer (heuristic)	no

Also known as: hyperinsulinemia hypoglycemia · hyperinsulinemic hypoglycemia (disease)

Data availability: 72 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › hyperinsulinemic hypoglycemia

Related subtypes (47): autoimmune disorder of endocrine system, parathyroid gland disorder, endocrine gland neoplasm, gonadal disorder, pancreas disorder, thyroid gland disorder, pituitary gland disorder, thymus gland disorder, liver disorder, adrenal gland disorder, non-neoplastic bile duct disorder, endocrine tuberculosis, campomelic dysplasia, polycystic ovary syndrome, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, hypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome, genito-palato-cardiac syndrome, hypoinsulinemic hypoglycemia and body hemihypertrophy, Bamforth-Lazarus syndrome, blepharophimosis - intellectual disability syndrome, SBBYS type, Wolfram-like syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, estrogen resistance syndrome, short stature, microcephaly, and endocrine dysfunction, polyendocrinopathy, pituitary deficiency, hereditary endocrine growth disease, diencephalic syndrome, muscular pseudohypertrophy-hypothyroidism syndrome, neonatal iodine exposure, disorders of vitamin D metabolism, rapid-onset childhood obesity-hypothalamic dysfunction-hypoventilation-autonomic dysregulation syndrome, duplication of the pituitary gland, familial hypocalciuric hypercalcemia, hypothalamic adipsic hypernatraemia syndrome, Leydig cell hypoplasia, inherited obesity, beta thalassemia, thyroid hormone metabolism, abnormal, neuroendocrine disorder, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, parneoplastic endocrine syndrome, 17,20-lyase deficiency, isolated, 17-alpha-hydroxylase/17,20-lyase deficiency, combined complete, 17-alpha-hydroxylase/17,20-lyase deficiency, combined partial, disorder of GNAS inactivation, acquired hypothalamic obesity

Subtypes (5): hyperinsulinemic hypoglycemia, familial, 1, familial hyperinsulinism, insulin autoimmune syndrome, hyperinsulinemic hypoglycemia, familial, 8, hyperinsulinemic hypoglycemia with polycystic kidney disease

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

72 retrieved; paginated sample, class counts are floors:

44 conflicting classifications of pathogenicity, 12 uncertain significance/uncertain risk allele, 8 benign/likely benign, 3 likely benign, 2 uncertain significance, 1 likely pathogenic, 1 likely risk allele, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
802082	NM_005327.7(HADH):c.261+1G>A	HADH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
659541	NM_005327.7(HADH):c.100G>C (p.Gly34Arg)	HADH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1007414	NM_005327.7(HADH):c.740C>T (p.Ala247Val)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
347124	NM_005327.7(HADH):c.-115del	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
347128	NC_000004.12:g.107989882del	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
347135	NM_005327.7(HADH):c.889G>A (p.Val297Ile)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
640701	NM_005327.7(HADH):c.266G>A (p.Gly89Asp)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
8018	NM_005327.7(HADH):c.118G>A (p.Ala40Thr)	HADH	Likely risk allele	criteria provided, single submitter
8019	NM_005327.7(HADH):c.171C>A (p.Asp57Glu)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
860765	NM_005327.7(HADH):c.494G>A (p.Arg165Gln)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
864194	NM_005327.7(HADH):c.479C>T (p.Thr160Ile)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
902197	NM_005327.7(HADH):c.809C>T (p.Thr270Met)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
902198	NM_005327.7(HADH):c.823G>A (p.Asp275Asn)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
917461	NM_005327.7(HADH):c.47C>T (p.Ser16Phe)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
917462	NM_005327.7(HADH):c.361G>A (p.Val121Met)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
1003601	NM_005327.7(HADH):c.725A>G (p.Glu242Gly)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005599	NM_005327.7(HADH):c.280G>C (p.Glu94Gln)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009098	NM_005327.7(HADH):c.761A>G (p.Tyr254Cys)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024954	NM_005327.7(HADH):c.820G>A (p.Val274Met)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197252	NM_005327.7(HADH):c.486A>G (p.Arg162=)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211125	NM_005327.7(HADH):c.132+7G>T	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211128	NM_005327.7(HADH):c.579A>G (p.Thr193=)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2499170	NM_005327.7(HADH):c.710-822C>T	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347130	NM_005327.7(HADH):c.-36C>T	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347131	NM_005327.7(HADH):c.21G>A (p.Gln7=)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347132	NM_005327.7(HADH):c.72G>A (p.Lys24=)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347133	NM_005327.7(HADH):c.240G>A (p.Lys80=)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347136	NM_005327.7(HADH):c.*59G>A	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347138	NM_005327.7(HADH):c.*305T>A	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
393393	NM_005327.7(HADH):c.881A>G (p.Asn294Ser)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
YARS1	Orphanet:100045	Autosomal dominant intermediate Charcot-Marie-Tooth disease type C
HADH	Orphanet:71212	Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency
KCNJ11	Orphanet:276580	Autosomal dominant hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:276603	Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:552	MODY
KCNJ11	Orphanet:79134	DEND syndrome
KCNJ11	Orphanet:79644	Autosomal recessive hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
KCNJ11	Orphanet:99886	Transient neonatal diabetes mellitus
KCNJ11	Orphanet:99989	Intermediate DEND syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
YARS1	HGNC:12840	ENSG00000134684	P54577	Tyrosine–tRNA ligase, cytoplasmic	clinvar
HADH	HGNC:4799	ENSG00000138796	Q16836	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	clinvar
KCNJ11	HGNC:6257	ENSG00000187486	Q14654	ATP-sensitive inward rectifier potassium channel 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
YARS1	Tyrosine–tRNA ligase, cytoplasmic	Tyrosine–tRNA ligase that catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).
HADH	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	Mitochondrial fatty acid beta-oxidation enzyme that catalyzes the third step of the beta-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10).
KCNJ11	ATP-sensitive inward rectifier potassium channel 11	Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	1	37.2×	0.027
Enzyme (other)	2	8.0×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
YARS1	Enzyme (other)	yes	6.1.1.1	aa-tRNA-synth_Ic, Tyr-tRNA-ligase, tRNA-bd_dom
HADH	Enzyme (other)	yes	1.1.1.35	3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd, 3-OHacyl-CoA_DH_CS
KCNJ11	Ion channel	yes		K_chnl_inward-rec_Kir6.2, K_chnl_inward-rec_Kir_cyto, Ig_E-set

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	2
left adrenal gland	1
right adrenal gland	1
heart right ventricle	1
skeletal muscle tissue of rectus abdominis	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
YARS1	290	ubiquitous	marker	islet of Langerhans, right adrenal gland, left adrenal gland
HADH	296	ubiquitous	marker	islet of Langerhans, heart right ventricle, skeletal muscle tissue of rectus abdominis
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
YARS1	4,793
HADH	2,386
KCNJ11	1,715

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HADH	Q16836	12
KCNJ11	Q14654	9
YARS1	P54577	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	1903.3×	0.005	KCNJ11
Defective ABCC8 can cause hypo- and hyper-glycemias	1	1903.3×	0.005	KCNJ11
ATP sensitive Potassium channels	1	951.7×	0.005	KCNJ11
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	1	761.3×	0.005	HADH
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	761.3×	0.005	HADH
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	1	761.3×	0.005	HADH
Beta oxidation of butanoyl-CoA to acetyl-CoA	1	761.3×	0.005	HADH
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	634.4×	0.005	HADH
Inwardly rectifying K+ channels	1	237.9×	0.013	KCNJ11
Cytosolic tRNA aminoacylation	1	146.4×	0.017	YARS1
ABC transporter disorders	1	146.4×	0.017	KCNJ11
tRNA Aminoacylation	1	95.2×	0.024	YARS1
Regulation of insulin secretion	1	73.2×	0.028	KCNJ11
Ion homeostasis	1	68.0×	0.028	KCNJ11
Integration of energy metabolism	1	58.6×	0.031	KCNJ11
Disorders of transmembrane transporters	1	46.4×	0.035	KCNJ11
Potassium Channels	1	44.8×	0.035	KCNJ11
ABC-family protein mediated transport	1	40.5×	0.037	KCNJ11
Mitochondrial protein degradation	1	38.1×	0.037	HADH
Cardiac conduction	1	36.2×	0.037	KCNJ11
Muscle contraction	1	25.7×	0.049	KCNJ11
Translation	1	20.7×	0.058	YARS1
Neuronal System	1	14.8×	0.078	KCNJ11
Transport of small molecules	1	8.4×	0.129	KCNJ11
Disease	1	4.4×	0.229	KCNJ11
Metabolism of proteins	1	4.1×	0.232	YARS1
Metabolism	1	3.9×	0.237	KCNJ11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of insulin secretion	2	330.4×	3e-04	HADH, KCNJ11
regulation of insulin secretion	2	261.3×	3e-04	HADH, KCNJ11
tyrosyl-tRNA aminoacylation	1	5617.3×	0.002	YARS1
response to xenobiotic stimulus	2	46.0×	0.004	HADH, KCNJ11
response to resveratrol	1	1123.5×	0.005	KCNJ11
CAMKK-AMPK signaling cascade	1	936.2×	0.005	KCNJ11
ventricular cardiac muscle tissue development	1	702.2×	0.006	KCNJ11
nervous system process	1	401.2×	0.009	KCNJ11
response to ATP	1	330.4×	0.009	KCNJ11
obsolete inorganic cation transmembrane transport	1	312.1×	0.009	KCNJ11
apoptotic process	2	19.1×	0.009	YARS1, KCNJ11
regulation of monoatomic ion transmembrane transport	1	244.2×	0.010	KCNJ11
cellular response to nutrient levels	1	156.0×	0.013	KCNJ11
response to starvation	1	156.0×	0.013	YARS1
determination of adult lifespan	1	144.0×	0.013	KCNJ11
fatty acid beta-oxidation	1	124.8×	0.013	HADH
potassium ion import across plasma membrane	1	122.1×	0.013	KCNJ11
action potential	1	119.5×	0.013	KCNJ11
response to activity	1	108.0×	0.014	HADH
glucose metabolic process	1	85.1×	0.016	KCNJ11
response to ischemia	1	83.8×	0.016	KCNJ11
response to insulin	1	77.0×	0.016	HADH
regulation of membrane potential	1	77.0×	0.016	KCNJ11
positive regulation of cold-induced thermogenesis	1	54.5×	0.021	HADH
potassium ion transmembrane transport	1	45.3×	0.025	KCNJ11
response to hypoxia	1	31.9×	0.033	KCNJ11
spermatogenesis	1	11.7×	0.086	HADH
cell differentiation	1	9.7×	0.100	HADH

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

3 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Avexitide	Phase 2
Dasiglucagon	Phase 2
Glucagon	Phase 2

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
YARS1	CAPSAICIN
KCNJ11	PINACIDIL ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNJ11	7	4
YARS1	2	4
HADH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPSAICIN	4	YARS1
PINACIDIL ANHYDROUS	4	KCNJ11
GLYBURIDE	4	KCNJ11
PROPAFENONE	4	KCNJ11
DIAZOXIDE	4	KCNJ11
CRENOLANIB	3	YARS1
CROMAKALIM	2	KCNJ11
CLAMIKALANT	2	KCNJ11
TIFENAZOXIDE	2	KCNJ11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KCNJ11	102	Functional:59, Binding:43
YARS1	16	Binding:16
HADH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
YARS1	6.1.1.1	tyrosine-tRNA ligase
HADH	1.1.1.35	3-hydroxyacyl-CoA dehydrogenase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KCNJ11	102

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

9 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CAPSAICIN	4	YARS1
PINACIDIL ANHYDROUS	4	KCNJ11
GLYBURIDE	4	KCNJ11
PROPAFENONE	4	KCNJ11
DIAZOXIDE	4	KCNJ11
CRENOLANIB	3	YARS1
CROMAKALIM	2	KCNJ11
CLAMIKALANT	2	KCNJ11
TIFENAZOXIDE	2	KCNJ11

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	YARS1, KCNJ11
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HADH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HADH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	4
PHASE1	3
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03770637	PHASE2	COMPLETED	Glucagon Ready to Use (RTU) in Subjects With Hyperinsulinemic Hypoglycemia After Bariatric Surgery
NCT03984370	PHASE2	COMPLETED	Dasiglucagon in the Treatment of Postprandial Hypoglycaemia After Roux-en-Y Gastric Bypass
NCT04652479	PHASE2	COMPLETED	Avexitide Safety and Efficacy to Treat Acquired Hyperinsulinemic Hypoglycemia
NCT04836273	PHASE2	COMPLETED	Treatment of Post-bariatric Hypoglycaemia
NCT02685852	PHASE1	COMPLETED	Evaluating Exenatide for the Treatment of Postprandial Hyperinsulinemic Hypoglycemia
NCT02996812	PHASE1	COMPLETED	Evaluation of Single Ascending Doses of Subcutaneous Exendin 9-39 in Patients With Post-Bariatric Hypoglycemia
NCT03103009	PHASE1	COMPLETED	Treatment Plan for an Individual Patient With Pasireotide for Hyperinsulinemic Hypoglycemia
NCT01933490	Not specified	COMPLETED	Post-Gastric Bypass Hypoglycemia
NCT03930368	Not specified	UNKNOWN	Application of Raw Corn Starch on Patients With Insulinoma
NCT05597475	Not specified	UNKNOWN	GLP1R-imaging in Post-RYGB Hypoglycemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ACARBOSE	4	1
EXENATIDE	4	1
PASIREOTIDE	4	1
AVEXITIDE	3	2
DASIGLUCAGON	3	2
CHEMBL4299399	0	1
CHEMBL4760828	0	1