Exercise-induced hyperinsulinism

Summary

Exercise-induced hyperinsulinism (MONDO:0012396) is a disease caused by SLC16A1 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC16A1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 80
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	exercise-induced hyperinsulinism
Mondo ID	MONDO:0012396
MeSH	C538376
OMIM	610021
Orphanet	165991
DOID	DOID:0070214
ICD-11	999935139
NCIT	C131839
SNOMED CT	715830008
UMLS	C1864902
MedGen	351246
GARD	0009932
Is cancer (heuristic)	no

Also known as: EIHI · exercise induced hyperinsulinemic hypoglycemia · exercise-induced hyperinsulinemic hypoglycemia · HHF7 · hyperinsulinemic hypoglycemia exercise-induced · hyperinsulinemic hypoglycemia familial 7 · hyperinsulinemic hypoglycemia, familial, 7 · hyperinsulinemic hypoglycemia, familial, type 7 · hyperinsulinism due to monocarboxylate transporter 1 deficiency · hyperinsulinism due to SLC16A1 deficiency · MCT1 hyperinsulinism · monocarboxylate transporter 1 hyperinsulinism

Data availability: 80 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › islet cell adenomatosis › congenital isolated hyperinsulinism › diazoxide-sensitive diffuse hyperinsulinism › exercise-induced hyperinsulinism

Related subtypes (7): hyperinsulinism-hyperammonemia syndrome, hyperinsulinemic hypoglycemia, familial, 4, hyperinsulinism due to HNF4A deficiency, hyperinsulinism due to UCP2 deficiency, autosomal dominant hyperinsulinism due to SUR1 deficiency, autosomal dominant hyperinsulinism due to Kir6.2 deficiency, hyperinsulinism due to HNF1A deficiency

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

80 retrieved; paginated sample, class counts are floors:

53 uncertain significance, 7 likely benign, 6 conflicting classifications of pathogenicity, 4 benign, 4 benign/likely benign, 4 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
8916	NM_003051.4(SLC16A1):c.-202G>A	LOC129931218	Pathogenic	no assertion criteria provided
8917	NC_000001.11:g.112956380_112956381insCCCCACCCCGCCACGTGACCGGCGT	LOC129931218	Pathogenic	no assertion criteria provided
160370	NM_003051.4(SLC16A1):c.982C>T (p.Arg328Ter)	SLC16A1	Pathogenic	criteria provided, single submitter
800884	NM_003051.4(SLC16A1):c.1079del (p.Ala360fs)	SLC16A1	Pathogenic	criteria provided, single submitter
3362614	NM_003051.4(SLC16A1):c.97del (p.Ser33fs)	SLC16A1	Likely pathogenic	criteria provided, single submitter
827804	NM_003051.4(SLC16A1):c.328C>T (p.Gln110Ter)	SLC16A1	Likely pathogenic	criteria provided, single submitter
258903	NM_003051.4(SLC16A1):c.441C>T (p.Asn147=)	SLC16A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291851	NM_003051.4(SLC16A1):c.1452G>A (p.Pro484=)	SLC16A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291854	NM_003051.4(SLC16A1):c.1342T>C (p.Leu448=)	SLC16A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291867	NM_003051.4(SLC16A1):c.489C>A (p.Pro163=)	SLC16A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874139	NM_003051.4(SLC16A1):c.540T>C (p.Ile180=)	SLC16A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876928	NM_003051.4(SLC16A1):c.1281C>T (p.Gly427=)	SLC16A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291915	NM_003051.3(SLC16A1):c.-226G>A	LOC129931218	Uncertain significance	criteria provided, single submitter
291917	NM_003051.3(SLC16A1):c.-248G>T	LOC129931218	Uncertain significance	criteria provided, single submitter
291918	NM_003051.3(SLC16A1):c.-249C>T	LOC129931218	Uncertain significance	criteria provided, single submitter
291921	NM_003051.3(SLC16A1):c.-313T>C	LOC129931218	Uncertain significance	criteria provided, single submitter
291924	NM_003051.3(SLC16A1):c.-349G>A	LOC129931218	Uncertain significance	criteria provided, single submitter
291925	NM_003051.3(SLC16A1):c.-360G>A	LOC129931218	Uncertain significance	criteria provided, single submitter
436732	NM_003051.4(SLC16A1):c.-201T>A	LOC129931218	Uncertain significance	criteria provided, multiple submitters, no conflicts
874247	NM_003051.3(SLC16A1):c.-214C>G	LOC129931218	Uncertain significance	criteria provided, single submitter
874248	NM_003051.3(SLC16A1):c.-218G>A	LOC129931218	Uncertain significance	criteria provided, single submitter
875169	NM_003051.3(SLC16A1):c.-316G>A	LOC129931218	Uncertain significance	criteria provided, single submitter
875170	NM_003051.3(SLC16A1):c.-324T>G	LOC129931218	Uncertain significance	criteria provided, single submitter
1712344	NM_003051.4(SLC16A1):c.785G>C (p.Gly262Ala)	SLC16A1	Uncertain significance	criteria provided, single submitter
291829	NM_003051.4(SLC16A1):c.*1801A>G	SLC16A1	Uncertain significance	criteria provided, single submitter
291832	NM_003051.4(SLC16A1):c.*1312G>C	SLC16A1	Uncertain significance	criteria provided, single submitter
291836	NM_003051.4(SLC16A1):c.*1072G>T	SLC16A1	Uncertain significance	criteria provided, single submitter
291837	NM_003051.4(SLC16A1):c.*1064G>T	SLC16A1	Uncertain significance	criteria provided, single submitter
291838	NM_003051.4(SLC16A1):c.*1051G>A	SLC16A1	Uncertain significance	criteria provided, single submitter
291839	NM_003051.4(SLC16A1):c.*1018T>G	SLC16A1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC16A1	Strong	Autosomal dominant	exercise-induced hyperinsulinism	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC16A1	Orphanet:165991	Exercise-induced hyperinsulinism
SLC16A1	Orphanet:171690	Metabolic myopathy due to lactate transporter defect
SLC16A1	Orphanet:438075	Ketoacidosis due to monocarboxylate transporter-1 deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC16A1	HGNC:10922	ENSG00000155380	P53985	Monocarboxylate transporter 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC16A1	Monocarboxylate transporter 1	Bidirectional proton-coupled monocarboxylate transporter.

Protein-family classification

Druggable: 1 · 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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC16A1	Transporter	yes		MCT, MFS, MFS_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
mucosa of transverse colon	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC16A1	134	ubiquitous	marker	mucosa of transverse colon, ventricular zone, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC16A1	2,296

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC16A1	P53985	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT)	1	5710.0×	0.002	SLC16A1
Proton-coupled monocarboxylate transport	1	1903.3×	0.003	SLC16A1
Basigin interactions	1	439.2×	0.010	SLC16A1
Aspirin ADME	1	317.2×	0.010	SLC16A1
Drug ADME	1	228.4×	0.010	SLC16A1
SLC transporter disorders	1	203.9×	0.010	SLC16A1
R-HSA-425366	1	181.3×	0.010	SLC16A1
Disorders of transmembrane transporters	1	139.3×	0.012	SLC16A1
Cell surface interactions at the vascular wall	1	95.2×	0.015	SLC16A1
SLC-mediated transmembrane transport	1	59.2×	0.022	SLC16A1
Hemostasis	1	36.0×	0.033	SLC16A1
Transport of small molecules	1	25.1×	0.043	SLC16A1
Disease	1	13.1×	0.076	SLC16A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mevalonate transport	1	16852.0×	4e-04	SLC16A1
behavioral response to nutrient	1	16852.0×	4e-04	SLC16A1
pyruvate transmembrane transport	1	5617.3×	7e-04	SLC16A1
plasma membrane lactate transport	1	4213.0×	7e-04	SLC16A1
succinate transmembrane transport	1	4213.0×	7e-04	SLC16A1
carboxylic acid transmembrane transport	1	2808.7×	8e-04	SLC16A1
pyruvate catabolic process	1	2106.5×	9e-04	SLC16A1
monocarboxylic acid transport	1	1532.0×	0.001	SLC16A1
response to food	1	495.6×	0.003	SLC16A1
regulation of insulin secretion	1	391.9×	0.004	SLC16A1
centrosome cycle	1	337.0×	0.004	SLC16A1
transport across blood-brain barrier	1	179.3×	0.007	SLC16A1
glucose homeostasis	1	130.6×	0.008	SLC16A1
lipid metabolic process	1	91.6×	0.011	SLC16A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC16A1	3	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SYROSINGOPINE	2	SLC16A1
LUTEOLIN	2	SLC16A1
AZD3965	1	SLC16A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC16A1	52	Binding:49, Functional:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
SYROSINGOPINE	2	SLC16A1
LUTEOLIN	2	SLC16A1
AZD3965	1	SLC16A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	SLC16A1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04846751	Not specified	UNKNOWN	Exercise Type That Faster Reduces Postprandial Glycemia.