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Exercise-induced hyperinsulinism (EIHI) is an autosomal dominant hypoglycemic disorder characterized by inappropriate insulin secretion during anaerobic exercise or on pyruvate load. The disease results from failure of cell-specific transcriptional silencing of the monocarboxylate transporter 1 in pancreatic β cells, encoded by SLC16A1, leading to pyruvate-stimulated insulin release in hypoglycemia. EIHI has been mapped to chromosome 1 by genome-wide linkage in two families with 10 affected individuals (LOD 3.6) (PMID:17701893).
Mutational analysis of the SLC16A1 promoter in 13 EIHI patients revealed heterozygous promoter-activating variants segregating with disease in all pedigrees (PMID:17701893). The recurrent variant c.-202G>A was identified in one family and co-segregated with affected status. No coding sequence changes were detected, highlighting a noncoding mechanism of pathogenicity.
Functional assays in patient fibroblasts showed elevated SLC16A1 transcript levels without altered monocarboxylate transport, indicating post-transcriptional control outside β cells. In β-cell models, promoter-reporter constructs bearing either of two EIHI mutations exhibited 3-fold and 10-fold increases in transcriptional activity compared with wild type (PMID:17701893).
These data support a gain-of-function mechanism in which promoter mutations disrupt β-cell silencing of SLC16A1, allowing aberrant MCT1 expression, pyruvate uptake, and insulin secretion despite hypoglycemia. No conflicting evidence has been reported to date.
The association between SLC16A1 promoter mutations and EIHI is classified as Strong based on segregation in multiple families and concordant functional data. Genetic testing of the SLC16A1 promoter should be considered in patients with exercise-induced hypoglycemia. Key take-home: Promoter-activating SLC16A1 variants cause dominantly inherited EIHI via ectopic MCT1 expression in β cells—informing diagnosis and management.
Gene–Disease AssociationStrong13 probands with promoter mutations, segregation in two families (LOD 3.6) and concordant functional data Genetic EvidenceStrongHeterozygous promoter variants in 13 EIHI patients with segregation in 10 affected relatives Functional EvidenceModeratePromoter-reporter assays in β cells show 3- to 10-fold transcriptional activation, consistent with disease mechanism |