A 94-bp Deletion in the Promoter of the Beta-Cell Disallowed gene SLC16A1 causing Adult-onset Hyperinsulinism

Non-coding variants in the promoter region of SLC16A1, a beta-cell-disallowed gene encoding Monocarboxylate Transporter 1 (MCT1), cause exercise-induced hyperinsulinism (EIHI). These variants are thought to cause aberrant expression of MCT1 in pancreatic beta-cells, enabling pyruvate uptake during exercise which triggers inappropriate insulin secretion. We identified a 94-bp deletion in the SLC16A1 promoter in 37 individuals from 11 families with childhood- or adult-onset hyperinsulinemic hypoglycemia (HI). Patient pancreatic tissue showed elevated MCT1 expression, confirming the disease mechanism. To investigate the functional impact of the deletion, we generated induced pluripotent stem cells from an affected individual and differentiated them into pancreatic stem-cell-derived islets (SC-islets). These patient-derived SC-islets showed increased SLC16A1 gene and protein expression in vitro and failed to repress MCT1 expression following in vivo maturation in immunocompromised mice. Ex vivo pyruvate stimulation selectively triggered insulin secretion in variant grafts, effectively recapitulating the EIHI phenotype. In individuals with the deletion, the hypoglycemia was triggered by physical activity, carbohydrate-rich meals, and fasting, with considerable variability in age at onset and clinical severity. These findings broaden the phenotypic spectrum of SLC16A1 promoter variants and support the inclusion of SLC16A1 promoter analysis in the genetic evaluation of individuals with unexplained HI across all ages.