Some of the major pathways regulating insulin secretion are shown. The proteins encoded by genes mutated in different forms of CHI are shown in red. Mutations in either ABCC8 (which encodes SUR1) or KCNJ11 (which encodes Kir6.2) result in defective K_ATP channel activity and continuous membrane depolarization regardless of glucose levels. Activating mutations in glucokinase (GCK) result in increased glucose metabolism at low circulating glucose levels, resulting in a decreased threshold for glucose-stimulated insulin secretion and thus inappropriate insulin secretion in the presence of hypoglycemia (18). Glutamate dehydrogenase 1 (GLUD1) mutations result in increased conversion of glutamate to α-ketoglutarate (αKG), thereby increasing ATP production and insulin secretion (19). Solute carrier family 16, member 1 (SLC16A1) promoter mutations result in inappropriate expression of this transporter in β cells, allowing pyruvate and lactate to enter the cell. Pyruvate can then enter the Krebs cycle, thus increasing ATP production and insulin secretion. Patients with mutations in this gene have a unique form of CHI characterized by exercise-induced hypoglycemia (20). Inactivating mutations in hydroxyacyl-CoA dehydrogenase (HADH) also cause CHI and have been shown to do so by regulating insulin secretion in a K_ATP channel–independent fashion (21) and by preventing HADH-mediated inhibition of GLUD1 in the β cell (22). Glucagon-like peptide 1 (GLP1), glucose-dependent insulinotrophic peptide (GIP), glucagon, somatostatin, and other signals not shown in this simplified diagram regulate critical amplifying pathways downstream from the CHI-related proteins.