Functional and Metabolomic Consequences of K_ATP Channel Inactivation in Human Islets

Loss-of-function mutations of β-cell K_ATP channels cause the most severe form of congenital hyperinsulinism (K_ATPHI). K_ATPHI is characterized by fasting and protein-induced hypoglycemia that is unresponsive to medical therapy. For a better understanding of the pathophysiology of K_ATPHI, we examined cytosolic calcium ([Ca²⁺] ), insulin secretion, oxygen consumption, and [U-¹³C]glucose metabolism in islets isolated from the pancreases of children with K_ATPHI who required pancreatectomy. Basal [Ca²⁺] and insulin secretion were higher in K_ATPHI islets compared with controls. Unlike controls, insulin secretion in K_ATPHI islets increased in response to amino acids but not to glucose. K_ATPHI islets have an increased basal rate of oxygen consumption and mitochondrial mass. [U-¹³C]glucose metabolism showed a twofold increase in alanine levels and sixfold increase in ¹³C enrichment of alanine in K_ATPHI islets, suggesting increased rates of glycolysis. K_ATPHI islets also exhibited increased serine/glycine and glutamine biosynthesis. In contrast, K_ATPHI islets had low γ-aminobutyric acid (GABA) levels and lacked ¹³C incorporation into GABA in response to glucose stimulation. The expression of key genes involved in these metabolic pathways was significantly different in K_ATPHI β-cells compared with control, providing a mechanism for the observed changes. These findings demonstrate that the pathophysiology of K_ATPHI is complex, and they provide a framework for the identification of new potential therapeutic targets for this devastating condition.