Functional and Metabolomic Consequences of KATP Channel Inactivation in Human Islets

Loss-of-function mutations of β-cell KATP channels cause the most severe form of congenital hyperinsulinism (KATPHI). KATPHI is characterized by fasting and protein-induced hypoglycemia that is unresponsive to medical therapy. For a better understanding of the pathophysiology of KATPHI, we examined cytosolic calcium, insulin secretion, oxygen consumption, and [U-(13)C]glucose metabolism in islets isolated from the pancreases of children with KATPHI who required pancreatectomy. Basal cytosolic calcium ([Ca(2+)] i ) and insulin secretion were higher in KATPHI islets compared to controls. Unlike controls, insulin secretion in KATPHI islets increased in response to amino acids but not to glucose. KATPHI islets have increased basal rate of oxygen consumption and mitochondrial mass. [U-(13)C]glucose metabolism showed a 2-fold increase in alanine levels and 6-fold increase in (13)C enrichment of alanine in KATPHI islets, suggesting increased rates of glycolysis. KATPHI islets also exhibited increased serine/glycine and glutamine biosynthesis. In contrast, KATPHI islets had low GABA levels and lacked of (13)C incorporation into GABA in response to glucose stimulation. The expression of key genes involved in these metabolic pathways was significantly different in KATPHI β-cells compared to control, providing a mechanism for the observed changes. These findings demonstrate that the pathophysiology of KATPHI is complex and they provide a framework for the identification of new potential therapeutic targets for this devastating condition.