Functional and Metabolomic Consequences of K ATP Channel Inactivation in Human Islets.

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