Diabetes 2017 07 25;66(7):1901-1913. Epub 2017 Apr 25.
Division of Endocrinology and Diabetes, Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Loss-of-function mutations of β-cell K channels cause the most severe form of congenital hyperinsulinism (KHI). KHI is characterized by fasting and protein-induced hypoglycemia that is unresponsive to medical therapy. For a better understanding of the pathophysiology of KHI, we examined cytosolic calcium ([Ca] ), insulin secretion, oxygen consumption, and [U-C]glucose metabolism in islets isolated from the pancreases of children with KHI who required pancreatectomy. Basal [Ca] and insulin secretion were higher in KHI islets compared with controls. Unlike controls, insulin secretion in KHI islets increased in response to amino acids but not to glucose. KHI islets have an increased basal rate of oxygen consumption and mitochondrial mass. [U-C]glucose metabolism showed a twofold increase in alanine levels and sixfold increase in C enrichment of alanine in KHI islets, suggesting increased rates of glycolysis. KHI islets also exhibited increased serine/glycine and glutamine biosynthesis. In contrast, KHI islets had low γ-aminobutyric acid (GABA) levels and lacked C incorporation into GABA in response to glucose stimulation. The expression of key genes involved in these metabolic pathways was significantly different in KHI β-cells compared with control, providing a mechanism for the observed changes. These findings demonstrate that the pathophysiology of KHI is complex, and they provide a framework for the identification of new potential therapeutic targets for this devastating condition.