DEFECTIVE PANCREATIC BETA-CELL GLYCOLYTIC SIGNALING IN HEPATOCYTE NUCLEAR FACTOR-1-ALPHA-DEFICIENT MICE

Mutations in the hepatocyte nuclear factor-1 alpha (HNF-1 alpha) gene cause maturity onset diabetes of the young type 3, a form of type 2 di abetes mellitus, In mice lacking the HNF-1 alpha gene, insulin secreti on and intracellular calcium ([Ca2+](i)) responses were impaired follo wing stimulation with nutrient secretagogues such as glucose and glyce raldehyde but normal with non-nutrient stimuli such as potassium chlor ide. Patch clamp recordings revealed ATP-sensitive K+ currents (KATP) in beta-cells that were insensitive to suppression by glucose but norm ally sensitive to ATP, Exposure to mitochondrial substrates suppressed KATP, elevated [Ca2+](i), and corrected the insulin secretion defect. NAD(P)H responses to glucose were substantially reduced, and inhibito rs of glycolytic NADH generation reproduced the mutant phenotype in no rmal islets. Flux of glucose through glycolysis in islets from mutant mice was reduced, as a result of which ATP generation in response to g lucose was impaired. We conclude that hepatocyte nuclear factor-1 alph a diabetes results from defective beta-cell glycolytic signaling, whic h is potentially correctable using substrates that bypass the defect.