Hepatocyte nuclear factor-4α is essential for glucosestimulated insulin secretion by pancreatic β-cells

Mutations in the hepatocyte nuclear factor (HNF)-4 alpha gene cause a form of maturity-onset diabetes of the young (MODY1) that is characterized by impairment of glucose- stimulated insulin secretion by pancreatic beta-cells. HNF-4 alpha, a transcription factor belonging to the nuclear receptor superfamily, is expressed in pancreatic islets as well as in the liver, kidney, and intestine. However, the role of HNF-4 alpha in pancreatic beta-cell is unclear. To clarify the role of HNF-4 alpha in beta-cells, we generated beta-cell-specific HNF-4 alpha knock-out (beta HNF-4 alpha KO) mice using the Cre-LoxP system. The beta HNF-4 alpha KO mice exhibited impairment of glucose- stimulated insulin secretion, which is a characteristic of MODY1. Pancreatic islet morphology, beta-cell mass, and insulin content were normal in the HNF-4 alpha mutant mice. Insulin secretion by beta HNF-4 alpha KO islets and the intracellular calcium response were impaired after stimulation by glucose or sulfonylurea but were normal after stimulation with KCl or arginine. Both NAD(P)H generation and ATP content at high glucose concentrations were normal in the beta HNF-4 alpha KO mice. Expression levels of Kir6.2 and SUR1 proteins in the beta HNF-4 alpha KO mice were unchanged as compared with control mice. Patch clamp experiments revealed that the current density was significantly increased in beta HNF-4 alpha KO mice compared with control mice. These results are suggestive of the dysfunction of K-ATP channel activity in the pancreatic beta-cells of HNF-4 alpha-deficient mice. Because the K-ATP channel is important for proper insulin secretion in beta-cells, altered K-ATP channel activity could be related to the impaired insulin secretion in the beta HNF-4 alpha KO mice.