The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion

J Clin Invest. 2005 Apr;115(4):1006-15. doi: 10.1172/JCI22365. Epub 2005 Mar 3.

Abstract

Mutations in the gene encoding hepatocyte nuclear factor-4alpha (HNF-4alpha) result in maturity-onset diabetes of the young (MODY). To determine the contribution of HNF-4alpha to the maintenance of glucose homeostasis by the beta cell in vivo, we derived a conditional knockout of HNF-4alpha using the Cre-loxP system. Surprisingly, deletion of HNF-4alpha in beta cells resulted in hyperinsulinemia in fasted and fed mice but paradoxically also in impaired glucose tolerance. Islet perifusion and calcium-imaging studies showed abnormal responses of the mutant beta cells to stimulation by glucose and sulfonylureas. These phenotypes can be explained in part by a 60% reduction in expression of the potassium channel subunit Kir6.2. We demonstrate using cotransfection assays that the Kir6.2 gene is a transcriptional target of HNF-4alpha. Our data provide genetic evidence that HNF-4alpha is required in the pancreatic beta cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Gene Expression Regulation*
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Glyburide / pharmacology
  • Hepatocyte Nuclear Factor 4
  • Hyperinsulinism
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / physiology
  • Mice
  • Mice, Knockout
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism*
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Promoter Regions, Genetic
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Hepatocyte Nuclear Factor 4
  • Hypoglycemic Agents
  • Insulin
  • Kir6.2 channel
  • Phosphoproteins
  • Potassium Channels, Inwardly Rectifying
  • Protein Subunits
  • Transcription Factors
  • Glucose
  • Glyburide
  • Calcium