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

Publication ,  Journal Article
Gupta, RK; Vatamaniuk, MZ; Lee, CS; Flaschen, RC; Fulmer, JT; Matschinsky, FM; Duncan, SA; Kaestner, KH
Published in: J Clin Invest
April 2005

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.

Duke Scholars

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

April 2005

Volume

115

Issue

4

Start / End Page

1006 / 1015

Location

United States

Related Subject Headings

  • Transcription Factors
  • Protein Subunits
  • Promoter Regions, Genetic
  • Potassium Channels, Inwardly Rectifying
  • Phosphoproteins
  • Mice, Knockout
  • Mice
  • Islets of Langerhans
  • Insulin
  • Immunology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gupta, R. K., Vatamaniuk, M. Z., Lee, C. S., Flaschen, R. C., Fulmer, J. T., Matschinsky, F. M., … Kaestner, K. H. (2005). The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest, 115(4), 1006–1015. https://doi.org/10.1172/JCI22365
Gupta, Rana K., Marko Z. Vatamaniuk, Catherine S. Lee, Reed C. Flaschen, James T. Fulmer, Franz M. Matschinsky, Stephen A. Duncan, and Klaus H. Kaestner. “The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion.J Clin Invest 115, no. 4 (April 2005): 1006–15. https://doi.org/10.1172/JCI22365.
Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, et al. The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest. 2005 Apr;115(4):1006–15.
Gupta, Rana K., et al. “The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion.J Clin Invest, vol. 115, no. 4, Apr. 2005, pp. 1006–15. Pubmed, doi:10.1172/JCI22365.
Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, Duncan SA, Kaestner KH. The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest. 2005 Apr;115(4):1006–1015.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

April 2005

Volume

115

Issue

4

Start / End Page

1006 / 1015

Location

United States

Related Subject Headings

  • Transcription Factors
  • Protein Subunits
  • Promoter Regions, Genetic
  • Potassium Channels, Inwardly Rectifying
  • Phosphoproteins
  • Mice, Knockout
  • Mice
  • Islets of Langerhans
  • Insulin
  • Immunology