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

Rana K Gupta, Marko Z. Vatamaniuk, Catherine S. Lee, Reed C. Flaschen, James T. Fulmer, Franz M. Matschinsky, Stephen A. Duncan, Klaus H. Kaestner

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Abstract

Mutations in the gene encoding hepatocyte nuclear factor-4α (HNF-4α) result in maturity-onset diabetes of the young (MODY). To determine the contribution of HNF-4α to the maintenance of glucose homeostasis by the β cell in vivo, we derived a conditional knockout of HNF-4α using the Cre-loxP system. Surprisingly, deletion of HNF-4α in β 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 β 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-4α. Our data provide genetic evidence that HNF-4α is required in the pancreatic β cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel.

Original languageEnglish (US)
Pages (from-to)1006-1015
Number of pages10
JournalJournal of Clinical Investigation
Volume115
Issue number4
DOIs
StatePublished - Apr 2005

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Hepatocyte Nuclear Factor 4
Insulin
Genes
Potassium Channels
Glucose
Glucose Intolerance
Secretory Pathway
Hyperinsulinism
Maturity-Onset Diabetes of the Young, Type 1
Homeostasis
Adenosine Triphosphate
Maintenance
Calcium
Phenotype
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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-4α regulates selected genes involved in insulin secretion. Journal of Clinical Investigation, 115(4), 1006-1015. https://doi.org/10.1172/JCI200522365

The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion. / Gupta, Rana K; Vatamaniuk, Marko Z.; Lee, Catherine S.; Flaschen, Reed C.; Fulmer, James T.; Matschinsky, Franz M.; Duncan, Stephen A.; Kaestner, Klaus H.

In: Journal of Clinical Investigation, Vol. 115, No. 4, 04.2005, p. 1006-1015.

Research output: Contribution to journalArticle

Gupta, RK, Vatamaniuk, MZ, Lee, CS, Flaschen, RC, Fulmer, JT, Matschinsky, FM, Duncan, SA & Kaestner, KH 2005, 'The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion', Journal of Clinical Investigation, vol. 115, no. 4, pp. 1006-1015. https://doi.org/10.1172/JCI200522365
Gupta, Rana K ; Vatamaniuk, Marko Z. ; Lee, Catherine S. ; Flaschen, Reed C. ; Fulmer, James T. ; Matschinsky, Franz M. ; Duncan, Stephen A. ; Kaestner, Klaus H. / The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion. In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 4. pp. 1006-1015.
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