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- Title
The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion.
- Authors
Gupta, Rana K.; Vatamaniuk, Marko Z.; Lee, Catherine S.; Flaschen, Reed C.; Fulmer, James T.; Matschinsky, Franz M.; Duncan, Stephen A.; Kaestner, Klaus H.
- 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.
- Subjects
INSULIN; GENETIC mutation; LIVER cells; DIABETES; GLUCOSE; HOMEOSTASIS; CALCIUM metabolism; POTASSIUM metabolism; PROTEIN metabolism; GLUCOSE metabolism; ANIMAL experimentation; CELL receptors; COMPARATIVE studies; GENES; GLUCOSE tolerance tests; HYPERINSULINISM; HYPOGLYCEMIC agents; HYPOGLYCEMIC sulfonylureas; ISLANDS of Langerhans; RESEARCH methodology; MEDICAL cooperation; MICE; TYPE 2 diabetes; PHOSPHOPROTEINS; POTASSIUM; PROTEINS; RESEARCH; TRANSCRIPTION factors; DNA-binding proteins; EVALUATION research; PHARMACODYNAMICS; PHYSIOLOGY
- Publication
Journal of Clinical Investigation, 2005, Vol 115, Issue 4, p1006
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI200522365