| First Author | Gupta RK | Year | 2005 |
| Journal | J Clin Invest | Volume | 115 |
| Issue | 4 | Pages | 1006-15 |
| PubMed ID | 15761495 | Mgi Jnum | J:97364 |
| Mgi Id | MGI:3575336 | Doi | 10.1172/JCI22365 |
| Citation | Gupta RK, et al. (2005) The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 115(4):1006-1015 |
| abstractText | 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. |
