[HTML][HTML] The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion
RK Gupta, MZ Vatamaniuk, CS Lee… - The Journal of …, 2005 - Am Soc Clin Investig
The Journal of clinical investigation, 2005•Am Soc Clin Investig
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-4 α using the Cre-loxP system. Surprisingly, deletion of HNF-4 α 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 …
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-4 α using the Cre-loxP system. Surprisingly, deletion of HNF-4 α 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 …
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.
The Journal of Clinical Investigation