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
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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Article Metabolism

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

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.

Authors

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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Deletion of HNF-4α in β cells results in hyperinsulinemia and impaired g...
Deletion of HNF-4α in β cells results in hyperinsulinemia and impaired glucose tolerance in vivo. (A) In the fed state (Fed) and after an overnight (16-hour) fast (Fast), blood glucose concentrations are decreased in HNF-4αloxP/loxP; Ins.Cre mice compared with littermate controls. (B) Plasma insulin levels are elevated in HNF-4α mutants in both the fed and overnight-fasted states. (C) Fasting plasma glucagon levels in the mutants were indistinguishable from controls. (D) The ratio of plasma insulin to plasma glucagon is elevated 70% in HNF-4αloxP/loxP; Ins.Cre mice. (E) Glucose tolerance test. After an overnight fast, 3- to 5-month-old HNF-4αloxP/loxP; Ins.Cre mice and littermate controls were challenged with 2 grams of glucose per kilogram of body weight. The blood glucose elevation is significantly higher in HNF-4αloxP/loxP; Ins.Cre mice than in controls, indicating impaired glucose tolerance in the HNF-4α mutants. (F) Following glucose injection (3 g/kg body weight), HNF-4α mutants exhibit a diminished first-phase insulin secretory response in comparison to controls. (G) Insulin tolerance test. Mutant and control mice that had fasted for 4 hours were injected with 0.75 units of insulin per kilogram of body weight. The insulin sensitivity of HNF-4α mutants is indistinguishable from that of controls. *P < 0.05 by Student’s t test or ANOVA; n = 8–13 animals per group for each experiment.