The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion
Rana K. Gupta, … , Stephen A. Duncan, Klaus H. Kaestner
Rana K. Gupta, … , Stephen A. Duncan, Klaus H. Kaestner
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):1006-1015. https://doi.org/10.1172/JCI22365.
View: Text | PDF
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

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
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.