Article

The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion. J Clin Invest

Department of Genetics, Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 05/2005; 115(4):1006-15. DOI: 10.1172/JCI22365
Source: PubMed

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.

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    • "It has been suggested that PPAR-a directs fatty acids to the b-oxidation pathway and promotes an elevation of insulin secretion during hypoglycaemia (Sugden & Holness 2004). This hypothesis is supported by the reduction in PPAR-a expression in b-cell Hnf4a-null mice (Gupta et al. 2005). Moreover, Ppara-null mice have also been reported to develop fasted HH (Gremlich et al. 2005). "
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    • "PPARα is a transcription factor that is known to control the expression of genes encoding enzymes of the beta oxidation pathway of fatty acids. Low levels of PPARα are reported in HNF-4α deficient β-cells.[37] It can be postulated that HNF-4α deficiency causes lower levels of PPARα and a decrease in beta-oxidation of fatty acids resulting in the accumulation of lipids (such as malonyl-CoA) in the cytoplasm. "
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