The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 2005 Apr;115(4):1006-15
Date
03/12/2005Pubmed ID
15761495Pubmed Central ID
PMC1059446DOI
10.1172/JCI22365Scopus ID
2-s2.0-16844366885 (requires institutional sign-in at Scopus site) 210 CitationsAbstract
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.
Author List
Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, Duncan SA, Kaestner KHMESH terms used to index this publication - Major topics in bold
AnimalsCalcium
DNA-Binding Proteins
Diabetes Mellitus, Type 2
Female
Gene Expression Regulation
Glucose
Glucose Tolerance Test
Glyburide
Hepatocyte Nuclear Factor 4
Hyperinsulinism
Hypoglycemic Agents
Insulin
Islets of Langerhans
Mice
Mice, Knockout
Phosphoproteins
Potassium Channels, Inwardly Rectifying
Promoter Regions, Genetic
Protein Subunits
Transcription Factors
