title: The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion.
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.
authors.affiliation: Department of Genetics, Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Rana K
authors.initials: RK
authors.lastname: Gupta
authors.forename: Marko Z
authors.initials: MZ
authors.lastname: Vatamaniuk
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Lee
authors.forename: Reed C
authors.initials: RC
authors.lastname: Flaschen
authors.forename: James T
authors.initials: JT
authors.lastname: Fulmer
authors.forename: Franz M
authors.initials: FM
authors.lastname: Matschinsky
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Duncan
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D005905:Glyburide / Q000494:pharmacology; D051557:Hepatocyte Nuclear Factor 4; D006946:Hyperinsulinism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000099161:Kcnj11 Channel
chemical_list: D002118:Calcium; D004268:DNA-Binding Proteins; D005947:Glucose; D005905:Glyburide; D051557:Hepatocyte Nuclear Factor 4; D007004:Hypoglycemic Agents; D007328:Insulin; D010750:Phosphoproteins; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D014157:Transcription Factors; D000099161:Kcnj11 Channel