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Selective Deletion of the Hnf1ß (MODY5) Gene in ß-Cells Leads to Altered Gene Expression and Defective Insulin Release

Pediatric Endocrine Unit (L.W., G.E., T.M., L.L.L., D.B.R.), MassGeneral Hospital for Children, and Laboratory of Molecular Endocrinology and Diabetes Unit (M.K.T.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and Unité Expression Génétique et Maladies (C.C., L.G., M.Y.), Unité de Recherche Associée, Centre National de la Recherche Scientifique 1644, Institut Pasteur, 75724 Paris, France

Address all correspondence and requests for reprints to: David B. Rhoads, Ph.D., Pediatric Endocrine Unit, MassGeneral Hospital for Children, 55 Fruit Street BHX410, Boston, Massachusetts 02114-2696. E-mail: drhoads{at}partners.org.

Hepatocyte nuclear factor 1 (HNF1) and HNF1ß (or vHNF1) are closely related transcription factors expressed in liver, kidney, gut, and pancreatic ß-cells. Many HNF1 target genes are involved in carbohydrate metabolism. Human mutations in HNF1 or HNF1ß lead to maturity-onset diabetes of the young (MODY3 and MODY5, respectively), and patients present with impaired glucose-stimulated insulin secretion. The underlying defect in MODY5 is not known. Analysis of HNF1ß deficiency in mice has not been possible because HNF1ß null mice die in utero. To examine the role of HNF1ß in glucose homeostasis, viable mice deleted for HNF1ß selectively in ß-cells (ß/H1ß-KO mice) were generated using a Cre-LoxP strategy. ß/H1ß-KO mice had normal growth, fertility, fed or fasted plasma glucose and insulin levels, pancreatic insulin content, and insulin sensitivity. However, ß/H1ß-KO mice exhibited impaired glucose tolerance with reduced insulin secretion compared with wild-type mice but preserved a normal insulin secretory response to arginine. Moreover, ß/H1ß-KO islets had increased HNF1 and Pdx-1, decreased HNF4 mRNA levels, and reduced glucose-stimulated insulin release. These results indicate that HNF1ß is involved in regulating the ß-cell transcription factor network and is necessary for glucose sensing or glycolytic signaling.

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