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PED/PEA-15 Regulates Glucose-Induced Insulin Secretion by Restraining Potassium Channel Expression in Pancreatic ß-Cells

¹ Department of Cellular and Molecular Biology and Pathology and Institute of Experimental Endocrinology and Oncology—CNR, "Federico II" University of Naples, Naples, Italy
² Department of Clinical and Experimental Medicine, University of Catanzaro "Magna Graecia," Catanzaro, Italy
³ Department of Biomorphological and Functional Sciences, "Federico II" University of Naples, Naples, Italy
⁴ Center for Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Autonomous University of Barcelona, Barcelona, Spain
⁵ INSERM U752, University Paris 5 René Descartes, Paris, France

Address correspondence and reprint requests to Dr. Francesco Beguinot, Department of Cellular and Molecular Biology and Pathology, "Federico II" University of Naples, via Sergio Pansini, 5, Naples 80131, Italy. E-mail: beguino{at}unina.it

Abbreviations: 2-DG, 2-[1-³H]deoxy-D-glucose; PED/PEA-15, phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes; PKC, protein kinase C; RIA, radioimmunoassay

The phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (ped/pea-15) gene is overexpressed in human diabetes and causes this abnormality in mice. Transgenic mice with ß-cell–specific overexpression of ped/pea-15 (ß-tg) exhibited decreased glucose tolerance but were not insulin resistant. However, they showed impaired insulin response to hyperglycemia. Islets from the ß-tg also exhibited little response to glucose. mRNAs encoding the Sur1 and Kir6.2 potassium channel subunits and their upstream regulator Foxa2 were specifically reduced in these islets. Overexpression of PED/PEA-15 inhibited the induction of the atypical protein kinase C (PKC)- by glucose in mouse islets and in ß-cells of the MIN-6 and INS-1 lines. Rescue of PKC- activity elicited recovery of the expression of the Sur1, Kir6.2, and Foxa2 genes and of glucose-induced insulin secretion in PED/PEA-15–overexpressing ß-cells. Islets from ped/pea-15–null mice exhibited a twofold increased activation of PKC- by glucose; increased abundance of the Sur1, Kir6.2, and Foxa2 mRNAs; and enhanced glucose effect on insulin secretion. In conclusion, PED/PEA-15 is an endogenous regulator of glucose-induced insulin secretion, which restrains potassium channel expression in pancreatic ß-cells. Overexpression of PED/PEA-15 dysregulates ß-cell function and is sufficient to impair glucose tolerance in mice.

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