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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 beta-cell-specific overexpression of ped/pea-15 (beta-tg) exhibited decreased glucose tolerance but were not insulin resistant. However, they showed impaired insulin response to hyperglycemia. Islets from the beta-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)-zeta by glucose in mouse islets and in beta-cells of the MIN-6 and INS-1 lines. Rescue of PKC-zeta 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 beta-cells. Islets from ped/pea-15-null mice exhibited a twofold increased activation of PKC-zeta 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 beta-cells. Overexpression of PED/PEA-15 dysregulates beta-cell function and is sufficient to impair glucose tolerance in mice. [ABSTRACT FROM AUTHOR]

The phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (ped/pea-15) gene is overexpressed in tissues of individuals with type 2 diabetes. Moreover, transgenic mice ubiquitously overexpressing ped/pea-15 feature impaired glucose tolerance and insulin resistance. We have now generated transgenic mice with beta-cell specific overexpressing of ped/pea-15 (beta-tg). Beta-tg mice exhibited decreased glucose tolerance but were not insulin-resistant. However, they showed impaired insulin response to hyperglycemia. Islets from the beta-tg also exhibited little response to glucose. mRNAs encoding the Surl 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 PKCzeta by glucose in mouse islets and in beta-cells of the MIN-6 and INS-1 lines. Rescue of PKCzeta 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 beta-cells. Islets from ped/pea-15 null mice exhibited a 2-fold increased activation of PKCzeta by glucose and increased abundance of the Surl, 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 beta-cells. Overexpression of ped/pea-15 dysregulates beta-cell function and is sufficient to impair glucose tolerance in mice. [ABSTRACT FROM AUTHOR]