PED/PEA-15 Regulates Glucose-Induced Insulin Secretion by Restraining Potassium Channel Expression in Pancreatic β-Cells
- 1 March 2007
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 56 (3), 622-633
- https://doi.org/10.2337/db06-1260
Abstract
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 β-cell–specific overexpression of ped/pea-15 (β-tg) exhibited decreased glucose tolerance but were not insulin resistant. However, they showed impaired insulin response to hyperglycemia. Islets from the β-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)-ζ by glucose in mouse islets and in β-cells of the MIN-6 and INS-1 lines. Rescue of PKC-ζ 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 β-cells. Islets from ped/pea-15–null mice exhibited a twofold increased activation of PKC-ζ 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 β-cells. Overexpression of PED/PEA-15 dysregulates β-cell function and is sufficient to impair glucose tolerance in mice.Keywords
This publication has 36 references indexed in Scilit:
- Overexpression of the ped/pea-15 Gene Causes Diabetes by Impairing Glucose-Stimulated Insulin Secretion in Addition to Insulin ActionMolecular and Cellular Biology, 2004
- RSK2 Activity Is Regulated by Its Interaction with PEA-15Published by Elsevier BV ,2003
- Protein Kinase B/Akt Binds and Phosphorylates PED/PEA-15, Stabilizing Its Antiapoptotic ActionMolecular and Cellular Biology, 2003
- Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Death-inducing Signaling Complex and Its Modulation by c-FLIP and PED/PEA-15 in Glioma CellsJournal of Biological Chemistry, 2002
- Foxa2 (HNF3β) Controls Multiple Genes Implicated in Metabolism-Secretion Coupling of Glucose-induced Insulin ReleaseJournal of Biological Chemistry, 2002
- Multiple Members of the Mitogen-activated Protein Kinase Family Are Necessary for PED/PEA-15 Anti-apoptotic FunctionJournal of Biological Chemistry, 2002
- Preserved Pancreatic β-Cell Development and Function in Mice Lacking the Insulin Receptor-Related ReceptorMolecular and Cellular Biology, 2001
- Effects of transiently expressed atypical (ζ, λ), conventional (α, β) and novel (δ, ε) protein kinase C isoforms on insulin-stimulated translocation of epitope-tagged GLUT4 glucose transporters in rat adipocytes: specific interchangeable effects of protein kinases C-ζ and C-λBiochemical Journal, 1999
- Possible Involvement of Atypical Protein Kinase C(PKC) in Glucose-Sensitive Expression of the Human Insulin Gene: DNA-Binding Activity and Transcriptional Activity of Pancreatic and Duodenal Homeobox Gene-1(PDX-1) Are Enhanced via Calphostin C-Sensitive but Phorbol 12-Myristate 13-Acetate(PMA) and Goe 6976-Insensitive Pathway.Endocrine Journal, 1999
- Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4Nature, 1970