PED/PEA-15 regulates glucose-induced insulin secretion by restraining potassium channel expression in pancreatic beta-cells.
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.
Miele
Claudia
C
Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, via Sergio Pansini 5, Naples 80131, Italy.
Raciti
Gregory Alexander
GA
Cassese
Angela
A
Romano
Chiara
C
Giacco
Ferdinando
F
Oriente
Francesco
F
Paturzo
Flora
F
Andreozzi
Francesco
F
Zabatta
Assunta
A
Troncone
Giancarlo
G
Bosch
Fatima
F
Pujol
Anna
A
Chneiweiss
Hervé
H
Formisano
Pietro
P
Beguinot
Francesco
F
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D000099221:Protein Kinase C zeta
D051017:Apoptosis Regulatory Proteins; D005947:Glucose; D007328:Insulin; D010750:Phosphoproteins; D015221:Potassium Channels; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta; C490444:Pea15 protein, mouse