PED/PEA-15 regulates glucose-induced insulin secretion by restraining potassium channel expression in pancreatic β-cells

Claudia Miele, Gregory Alexander Raciti, Angela Cassese, Chiara Romano, Ferdinando Giacco, Francesco Oriente, Flora Paturzo, Francesco Andreozzi, Assunta Zabatta, Giancarlo Troncone, Fatima Bosch, Anna Pujol, Hervé Chneiweiss, Pietro Formisano, Francesco Beguinot

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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.

Original languageEnglish (US)
Pages (from-to)622-633
Number of pages12
JournalDiabetes
Volume56
Issue number3
DOIs
StatePublished - Mar 1 2007

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Miele, C., Raciti, G. A., Cassese, A., Romano, C., Giacco, F., Oriente, F., Paturzo, F., Andreozzi, F., Zabatta, A., Troncone, G., Bosch, F., Pujol, A., Chneiweiss, H., Formisano, P., & Beguinot, F. (2007). PED/PEA-15 regulates glucose-induced insulin secretion by restraining potassium channel expression in pancreatic β-cells. Diabetes, 56(3), 622-633. https://doi.org/10.2337/db06-1260