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Protein phosphatase 1 (PP-1)-dependent inhibition of insulin secretion by leptin in INS-1 pancreatic β-cells and human pancreatic islets

Item Type:Article
Title:Protein phosphatase 1 (PP-1)-dependent inhibition of insulin secretion by leptin in INS-1 pancreatic β-cells and human pancreatic islets
Creators Name:Kuehnen, P. and Laubner, K. and Raile, K. and Schoefl, C. and Jakob, F. and Pilz, I. and Paeth, G. and Seufert, J.
Abstract:Leptin inhibits insulin secretion from pancreatic beta-cells, and in turn, insulin stimulates leptin biosynthesis and secretion from adipose tissue. Dysfunction of this adipoinsular feedback loop has been proposed to be involved in the development of hyperinsulinemia and type 2 diabetes mellitus. At the molecular level, leptin acts through various pathways, which in combination confer inhibitory effects on insulin biosynthesis and secretion. The aim of this study was to identify molecular mechanisms of leptin action on insulin secretion in pancreatic beta-cells. To identify novel leptin-regulated genes, we performed subtraction PCR in INS-1 beta-cells. Regulated expression of identified genes was confirmed by RT-PCR and Northern and Western blotting. Furthermore, functional impact on beta-cell function was characterized by insulin-secretion assays, intracellular Ca(2+) concentration measurements, and enzyme activity assays. PP-1alpha, the catalytic subunit of protein phosphatase 1 (PP-1), was identified as a novel gene down-regulated by leptin in INS-1 pancreatic beta-cells. Expression of PP-1alpha was verified in human pancreatic sections. PP-1alpha mRNA and protein expression is down-regulated by leptin, which culminates in reduction of PP-1 enzyme activity in beta-cells. In addition, glucose-induced insulin secretion was inhibited by nuclear inhibitor of PP-1 and calyculin A, which was in part mediated by a reduction of PP-1-dependent calcium influx into INS-1 beta-cells. These results identify a novel molecular pathway by which leptin confers inhibitory action on insulin secretion, and impaired PP-1 inhibition by leptin may be involved in dysfunction of the adipoinsular axis during the development of hyperinsulinemia and type 2 diabetes mellitus.
Keywords:Calcium, Confocal Microscopy, Cultured Cells, Cytosol, Gene Expression Regulation, Hela Cells, Hep G2 Cells, Immunohistochemistry, Insulin, Insulin-Secreting Cells, Insulinoma, Leptin, Northern Blotting, Pancreas, Protein Phosphatase 1, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cell Line, Western Blotting, Animals, Rats
Source:Endocrinology
ISSN:0013-7227
Publisher:Endocrine Society (U.S.A.)
Volume:152
Number:5
Page Range:1800-1808
Date:May 2011
Official Publication:https://doi.org/10.1210/en.2010-1094
PubMed:View item in PubMed

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