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Erik Renström

Erik Renström

Vice-chancellor

Erik Renström

Glutaredoxin-1 mediates NADPH-dependent stimulation of calcium-dependent insulin secretion.

Author

  • Thomas Reinbothe
  • Rosita Ivarsson
  • Dai-Qing Li
  • Omid Niazi
  • Xingjun Jing
  • Enming Zhang
  • Lena Stenson
  • Ulrika Bryborn
  • Erik Renström

Summary, in English

Nicotinamide adenine dinucleotide phosphate (NADPH) enhances Ca(2+)-induced exocytosis in pancreatic beta-cells, an effect suggested to involve the cytosolic redox protein glutaredoxin-1 (GRX-1). We here detail the role of GRX-1 in NADPH-stimulated beta-cell exocytosis and glucose-stimulated insulin secretion. Silencing of GRX-1 by RNA interference reduced glucose-stimulated insulin secretion in both clonal INS-1 832/13 cells and primary rat islets. GRX-1 silencing did not affect cell viability or the intra-cellular redox environment, suggesting that GRX-1 regulates the exocytotic machinery by a local action. By contrast, knockdown of the related protein thioredoxin-1 (TRX-1) was ineffective. Confocal immunocytochemistry revealed that GRX-1 locates to the cell periphery, whereas TRX-1 expression is uniform. These data suggest that the distinct subcellular localizations of TRX-1 and GRX-1 result in differences in substrate specificities and actions on insulin secretion. Single-cell exocytosis was likewise suppressed by GRX-1 knockdown in both rat beta-cells and clonal 832/13 cells, whereas after overexpression exocytosis increased by approximately 40%. Intracellular addition of NADPH (0.1 mM) stimulated Ca(2+)-evoked exocytosis in both cell types. Interestingly, the stimulatory action of NADPH on the exocytotic machinery coincided with a approximately 30% inhibition in whole-cell Ca(2+) currents. After GRX-1 silencing, NADPH failed to amplify insulin release, but still inhibited Ca(2+) currents in 832/13 cells. In conclusion, NADPH stimulates the exocytotic machinery in pancreatic beta-cells. This effect is mediated by the NADPH acceptor protein GRX-1 by a local redox reaction that accelerates beta-cell exocytosis and, in turn, insulin secretion.

Department/s

  • Diabetes - Islet Patophysiology
  • Insulin Signal Transduction

Publishing year

2009

Language

English

Pages

893-900

Publication/Series

Molecular Endocrinology

Volume

23

Document type

Journal article

Publisher

The Endocrine Society

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Islet Patophysiology
  • Insulin Signal Transduction

ISBN/ISSN/Other

  • ISSN: 0888-8809