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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue

Author

  • A Boucher
  • DH Lu
  • SC Burgess
  • S Telemaque-Potts
  • MV Jensen
  • Hindrik Mulder
  • MY Wang
  • RH Unger
  • AD Sherry
  • CB Newgard

Summary, in English

Hyperlipidemia appears to play an integral role in loss of glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. This impairment can be simulated in vitro by chronic culture of 832/13 insulinoma cells with high concentrations of free fatty acids, or by study of lipid-laden islets from Zucker diabetic fatty rats. Here we show that impaired GSIS is not a simple result of saturation of lipid storage pathways, as adenovirus-mediated overexpression of a cytosolically localized variant of malonyl-CoA decarboxylase in either cellular model results in dramatic lowering of cellular triglyceride stores but no improvement in GSIS. Instead, the glucose-induced increment in "pyruvate cycling" activity ( pyruvate exchange with tricarboxylic acid cycle intermediates measured by C-13 NMR), previously shown to play an important role in GSIS, is completely ablated in concert with profound suppression of GSIS in lipid-cultured 832/13 cells, whereas glucose oxidation is unaffected. Moreover, GSIS is partially restored in both lipid-cultured 832/13 cells and islets from Zucker diabetic fatty rats by addition of a membrane permeant ester of a pyruvate cycling intermediate ( dimethyl malate). We conclude that chronic exposure of islet beta-cells to fatty acids grossly alters a mitochondrial pathway of pyruvate metabolism that is important for normal GSIS.

Department/s

  • Department of Experimental Medical Science

Publishing year

2004

Language

English

Pages

27263-27271

Publication/Series

Journal of Biological Chemistry

Volume

279

Issue

26

Document type

Journal article

Publisher

ASBMB

Topic

  • Endocrinology and Diabetes

Status

Published

ISBN/ISSN/Other

  • ISSN: 1083-351X