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

Boucher, A; Lu, DH; Burgess, SC; Telemaque-Potts, S; Jensen, MV; Mulder, Hindrik LU ; Wang, MY; Unger, RH; Sherry, AD and Newgard, CB (2004) In Journal of Biological Chemistry 279(26). p.27263-27271
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
279
issue
26
pages
27263 - 27271
publisher
ASBMB
external identifiers
  • wos:000222120400055
  • scopus:3042591440
ISSN
1083-351X
DOI
10.1074/jbc.M401167200
language
English
LU publication?
yes
id
fa7af9d8-09e4-425c-a1aa-75863431cdc8 (old id 273900)
date added to LUP
2007-10-17 11:24:30
date last changed
2017-07-30 03:30:58
@article{fa7af9d8-09e4-425c-a1aa-75863431cdc8,
  abstract     = {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.},
  author       = {Boucher, A and Lu, DH and Burgess, SC and Telemaque-Potts, S and Jensen, MV and Mulder, Hindrik and Wang, MY and Unger, RH and Sherry, AD and Newgard, CB},
  issn         = {1083-351X},
  language     = {eng},
  number       = {26},
  pages        = {27263--27271},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue},
  url          = {http://dx.doi.org/10.1074/jbc.M401167200},
  volume       = {279},
  year         = {2004},
}