Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/273900
- author
- Boucher, A ; Lu, DH ; Burgess, SC ; Telemaque-Potts, S ; Jensen, MV ; Mulder, Hindrik LU ; Wang, MY ; Unger, RH ; Sherry, AD and Newgard, CB
- organization
- publishing date
- 2004
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 279
- issue
- 26
- pages
- 27263 - 27271
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000222120400055
- scopus:3042591440
- pmid:15073188
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M401167200
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Metabolism (013212001)
- id
- fa7af9d8-09e4-425c-a1aa-75863431cdc8 (old id 273900)
- date added to LUP
- 2016-04-01 11:35:21
- date last changed
- 2022-03-20 08:05:46
@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 = {{American Society for Biochemistry and Molecular Biology}}, 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}}, doi = {{10.1074/jbc.M401167200}}, volume = {{279}}, year = {{2004}}, }