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Biochemical mechani...
Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue
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Boucher, A (author)
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Lu, DH (author)
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Burgess, SC (author)
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Telemaque-Potts, S (author)
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Jensen, MV (author)
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- Mulder, Hindrik (author)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
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Wang, MY (author)
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Unger, RH (author)
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Sherry, AD (author)
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Newgard, CB (author)
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(creator_code:org_t)
- 2004
- 2004
- English.
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In: Journal of Biological Chemistry. - 1083-351X. ; 279:26, s. 27263-27271
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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- art (subject category)
- ref (subject category)
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- By the author/editor
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Boucher, A
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Lu, DH
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Burgess, SC
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Telemaque-Potts, ...
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Jensen, MV
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Mulder, Hindrik
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show more...
-
Wang, MY
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Unger, RH
-
Sherry, AD
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Newgard, CB
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
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Journal of Biolo ...
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Lund University