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Molecular or Pharmacologic Perturbation of the Link between Glucose and Lipid Metabolism Is without Effect on Glucose-stimulated Insulin Secretion
The mechanism by which glucose stimulates insulin secretion from the pancreatic islets of Langerhans is incompletely understood. It has been suggested that malonyl-CoA plays a regulatory role by inhibiting fatty acid oxidation and promoting accumulation of cytosolic long-chain acyl-CoA (LC-CoA). In...
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Published in: | The Journal of biological chemistry 1998-06, Vol.273 (26), p.16146-16154 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | The mechanism by which glucose stimulates insulin secretion from the pancreatic islets of Langerhans is incompletely understood.
It has been suggested that malonyl-CoA plays a regulatory role by inhibiting fatty acid oxidation and promoting accumulation
of cytosolic long-chain acyl-CoA (LC-CoA). In the current study, we have re-evaluated this âlong-chain acyl-CoA hypothesisâ
by using molecular and pharmacologic methods to perturb lipid metabolism in INS-1 insulinoma cells or rat islets during glucose
stimulation. First, we constructed a recombinant adenovirus containing the cDNA encoding malonyl-CoA decarboxylase (AdCMV-MCD),
an enzyme that decarboxylates malonyl-CoA to acetyl-CoA. INS-1 cells treated with AdCMV-MCD had dramatically lowered intracellular
malonyl CoA levels compared with AdCMV-βGal-treated cells at both 3 and 20 m m glucose. Further, at 20 m m glucose, AdCMV-MCD-treated cells were less effective at suppressing [1- 14 C]palmitate oxidation and incorporated 43% less labeled palmitate and 50% less labeled glucose into cellular lipids than either
AdCMV-βGAL-treated or untreated INS-1 cells. Despite the large metabolic changes caused by expression of MCD, insulin secretion
in response to glucose was unaltered relative to controls. The alternative, pharmacologic approach for perturbing lipid metabolism
was to use triacsin C to inhibit long-chain acyl-CoA synthetase. This agent caused potent attenuation of palmitate oxidation
and glucose or palmitate incorporation into cellular lipids and also caused a 47% decrease in total LC-CoA. Despite this,
the drug had no effect on glucose-stimulated insulin secretion in islets or INS-1 cells. We conclude that significant disruption
of the link between glucose and lipid metabolism does not impair glucose-stimulated insulin secretion in pancreatic islets
or INS-1 cells. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.273.26.16146 |