Abstract
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 "long-chain acyl-CoA hypothesis" 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-betaGal-treated cells at both 3 and 20 mM glucose. Further, at 20 mM glucose, AdCMV-MCD-treated cells were less effective at suppressing [1-14C]palmitate oxidation and incorporated 43% less labeled palmitate and 50% less labeled glucose into cellular lipids than either AdCMV-betaGAL-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.
Highlights
The mechanism by which glucose stimulates insulin secretion from the pancreatic islets of Langerhans is incompletely understood
Two important observations that led to development of the hypothesis were: 1) increasing glycolytic flux in -cells by increasing the extracellular glucose concentration led to an increase in malonyl-CoA levels proportional to insulin secretion [3, 4], and 2) glucose-mediated alterations in malonyl-CoA levels were linked to changes in lipid metabolism and the cytosolic long-chain acyl-CoA (LC-CoA) pool, which in turn was suggested to trigger insulin secretion by an undefined mechanism [3,4,5]
Increasing glycolytic flux in -cells by increasing the extracellular glucose concentration leads to an increase in malonyl-CoA levels that is proportional to insulin secretion
Summary
The mechanism by which glucose stimulates insulin secretion from the pancreatic islets of Langerhans is incompletely understood. 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 caused a 47% decrease in total LC-CoA. The increase in malonyl-CoA, acting via its capacity to inhibit the mitochondrial enzyme carnitine palmitoyltransferase I [6], results in inhibition of fatty acid oxidation, increased de novo lipid synthesis, and a rise in diacylglycerol content These findings led Prentki and colleagues [3, 4] to propose that increases in the levels of cytosolic long-chain acyl-CoA (LC-CoA) esters are a signal transduction intermediate in glucose-stimulated insulin secretion, and this idea has come to be known as the “long-chain acyl-CoA hypothesis.”. We demonstrate that while both approaches have a large impact on lipid metabolism in the -cell, neither maneuver influences glycolytic flux or glucose-stimulated insulin secretion
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