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Adenovirus-mediated overexpression of liver carnitine palmitoyltransferase I in INS1E cells: effects on cell metabolism and insulin secretion.

Authors: Rubi, B  Antinozzi, PA  Herrero, L  Ishihara, H  Asins, G  Serra, D  Wollheim, CB  Maechler, P  Hegardt, FG 
Citation: Rubi B, etal., Biochem J 2002 May 15;364(Pt 1):219-26.
Pubmed: (View Article at PubMed) PMID:11988095

Lipid metabolism in the beta-cell is critical for the regulation of insulin secretion. Pancreatic beta-cells chronically exposed to fatty acids show higher carnitine palmitoyltransferase I (CPT I) protein levels, higher palmitate oxidation rates and an altered insulin response to glucose. We examined the effect of increasing CPT I levels on insulin secretion in cultured beta-cells. We prepared a recombinant adenovirus containing the cDNA for the rat liver isoform of CPT I. The overexpression of CPT I in INS1E cells caused a more than a 5-fold increase in the levels of CPT I protein (detected by Western blotting), a 6-fold increase in the CPT activity, and an increase in fatty acid oxidation at 2.5 mM glucose (1.7-fold) and 15 mM glucose (3.1-fold). Insulin secretion was stimulated in control cells by 15 mM glucose or 30 mM KCl. INS1E cells overexpressing CPT I showed lower insulin secretion on stimulation with 15 mM glucose (-40%; P<0.05). This decrease depended on CPT I activity, since the presence of etomoxir, a specific inhibitor of CPT I, in the preincubation medium normalized the CPT I activity, the fatty-acid oxidation rate and the insulin secretion in response to glucose. Exogenous palmitate (0.25 mM) rescued glucose-stimulated insulin secretion (GSIS) in CPT I-overexpressing cells, indicating that the mechanism of impaired GSIS was through the depletion of a critical lipid. Depolarizing the cells with KCl or intermediary glucose concentrations (7.5 mM) elicited similar insulin secretion in control cells and cells overexpressing CPT I. Glucose-induced ATP increase, glucose metabolism and the triacylglycerol content remained unchanged. These results provide further evidence that CPT I activity regulates insulin secretion in the beta-cell. They also indicate that up-regulation of CPT I contributes to the loss of response to high glucose in beta-cells exposed to fatty acids.


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CRRD Object Information
CRRD ID: 1298597
Created: 2004-06-01
Species: All species
Last Modified: 2004-06-01
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.