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-cell fatty acid metabolism to synthesis of diacylglycerol - a mechanism that may result in PKC-dependent and KATP-independent insulin exocytosis
1 Department of Internal Medicine, Karolinska Institutet, Stockholm, Sweden
2 Department of Medical Cell Biology, University of Uppsala, Uppsala, Sweden
3 Department of Molecular Medicine, Karolinska Institutet, The Rolf Luft Center for Diabetes Research, Stockholm, Sweden
4 Department of Pharmacology, University of Tennessee, College of Medicine, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: ake.sjoholm{at}sos.sll.se.
Hypoglycemic sulfonylureas, such as glibenclamide, have been widely used clinically in the treatment of patients with type 2 diabetes mellitus for the past 40 years, but there is still much controversy about their mode of action. The widely held view is that they promote rapid insulin exocytosis by binding to, and thereby blocking, pancreatic 
-cell ATP-dependent K+ (KATP) channels in the plasma membrane. This event stimulates Ca2+ influx and sets in motion the exocytotic release of insulin. However, recent reports show that > 90 % of glibenclamide binding sites are localized intracellularly and that the drug can stimulate insulin release independently of changes in KATP channels and cytoplasmic free Ca2+. Additionally, glibenclamide among the sulfonylureas specifically and progressively accumulates in islets in association with secretory granules and mitochondria, and causes long-lasting insulin secretion. It has been proposed that nutrient insulin secretagogues stimulate insulin release by increasing the formation of malonyl-CoA, which, by blocking carnitine palmitoyltransferase 1 (CPT-1), switches fatty acid catabolism to synthesis of PKC-activating lipids. We now show that glibenclamide dose-dependently inhibits -cell CPT-1 activity and, consequently, suppresses fatty acid oxidation to the same extent as glucose in cultured fetal rat islets. This is associated with enhanced diacylglycerol formation, PKC activation, and KATP-independent glibenclamide-stimulated insulin exocytosis. The fat oxidation inhibitor, etomoxir, stimulated KATP-independent insulin secretion to the same extent as glibenclamide and the action of both drugs was not additive. We propose a mechanism in which inhibition of CPT-1 activity by glibenclamide switches -cell fatty acid metabolism to the synthesis of diacylglycerol and subsequent PKC-dependent, KATP-independent insulin exocytosis. We suggest that chronic CPT inhibition, through the progressive islet accumulation of glibenclamide, may explain the prolonged stimulation of insulin secretion in some diabetic patients even after drug removal that contributes to the sustained hypoglycemia of the sulfonylurea.
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