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TRANSLATIONAL PHYSIOLOGY

Glibenclamide inhibits islet carnitine palmitoyltransferase 1 activity, leading to PKC-dependent insulin exocytosis

¹Department of Internal Medicine, Karolinska Institutet, Stockholm South Hospital, SE-118 83 Stockholm; ²Department of Medical Cell Biology, University of Uppsala, SE-751 23 Uppsala; ³Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Institutet, Karolinska Hospital, SE-171 76 Stockholm, Sweden; and ⁴Department of Pharmacology, College of Medicine, University of Tennessee, Memphis, Tennessee 38163

Submitted 10 February 2003 ; accepted in final form 6 April 2003

Hypoglycemic sulfonylureas such as glibenclamide have been widely used to treat type 2 diabetic patients for 40 yr, but controversy remains about their mode of action. The widely held view is that they promote rapid insulin exocytosis by binding to and blocking pancreatic -cell ATP-dependent K⁺ (K_ATP) 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 K_ATP channels and cytoplasmic free Ca²⁺. Also, glibenclamide 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 formation of malonyl-CoA, which, by blocking carnitine palmitoyltransferase 1 (CPT-1), switches fatty acid (FA) catabolism to synthesis of PKC-activating lipids. We show that glibenclamide dose-dependently inhibits -cell CPT-1 activity, consequently suppressing FA oxidation to the same extent as glucose in cultured fetal rat islets. This is associated with enhanced diacylglycerol (DAG) formation, PKC activation, and K_ATP-independent glibenclamide-stimulated insulin exocytosis. The fat oxidation inhibitor etomoxir stimulated K_ATP-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 FA metabolism to DAG synthesis and subsequent PKC-dependent and K_ATP-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.

diabetes mellitus; pancreatic islet; insulin secretion; sulfonylurea; protein kinase C; ATP-dependent K⁺ channels

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