Inhibition of glucose-induced insulin secretion by a peripheral-type benzodiazepine receptor ligand (PK 11195)

We have recently shown that benzodiazepines with high affinity for peripher al-type receptors such as 4'-chlordiazepam inhibit insulin secretion in vit ro. PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline -carboxamide], a potent and selective ligand for peripheral benzodiazepine binding sites, was also shown to inhibit insulin release from rat pancreati c islets. Both substances have been reported to interact with mitochondrial binding sites. Hence, the present study was performed to investigate the e ffects of PK 11195 on insulin secretion induced by either a metabolic or a non-metabolic stimulus. In the rat isolated pancreas perfused at a constant pressure with a Krebs-bicarbonate buffer containing a slightly stimulating glucose concentration (8.3 mM), PK 11195 (10(-7)-10(-5) M) induced a progr essive and concentration-dependent decrease in insulin secretion. Simultane ously, we recorded the effects on the pancreatic now rate: in contrast to 4 '-chlordiazepam. previously shown to induce vasodilation in the same prepar ation, PK 11195 was ineffective. The differential effects of these two subs tances on vascular resistance and insulin secretion may suggest the existen ce of different subtypes of peripheral benzodiazepine receptors on pancreat ic p-cells and vessels. A metabolic stimulation of insulin secretion was in duced by a glucose increment from 4.2 mM to 8.4 mM or by 2 mM alpha-ketoiso caproic acid (KIC), which is directly metabolized in the mitochondria; thes e stimulations could be reduced by 10(-5) M PK 11195 (P<0.05). In contrast, the drug was ineffective on the insulin secretion induced by 5 mM or 10 mM KCl in the presence of a non-stimulating glucose concentration (4.2 mM). T hese results suggest that PK 11195 inhibits insulin secretion by interferin g with mitochondrial oxidative metabolism.