Inhibition of glucose-induced insulin secretion by a peripheral-type benzodiazepine receptor ligand (PK11195).
We have recently shown that benzodiazepines with high affinity for peripheral-type receptors such as 4'-chlordiazepam inhibit insulin secretion in vitro. PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxami de], a potent and selective ligand for peripheral benzodiazepine binding sites, was also shown to inhibit insulin release from rat pancreatic islets. Both substances have been reported to interact with mitochondrial binding sites. Hence, the present study was performed to investigate the effects 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 progressive and concentration-dependent decrease in insulin secretion. Simultaneously, we recorded the effects on the pancreatic flow rate; in contrast to 4'-chlordiazepam, previously shown to induce vasodilation in the same preparation, PK 11195 was ineffective. The differential effects of these two substances on vascular resistance and insulin secretion may suggest the existence of different subtypes of peripheral benzodiazepine receptors on pancreatic beta-cells and vessels. A metabolic stimulation of insulin secretion was induced by a glucose increment from 4.2 mM to 8.4 mM or by 2 mM alpha-ketoisocaproic acid (KIC), which is directly metabolized in the mitochondria; these 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 nonstimulating glucose concentration (4.2 mM). These results suggest that PK 11195 inhibits insulin secretion by interfering with mitochondrial oxidative metabolism.
Laboratory of Pharmacology, Faculty of Medicine, Institute of Biology, Montpellier I University, France.
D
D
Pujalte
S
S
Claeysen
S
S
Dietz
J
J
Chapal
D
D
Hillaire-Buys
P
P
Petit
D000818:Animals; D058787:GABA-A Receptor Antagonists; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D007651:Keto Acids / Q000494:pharmacology; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D058787:GABA-A Receptor Antagonists; D007328:Insulin; D007546:Isoquinolines; D007651:Keto Acids; D011189:Potassium Chloride; C013082:alpha-ketoisocaproic acid; D005947:Glucose; C037850:PK 11195