Evidence of Increased CB-1 Receptor Activity in Isolated Pancreatic Islets from High Fat-Fed Dogs

Evidence of Increased CB-1 Receptor Activity in Isolated Pancreatic Islets from High Fat-Fed Dogs Endocannabinoid CB1 receptors Endocannabinoid CB1 receptors have been identified in pancreatic b-cells. However, the role of these receptors in insulin release is poorly understood. Recent data in isolated islets from rodents suggest that CB-1 receptor antagonism with rimonabant (RIM) suppresses insulin release. We investigated the role of the CB-1 receptor in insulin secretion (InsSec) under non-stimulated (NS, 3 mM) and glucose-stimulated (GS, 15mM) conditions in isolated islets from lean and diet-induced obese dogs.Nine male mongrel dogs were studied: 5 obese (body weight: 34 ± 1.7 kg) maintained on a 22 week hypercaloric high-fat diet (HFD group) and 4 lean (29.7 ± 0.5 kg) maintained on a standard diet (L). The effects of RIM and anandamide (AEA; CB1 receptor agonist) on InsSec were tested in isolated pancreatic islets. After 1 h incubation with 3 mM glucose, islets were incubated for an additional hour in low 3 mM (NS) or high glucose 15 mM (GS) and then exposed to one of 3 experimental conditions; RIM (10 mM) alone, AEA (10 mM) alone, or both AEA + RIM. β-Cell response was calculated from the ratio of stimulated to basal InsSec (stimulation index, SI). In contrast to previous reports, RIM alone did not decrease InsSec and essentially had no effect in either group, under NS or GS conditions. However, AEA potentiated insulin release in both HFD (by 311 ± 84%, p<0.001) and L groups (213 ± 89%, p<0.05) under NS conditions. Interestingly, AEA +RIM diminished the effect of AEA alone in the L group p<0.01) but not in the HFD group (p=n.s.) under NS conditions. Under GS conditions, AEA significantly enhanced InsSec in the L group (SI: 6.0 ± 0.9 vs. 19.2 ± 2.9 [p<0.01]), but not in the HFD group (SI: 13.2 ± 3.8 vs. 26.4 ± 7.9 [p=n.s.]). In conclusion, we found no evidence of an effect of RIM alone to alter insulin release. In comparison to the L group under NS conditions, RIM was unable to block the potentiating effects of AEA in the HFD group. In addition, under GS conditions, AEA produced a further increase in InsSec in the L group but not in the HFD group. These data suggest possible increased activity of CB-1 receptors in a state of obesity, consistent with data supporting amplification of the endocannabinoid system in obesity. ORISON O. WOOLCOTT, JOYCE M. RICHEY, ROBERT CHOW, ERLINDA L. KIRKMAN, DARKO STEFANOVSKI, ISABEL R. HSU, MAYA LOTTATI, VIORICA IONUT, DAN ZHENG, L. NICOLE HARRISON, MORVARID KABIR, CATHRYN M. KOLKA, STELLA P. KIM, RICHARD N. BERGMAN 1643-P Los Angeles, CA Islet Biology - Metabolic Regulation