Physiological Anandamide Levels Potentiate Glucose-Stimulated Insulin Secretion in Isolated Canine Pancreatic Islets

Physiological Anandamide Levels Potentiate Glucose-Stimulated Insulin Secretion in Isolated Canine Pancreatic Islets Anandamide (AEA) is an endogen Anandamide (AEA) is an endogenous cannabinoid ligand and known to stimulate insulin secretion. Interestingly, AEA plasma levels are elevated in obesity. Therefore we hypothesize that AEA may contribute to the well-characterized insulin hypersecretion in response to insulin resistance in obesity.[br]Dog pancreatic islets were isolated at sacrifice. Insulin secretion, expressed as stimulation index (Sindex, ratio of glucose-stimulated insulin secretion [GSIS, insulin secreted during 1h-stimulation with glucose 15 mmol/L] over basal insulin secretion [BIS, 1h-unstimulated period with glucose 3 mmol/L]) was assessed in batches of 15 islets during static incubation in presence or absence of AEA. All experiments were done in 3-6 replicates. Supraphysiological concentrations of AEA (10 [mu]mol/L) stimulated BIS two-fold (p=0.018) in lean animals (n=7, BW=28.8 [plusmn] 1.0 kg). In another group maintained on a high fat diet for 22 weeks (n=5, BW=34.2 [plusmn] 1.6 kg), AEA stimulated BIS four-fold (p=0.043). Similarly, AEA 10 [mu]mol/L potentiated GSIS in lean and HFD animals (by three- [p=0.018] and four-fold [p=0.043], respectively). Cannabinoid 1 receptor (CB1R) antagonist rimonabant inhibited AEA effects on GSIS but not BIS, in both groups. Together, these results suggest that supraphysiological AEA effects on GSIS are mediated through CB1R. The presence of CB1R and CB2R in isolated islets was confirmed by real-time PCR. In addition, physiological AEA concentrations (10 nmol/L) potentiated GSIS (Sindex: 8.26 [plusmn] 1.72 vs. 6.69 [plusmn] 1.83; p=0.043) in another group of lean dogs (n=5, BW=27.2 [plusmn] 0.1 kg). Rimonabant (100 nmol/L) and the transient receptor potential vanilloid 1 channel (TRPV1) antagonist iodoresiniferatoxin (100 nmol/L) but not CB2R antagonist AM 630 (100 nmol/L) showed a trend to inhibit AEA effects on GSIS (p=0.138). Taken together, these results suggest that AEA effects on GSIS, at physiological concentrations, might be mediated partially through CB1R and TRPV1.[br]Our results are consistent with the notion that elevated anandamide plasma concentrations in obese patients might be sufficient to contribute to the compensatory hyperinsulinemia in response to insulin resistance. ORISON O. WOOLCOTT, JOYCE M. RICHEY, ROBERT H. CHOW, MORVARID KABIR, MALINI IYER, ERLINDA L. KIRKMAN, DARKO STEFANOVSKI, MAYA LOTTATI, L. NICOLE HARRISON, VIORICA IONUT, DAN ZHENG, ISABEL R. HSU, STELLA P. KIM, KARYN J. CATALANO, JENNY D. CHIU, RICHARD N. BERGMAN 1840-P Los Angeles, CA Obesity - Animal