Effect of CB-1 Antagonist (Rimonabant) to Increase Insulin Sensitivity, Independent of Weight Loss

Effect of CB-1 Antagonist (Rimonabant) to Increase Insulin Sensitivity, Independent of Weight Loss Recent evidence demonstrates t Recent evidence demonstrates that the CB1 receptor antagonist rimonabant (RIM) may have beneficial effects on glucose metabolism due to its promotion of weight loss, and reduced central adiposity. But clinical trials have suggested that RIM has positive metabolic effects that cannot be explained by weight loss alone. We undertook this study to assess the effects of chronic RIM treatment on insulin sensitivity (SI) and adiposity in dogs with established obesity-induced insulin resistance. At week -6, male mongrel dogs (n=9) were fed a hypercaloric high fat diet (HFD) ([sim]5400 kcal/d, 53% kcal from fat) for 6 weeks and subsequently treated orally with 1.25 mg/kg RIM (n=5) or placebo (n=4) for an additional 16 weeks, while being maintained on the HFD. Euglycemic clamps and MRIs were performed to assess SI and body adiposity, respectively, during pre-fat (W:-6), post-fat (W:0) and 16 weeks (W:16) of RIM. The initial fat feeding reduced whole body SI by more than 40% (p[lt]0.001) and increased body weight (+2.5+/-0.3 kg, p=0.04). Interestingly, by W:16 of RIM treatment, SI returned to normal pre-fat values (3.1[plusmn]0.3, W:0 vs. 2.6[plusmn]0.5, W:16, p=NS) In contrast, the placebo group remained insulin resistant (4.4[plusmn]0.9 W:0 vs. 1.9[plusmn]0.4 W:16, p=0.01) The placebo group continued to gain weight over the 16 weeks (+2.3 kg, p=0.03), while the RIM treated group maintained body weight. Similarly, omental fat content did not change in the RIM group (619[plusmn]89 to 583[plusmn]156 cm³, p=NS) but was increased in the placebo group (572[plusmn]308 to 784[plusmn]408 cm³, p=0.03). Thus, RIM did not lead to a reduction, but prevented, further fat accumulation and body weight. These data, however, are not consistent with the degree of enhancement of insulin sensitivity with RIM treatment. That RIM completely restored insulin sensitivity without significant reductions in either body weight or omental fat content supports a body-weight independent effect of rimonabant as an insulin sensitizer.[figure1] JOYCE M. RICHEY, ORISON WOOLCOTT, STELLA KIM, DARKO STEFANOVSKI, VIORICA IONUT, KARYN CATALANO, JENNY CHIU, ISABEL HSU, LISA HARRISON, MAYA LOTTATI, DAN ZHENG, MORVARID KABIR, EDWARD ZUNIGA, ERLINDA KIRKMAN, CATHRYN KOLKA, RICHARD BERGMAN, Los Angeles, CA 0248-OR Clinical Therapeutics/New Technology - Treatment of Insulin Resistance