Beneficial effect of a chronic treatment with rimonabant on pancreatic function and β-cell morphology in Zucker Fatty rats

Abstract

Recent studies suggested the involvement of the endocannabinoid pathway on insulin secretion in RINm5F cells or rat islets. Animal and clinical studies have reported beneficial effects of the selective cannabinoid 1 receptor antagonist rimonabant on glucose homeostasis. The aim of this study was to investigate the in vivo effects of rimonabant on pancreatic function in Zucker Fatty rats. Zucker Fatty rats were treated with rimonabant (10 mg⁎kg − 1 ⁎day − 1 ) or vehicle for up to 3 months. Pancreatic function was assessed by oral glucose tolerance test and by static incubation of islets in the presence of different glucose concentrations. Islet morphology was assessed by immuno-histochemistry on pancreatic sections. After 3 months, there was no difference in fasting glycaemia or AUC glucose during oral glucose tolerance test between rimonabant- and vehicle-treated animals. However, vehicle-treated rats developed a marked hyperinsulinaemia with time in contrast to rimonabant-treated animals, which maintained at 3 months significantly lower fasting insulin levels (7.76 ± 0.67 μg⁎l − 1 vs. 5.59 ± 0.59 μg⁎l − 1 , P < 0.01) and lower AUC insulin (1380 ± 98 μg⁎l − 1 ⁎min vs. 926 ± 58 μg⁎l − 1 ⁎min, respectively, P < 0.001). In static incubation, rimonabant significantly decreased insulin secretion in response to low glucose concentration (3 months: 7.68 ± 1.29 vs. 12.25 ± 2.01 μg⁎l − 1 ⁎5islets − 1 ⁎45 min − 1 in rimonabant and vehicle respectively, P < 0.01), resulting in a trend to increase stimulation index in the presence of 16.7 mM glucose (10.64 ± 0.92 vs. 8.52 ± 1.70 respectively). Morphological analysis at 3 months showed that rimonabant reduced islet-cell surface (− 60%) and the percentage of disorganized islets (− 54%).In conclusion, our data suggest that rimonabant has a protective role against the development of hyperinsulinaemia, β-cell dysfunction and islet modification in Zucker Fatty rats.