Acute Activation of Cannabinoid Receptors by Anandamide Reduces Gastrointestinal Motility and Improves Postprandial Glycemia in Mice

Abstract

The endocannabinoid system (ECS) is associated with an alteration of glucose homeostasis dependent on cannabinoid receptor-1 (CB1R) activation. However, very little information is available concerning the consequences of ECS activation on intestinal glucose absorption. Mice were injected intraperitoneally with anandamide, an endocannabinoid binding both CB1R and CB2R. We measured plasma glucose and xylose appearance after oral loading, gastrointestinal motility, and glucose transepithelial transport using the everted sac method. Anandamide improved hyperglycemia after oral glucose charge whereas glucose clearance and insulin sensitivity were impaired, pointing out some gastrointestinal events. Plasma xylose appearance was delayed in association with a strong decrease in gastrointestinal transit, while anandamide did not alter transporter-mediated glucose absorption. Interestingly, transit was nearly normalized by coinjection of SR141716 and AM630 (CB1R and CB2R antagonist, respectively), and AM630 also reduced the delay of plasma glucose appearance induced by anandamide. When gastric emptying was bypassed by direct glucose administration in the duodenum, anandamide still reduced plasma glucose appearance in wild-type but not in CB1R−/− mice. In conclusion, our findings demonstrated that acute activation of intestinal ECS reduced postprandial glycemia independently on intestinal glucose transport but rather inhibiting gastric emptying and small intestine motility and strongly suggest the involvement of both CB1R and CB2R.

Gut microbiota, obesity and diabetes

“…The second proposed target for T2D probiotic therapy is the eCB system, already discussed in relation to obesity 226. CB 1 is involved in gut permeability and modulation of the gut microbiota appears to yield similar responses to CB 1 antagonists, upregulating expression and correcting the localisation of intestinal epithelial tight junction proteins, occludin and zonula occludens1 227.…”

Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice

“…Central CB1 stimulation leads to increase food intake (Di Marzo et al, 2001; Silvestri and Di Marzo, 2013), and CB1 blockade induces weight loss (Van Gaal et al, 2005). Conversely, peripheral CB1s play an important role in glucose homeostasis by modulating lipogenesis in liver and adipose tissues (Cota et al, 2003; Matias et al, 2006; Osei-Hyiaman et al, 2005), glucose uptake in skeletal muscle (Esposito et al, 2008) and motility of the gastrointestinal tract (Izzo and Sharkey, 2010; Troy-Fioramonti et al, 2014). While most researchers agree that pancreatic beta (β) cells also contain CB1 (Bermúdez-Silva et al, 2008; Kim et al, 2011; Starowicz et al, 2008), its exact role in insulin secretion remains controversial.…”

“…Activation of CB1 stimulates G i/o , which inhibits AC activity and cAMP synthesis (Turu and Hunyady, 2010). In mouse, enteroendocrine cells express CB1 receptor (Sykaras et al, 2012), and its activation inhibits GIP secretion (Moss et al, 2012; Troy-Fioramonti et al, 2014), which suggests that blockade of CB1 would at least indirectly stimulate insulin secretion through GIPR. Several recent studies have suggested a potential interaction between incretin receptors and CB1, particularly with regard to food intake (E.…”

High-Fat Diet-Induced Insulin Resistance Does Not Increase Plasma Anandamide Levels or Potentiate Anandamide Insulinotropic Effect in Isolated Canine Islets

“…These findings indicate that hyperinsulinemia does not require elevation of plasma anandamide. Since acute in vivo treatment with anandamide has been shown to decrease intraperitoneal glucose tolerance in wild type mice [ 34 , 35 ] but not in CB1R -/- mice [ 34 ], there is a possibility that elevation of plasma anandamide levels may be a cause rather than consequence (compensatory signal) of insulin resistance. Future studies exploring the chronic effect of anandamide treatment in vivo may help to elucidate this question.…”