The endocannabinoid system (ECS) is an intercellular signalling
mechanism that is present in the islets of Langerhans and plays a
role in the modulation of insulin secretion and expansion of the β-cell
mass. The downstream signalling pathways mediating these effects
are poorly understood. Mammalian target of rapamycin complex 1
(mTORC1) signalling is a key intracellular pathway involved in
energy homeostasis and is known to importantly affect the
physiology of pancreatic islets. We investigated the possible
relationship between cannabinoid type 1 (CB1) receptor signalling
and the mTORC1 pathway in the endocrine pancreas of mice by
using pharmacological analysis as well as mice genetically lacking
the CB1 receptor or the downstream target of mTORC1, the kinase
p70S6K1. In vitro static secretion experiments on islets, western
blotting, and in vivo glucose and insulin tolerance tests were
performed. The CB1 receptor antagonist rimonabant decreased
glucose-stimulated insulin secretion (GSIS) at 0.1 µM while
increasing phosphorylation of p70S6K1 and ribosomal protein S6
(rpS6) within the islets. Specific pharmacological blockade of
mTORC1 by 3 nM rapamycin, as well as genetic deletion of
p70S6K1, impaired the CB1-antagonist-mediated decrease in
GSIS. In vivo experiments showed that 3 mg/kg body weight
rimonabant decreased insulin levels and induced glucose
intolerance in lean mice without altering peripheral insulin
sensitivity; this effect was prevented by peripheral administration
of low doses of rapamycin (0.1 mg/kg body weight), which increased
insulin sensitivity. These findings suggest a functional interaction
between the ECS and the mTORC1 pathway within the endocrine
pancreas and at the whole-organism level, which could have
implications for the development of new therapeutic approaches
for pancreatic β-cell diseases.
