Approximately 1.25 million Americans have type 1 diabetes mellitus (T1DM), resulting from β-cell destruction. There is no known way to prevent it or to stop destruction of any remaining β-cells. Although the cannabinoid system, specifically cannabinoid 1 receptor (CB1R), is implicated in obesity and T2DM, its role, if any, in T1DM has not been studied. To address this, we induced β-cell destruction in wild type mice (WT: n=8) and mice in which CB1R was genetically nullified in β-cells only (β-CB1R-/-: n=8) in adulthood by five injections of streptozotocin (50 mg/kg intraperitoneally [IP]), a toxin selective for β-cells. We found that β-CB1R-/- mice had random blood glucose (BG) levels in the range of 137-289 mg/dL throughout the study period (28 days) as well as preserved insulin secretion with superior glucose tolerance after IP glucose (2g/kg) at day 8, 15 or 27, relative to their (random BG 500-600 mg/dL) WT littermates. CB1R knockout drove significant increases in pancreatic islet autophagic activity based on increased accumulation of autophagosome hallmarks (LC3B, Beclin-1, ATG5 and ATG7) and reduced p62 expression. Insulin and LC3B were colocalized in CB1R-deficient β-cells. Remarkably, the islets did not show the upregulation of ER unfolded protein response, which was present in β-cells of WT mice, while exerting the induction of protective chaperones. These anti-stress functions were accompanied by increased phosphorylation of AKT (ser) 473 and ERK in β-cells, which reveals a previously unrecognized route for PI3K-AKT pathway to activate the anti-apoptotic NFkB/p65 signaling that coordinately is permissive to β-cell survival. We conclude that CB1R nullification restores autophagy machinery as a novel signaling pathway to counteract ER stress-mediated cell death and confers resistance to β-cell destruction. We propose that CB1R is a potential therapeutic target during the honeymoon phase of T1DM.
K. Aseer: None. J.M. Egan: None.
