Approximately 1.25 million Americans have type 1 diabetes mellitus (T1DM), resulting from autoimmune β-cell destruction: there is no known way to prevent such destruction of β-cells. We have already reported that activation of cannabinoid 1 receptor (CB1R) contributes to the pathogenesis of pancreatic β-cell dysfunction during high fat feeding. To uncover if CB1R signaling might influence toxin-induced β-cell injury, we induced β-cell destruction in wild type mice (WT: n=8) and in mice in which CB1R was genetically nullified in β-cells only (β-CB1R-/-: n=8) in adulthood by five daily injections of streptozotocin (STZ; 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 137-220 mg/dL throughout the study period (28 days following STZ) as well as preserved insulin secretion with superior glucose tolerance after a glucose challenge (2g/kg) at day 8, 15 or 27, relative to their WT littermates (random BG 500-600 mg/dL). CB1R-deficient β-cells exhibited significant increases in autophagy flux following STZ. We determined that mice or β-cells lacking CB1R had reduced mTOR activation and increased nuclear translocation of TFEB, a key prerequisite for lysosome biogenesis and autophagy. Importantly, we found that CB1R deletion protected against oxidative stress, endoplasmic reticulum stress, and prevented the induction of apoptosis by STZ. These anti-stress functions were accompanied by increased phosphorylation of AKT (ser) 473 and ERK1/2 in β-cells, which reveals a previously unrecognized route for mTOR/AKT axis to regulate autophagy that coordinately is permissive to β-cell survival. We conclude that CB1R nullification confers resistance to pancreatic β-cell dysfunction by upregulating autophagy and subsequently antagonizing the decline in lysosomal activity. Altogether, we propose that CB1R is a potential therapeutic target during the honeymoon phase of T1DM.


K. Aseer: None. J.F. O’Connell: None. J.M. Egan: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at