Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes
- Nat Med. 2013 Sep;19(9):1132-40. doi: 10.1038/nm.3265.
- 1. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland.
Type 2 Diabetes mellitus (T2DM) progresses from compensated Insulin Resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The NLRP3 inflammasome has been implicated in obesity-induced Insulin Resistance and beta cell failure. Endocannabinoids contribute to Insulin Resistance through activation of peripheral CB1 receptors (CB₁Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB₁R signaling in beta cells, but rather in M1 Macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the Macrophages. These effects are replicated in vitro by incubating wild-type human or rodent Macrophages, but not Macrophages from CB₁R-deficient (Cnr1(-/-)) or NLRP3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB₁R blockade, in vivo depletion of Macrophages or macrophage-specific knockdown of CB₁R reverses or prevents these changes and restores normoglycemia and glucose-induced Insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB₁R as a therapeutic target in T2DM.