title: Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.
abstract: 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.
authors: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland.
authors: Tony
authors: T
authors: Jourdan
authors: Grzegorz
authors: G
authors: Godlewski
authors: Resat
authors: R
authors: Cinar
authors: Adeline
authors: A
authors: Bertola
authors: Gergő
authors: G
authors: Szanda
authors: Jie
authors: J
authors: Liu
authors: Joseph
authors: J
authors: Tam
authors: Tiffany
authors: T
authors: Han
authors: Bani
authors: B
authors: Mukhopadhyay
authors: Monica C
authors: MC
authors: Skarulis
authors: Cynthia
authors: C
authors: Ju
authors: Myriam
authors: M
authors: Aouadi
authors: Michael P
authors: MP
authors: Czech
authors: George
authors: G
authors: Kunos
mesh_terms: D000818:Animals; D017209:Apoptosis; D001095:Arachidonic Acids / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D063388:Endocannabinoids / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D002352:Carrier Proteins; D063388:Endocannabinoids; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053284:Polyunsaturated Alkamides; D034741:RNA, Small Interfering; C078814:anandamide
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