Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.
Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.
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2型糖尿病（T2DM）从代偿性胰岛素抵抗发展为β - ceil衰竭，导致无代偿性高血糖，这一过程在Zucker糖尿病脂肪（ZDF）大鼠中得到了重复。Nlrp3炎性小体与肥胖诱导的胰岛素抵抗和β细胞衰竭有关。内源性大麻素通过激活外周CB1受体（CB1Rs）促进胰岛素抵抗，并促进β细胞衰竭。本研究表明，成年ZDF大鼠的β细胞衰竭与β细胞中的CB1R信号传导无关，而与M1巨噬细胞浸润到胰岛有关，这导致巨噬细胞中Nlrp3-ASC炎性体的激活。内源性大麻素anandamide在体外培养野生型人或啮齿动物巨噬细胞，但不包括cb1r缺陷[Cnr1−/−)或Nlrp3−/−小鼠的巨噬细胞，可以复制这些效果。外周CB1R阻断、巨噬细胞体内耗竭或巨噬细胞特异性敲低CB1R可逆转或阻止这些变化，并恢复正常血糖和葡萄糖诱导的胰岛素分泌。这些发现暗示内源性大麻素和炎性体激活在β细胞衰竭中，并确定巨噬细胞表达的CB1R是T2DM的治疗靶点。
Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta ceil 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 insuiin 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 ceils, 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.
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29
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Lerner AG;Upton JP;Praveen PV;Ghosh R;Nakagawa Y;Igbaria A;Shen S;Nguyen V;Backes BJ;Heiman M;Heintz N;Greengard P;Hui S;Tang Q;Trusina A;Oakes SA;Papa FR
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