Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland.
Nat Med. 2013 Sep;19(9):1132-40. doi: 10.1038/nm.3265. Epub 2013 Aug 18.
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.
2 型糖尿病（T2DM）是从代偿性胰岛素抵抗发展为β细胞衰竭导致代偿性高血糖的过程，这一过程在 Zucker 糖尿病肥胖（ZDF）大鼠中得到了复制。Nlrp3 炎性小体与肥胖引起的胰岛素抵抗和β细胞衰竭有关。内源性大麻素通过激活外周 CB1 受体（CB₁Rs）导致胰岛素抵抗，并促进β细胞衰竭。在这里，我们表明成年 ZDF 大鼠的β细胞衰竭与β细胞中 CB₁R 信号无关，而是与浸润胰岛的 M1 巨噬细胞有关，这导致巨噬细胞中 Nlrp3-ASC 炎性小体的激活。这些作用在体外通过孵育野生型人或啮齿动物巨噬细胞来复制，但不能通过 CB₁R 缺失（Cnr1(-/-)）或 Nlrp3(-/-)小鼠的巨噬细胞来复制，用内源性大麻素大麻素 anandamide。外周 CB₁R 阻断、体内巨噬细胞耗竭或巨噬细胞特异性 CB₁R 敲低可逆转或预防这些变化，并恢复正常血糖和葡萄糖诱导的胰岛素分泌。这些发现表明内源性大麻素和炎性小体激活参与了β细胞衰竭，并确定了巨噬细胞表达的 CB₁R 是 T2DM 的治疗靶点。
