Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
Nat Commun. 2020 Sep 23;11(1):4737. doi: 10.1038/s41467-020-18528-z.
Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetes-related stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. Nucleoside reverse-transcriptase inhibitors (NRTI), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation. Here, we show, by analyzing five health insurance databases, that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B (adjusted hazard ratio for NRTI exposure, 0.673; 95% confidence interval, 0.638 to 0.710; P < 0.0001; 95% prediction interval, 0.618 to 0.734). Meanwhile, an NRTI, lamivudine, improves insulin sensitivity and reduces inflammasome activation in diabetic and insulin resistance-induced human cells, as well as in mice fed with high-fat chow; mechanistically, inflammasome-activating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINE-catabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes.
先天免疫信号通过 NLRP3 炎性小体被多种与糖尿病相关的应激源激活，但针对炎性小体是否有益于糖尿病仍不清楚。核苷逆转录酶抑制剂（NRTI）是一种被批准用于治疗 HIV-1 和乙型肝炎感染的药物，也可阻断炎性小体的激活。在这里，我们通过分析五个健康保险数据库，在 128861 名 HIV-1 或乙型肝炎患者中，NRTI 暴露的患者新发糖尿病的风险降低了 33%（NRTI 暴露的调整后的危险比为 0.673；95%置信区间，0.638 至 0.710；P<0.0001；95%预测区间，0.618 至 0.734）。同时，NRTI 拉米夫定在糖尿病和胰岛素抵抗诱导的人类细胞以及高脂饮食喂养的小鼠中改善了胰岛素敏感性并减少了炎性小体的激活；从机制上讲，在糖尿病细胞和小鼠中，炎性小体激活的短散布核元件（SINE）转录本升高，而 SINE 代谢 DICER1 减少。这些数据表明，重新利用一类已批准的药物来预防糖尿病是可能的。
