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.
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J.A. was supported by the UVA Strategic Investment Fund, United States National Institutes of Health (NIH) grants (DP1GM114862, R01EY022238, R01EY024068, R01EY028027, and R01EY029799), John Templeton Foundation Grant 60763, DuPont Guerry, III, Professorship, N.K. by NIH grants (K99EY024336, R00EY024336, R01AI48741, and R21EY030651) and Beckman Initiative for Macular Research grant; B.J.F. by NIH grants (T32HL091812 and UL1RR033173); B.D.G. by NIH grant R01EY028027 and American Heart Association grant; N.L. by NIH grants (R01DK096076 and P01HL120840); C.L.B. by NIH grant R01CA165609 and grants from Doris Levkoff Meddin and the South Carolina SmartState Program; S.F. by Japan Eye Bank Association Research Grant.
Ambati, Jayakrishna; Magagnoli, Joseph; Leung, Hannah; Wang, Shao-Bin; Andrews, Chris A.; Fu, Dongxu; Pandey, Akshat; Sahu, Srabani; Narendran, Siddharth; Hirahara, Shuichiro; Fukuda, Shinichi; Sun, Jian; Pandya, Lekha; Ambati, Meenakshi; Pereira, Felipe; Varshney, Akhil; Cummings, Tammy; Hardin, James W.; Edun, Babatunde; Bennett, Charles L.; Ambati, Kameshwari; Fowler, Benjamin J.; Kerur, Nagaraj; Röver, Christian; Leitinger, Norbert; Werner, Brian C.; Stein, Joshua D.; Sutton, S. Scott; and Gelfand, Bradley D., "Repurposing Anti-Inflammasome NRTIs for Improving Insulin Sensitivity and Reducing Type 2 Diabetes Development" (2020). Ophthalmology and Visual Science Faculty Publications. 16.