Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development
Author Department
Medicine; Internal Medicine
Document Type
Article, Peer-reviewed
Publication Date
9-2020
Abstract
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.
Recommended Citation
Ambati J, Magagnoli J, Leung H, Wang SB, Andrews CA, Fu D, Pandey A, Sahu S, Narendran S, Hirahara S, Fukuda S, Sun J, Pandya L, Ambati M, Pereira F, Varshney A, Cummings T, Hardin JW, Edun B, Bennett CL, Ambati K, Fowler BJ, Kerur N, Röver C, Leitinger N, Werner BC, Stein JD, Sutton SS, Gelfand BD. Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development. Nat Commun. 2020 Sep 23;11(1):4737. doi: 10.1038/s41467-020-18528-z.
PMID
32968070