Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development

Jayakrishna Ambati,Christian Röver,Shao-Bin Wang,Norbert Leitinger,Charles L Bennett,Akhil Varshney,Joseph Magagnoli,Felipe Pereira,Lekha Pandya,Jian Sun,Dongxu Fu,S Scott Sutton ,Shin–Ichi Fukuda ,Tammy H Cummings ,Akhilesh Kumar Pandey ,Chris Andrews ,Joshua D Stein,Siddharth Narendran,Srabani Sahu,Shuichiro Hirahara,Kameshwari Ambati,Brian C Werner,James W Hardin,Babatunde Edun,Benjamin J Fowler,Nagaraj Kerur,Meenakshi Ambati,Hannah Leung,Bradley D Gelfand

doi:10.1038/s41467-020-18528-z

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.

Highlights

Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetesrelated stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear
We examined associations between exposure to Nucleoside reverse-transcriptase inhibitors (NRTI) and subsequent development of type 2 diabetes in the Veterans Health Administration, the largest integrated healthcare system in the United States, that was studied for over a 17-year period
In each of the five cohorts that included a total of 128,861 patients (Supplementary Fig. 1), we determined the association between NRTI use and the hazard of developing type 2 diabetes after adjustment for sociodemographic factors, overall health, comorbidities, and use of medications that are known to alter risk of diabetes development

Summary

Introduction

Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetesrelated stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. 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, inflammasomeactivating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINEcatabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes. We seek to determine whether, among patients with HIV-1 or hepatitis B, there is a relation between exposure to NRTIs and development of type 2 diabetes

Methods

Results

Conclusion