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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

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

doi

10.1038/s41467-020-18528-z

subject

Has Abstract

pub_date

2020-09-23 00:00:00

pages

4737

issue

1

issn

2041-1723

pii

10.1038/s41467-020-18528-z

journal_volume

11

pub_type

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