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.

Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration

“…Randomized controlled trials can yield better causal insights. Recently, we demonstrated NRTI use is associated with reduced development of type 2 diabetes (58). The current findings provide a rationale for prospective testing of NRTIs or alkylated NRTI derivatives, which block inflammasome activation but are less toxic than NRTIs (11), as potential therapies for geographic atrophy as well.…”

“…First, a large amount of the variance across studies is attributable to heterogeneity (I 2 = 83.1%; 95% CI, 49.3-98.6%; P < 0.001, test A-C) Using methodology employed in ref. 58, aHRs estimated separately for each database shown in black along with their 95% CIs, along with fixed-effect and random-effects meta-analyses shown in diamonds. The dashed vertical line denotes a HR of 1.0, which represents no difference in risk between nucleoside reverse-transcriptase inhibitor (NRTI) exposure and nonexposure.…”

Inflammasomes as therapeutic targets in human diseases

“…The role of chronic inflammation in the development of T2D has been well documented, 109 – 111 and the NLRP3 inflammasome was shown to mediate obesity-induced inflammation and insulin resistance. 112 , 113 A number of molecules such as high glucose, islet amyloid polypeptide, saturated fatty acids, and mitochondrial ROS are involved in activating the NLRP3 inflammasome and contribute to the pathogenesis of T2D.…”

A Mechanism Leading to Changes in Copy Number Variations Affected by Transcriptional Level Might Be Involved in Evolution, Embryonic Development, Senescence, and Oncogenesis Mediated by Retrotransposons

“…Moreover, the Prospective Urban Rural Epidemiological study showed that high consumption of white rice can result in an increased risk for incident diabetes (Hu et al, 2012 ; Bhavadharini and Mohan, 2020 ). Moreover, the result of a recent study that nucleotide reverse transcriptase inhibitors can improve insulin sensitivity and reduce the development of type 2 diabetes supports the relationship between the development of type II diabetes mellitus and CNVs extension as well (Ambati et al, 2020 ).…”