TY - JOUR
T1 - Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development
AU - Ambati, Jayakrishna
AU - Magagnoli, Joseph
AU - Leung, Hannah
AU - Wang, Shao bin
AU - Andrews, Chris A.
AU - Fu, Dongxu
AU - Pandey, Akshat
AU - Sahu, Srabani
AU - Narendran, Siddharth
AU - Hirahara, Shuichiro
AU - Fukuda, Shinichi
AU - Sun, Jian
AU - Pandya, Lekha
AU - Ambati, Meenakshi
AU - Pereira, Felipe
AU - Varshney, Akhil
AU - Cummings, Tammy
AU - Hardin, James W.
AU - Edun, Babatunde
AU - Bennett, Charles L.
AU - Ambati, Kameshwari
AU - Fowler, Benjamin J.
AU - Kerur, Nagaraj
AU - Röver, Christian
AU - Leitinger, Norbert
AU - Werner, Brian C.
AU - Stein, Joshua D.
AU - Sutton, S. Scott
AU - Gelfand, Bradley D.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85091545740
U2 - 10.1038/s41467-020-18528-z
DO - 10.1038/s41467-020-18528-z
M3 - Article
C2 - 32968070
AN - SCOPUS:85091545740
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4737
ER -