SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease

So Ra Kim, Sang-Guk Lee, Soo Hyun Kim, Jin Hee Kim, Eunhye Choi, Wonhee Cho, John Hoon Rim, Inhwa Hwang, Chan Joo Lee, Minyoung Lee, Chang-Myung Oh, Justin Y. Jeon, Heon Yung Gee, Jeong-Ho Kim, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Myung-Shik Lee, Je-Wook Yu, Jin Won Cho, Jung-Sun Kim () and Yong-ho Lee ()
Additional contact information
So Ra Kim: Yonsei University College of Medicine
Sang-Guk Lee: Yonsei University College of Medicine
Soo Hyun Kim: Yonsei University College of Medicine
Jin Hee Kim: Yonsei University College of Medicine
Eunhye Choi: Yonsei University College of Medicine
Wonhee Cho: Yonsei University
John Hoon Rim: Yonsei University College of Medicine
Inhwa Hwang: Yonsei University College of Medicine
Chan Joo Lee: Yonsei University College of Medicine
Minyoung Lee: Yonsei University College of Medicine
Chang-Myung Oh: Gwangju Institute of Science and Technology
Justin Y. Jeon: Yonsei University
Heon Yung Gee: Yonsei University College of Medicine
Jeong-Ho Kim: Yonsei University College of Medicine
Byung-Wan Lee: Yonsei University College of Medicine
Eun Seok Kang: Yonsei University College of Medicine
Bong-Soo Cha: Yonsei University College of Medicine
Myung-Shik Lee: Yonsei University College of Medicine
Je-Wook Yu: Yonsei University College of Medicine
Jin Won Cho: Yonsei University
Jung-Sun Kim: Yonsei University College of Medicine
Yong-ho Lee: Yonsei University College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor’s glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.

Date: 2020
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DOI: 10.1038/s41467-020-15983-6

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