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 ChoJung Sun Kim, Yong ho Lee

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)

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.

Original languageEnglish
Article number2127
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

Bibliographical note

Funding Information:
The authors would like to thank Dong-Su Jang, MFA, (Medical Illustrator) for his help with producing the illustration (Fig. 5). Editorial assistance was provided by Caron Modeas. This work was supported by the National Research Foundation of Korea (NRF) Grant [NRF-2016R1A5A1010764 and NRF-2017R1C1B5015044] funded by the Korean Government (MSIP), the grant of the Korea Health technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea [HI17C0913], and the grant of the Industry Technology Development Program [10063335] funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea). It was also supported by a faculty research grant of Yonsei University College of Medicine for [6-2016-0082 to J.-S.K].

Publisher Copyright:
© 2020, The Author(s).

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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