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

Author

Listed:
  • So Ra Kim

    (Yonsei University College of Medicine
    Yonsei University College of Medicine
    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
    Yonsei University College of Medicine)

  • Eunhye Choi

    (Yonsei University College of Medicine)

  • Wonhee Cho

    (Yonsei University)

  • John Hoon Rim

    (Yonsei University College of Medicine
    Yonsei University Graduate School of Medicine)

  • Inhwa Hwang

    (Yonsei University College of Medicine
    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
    Yonsei University Graduate School of Medicine)

  • Jeong-Ho Kim

    (Yonsei University College of Medicine)

  • Byung-Wan Lee

    (Yonsei University College of Medicine
    Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Eun Seok Kang

    (Yonsei University College of Medicine
    Yonsei University College of Medicine
    Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Bong-Soo Cha

    (Yonsei University College of Medicine
    Yonsei University College of Medicine
    Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Myung-Shik Lee

    (Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Je-Wook Yu

    (Yonsei University College of Medicine
    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
    Yonsei University College of Medicine
    Yonsei University College of Medicine
    Yonsei University College of Medicine)

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.

Suggested Citation

  • 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-H, 2020. "SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15983-6
    DOI: 10.1038/s41467-020-15983-6
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