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; Yong ho Lee

doi:10.1038/s41467-020-15983-6

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 journal › Article › peer-review

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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 language	English
Article number	2127
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15983-6
Publication status	Published - 2020 Dec 1

Bibliographical note

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

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-020-15983-6

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Kim, S. R., Lee, S. G., Kim, S. H., Kim, J. H., Choi, E., Cho, W., Rim, J. H., Hwang, I., Lee, C. J., Lee, M., Oh, C. M., Jeon, J. Y., Gee, H. Y., Kim, J. H., Lee, B. W., Kang, E. S., Cha, B. S., Lee, M. S., Yu, J. W., ... Lee, Y. H. (2020). SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nature communications, 11(1), Article 2127. https://doi.org/10.1038/s41467-020-15983-6

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title = "SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease",

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{\textquoteright}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.",

author = "Kim, {So Ra} and Lee, {Sang Guk} and Kim, {Soo Hyun} and Kim, {Jin Hee} and Eunhye Choi and Wonhee Cho and Rim, {John Hoon} and Inhwa Hwang and Lee, {Chan Joo} and Minyoung Lee and Oh, {Chang Myung} and Jeon, {Justin Y.} and Gee, {Heon Yung} and Kim, {Jeong Ho} and Lee, {Byung Wan} and Kang, {Eun Seok} and Cha, {Bong Soo} and Lee, {Myung Shik} and Yu, {Je Wook} and Cho, {Jin Won} and Kim, {Jung Sun} and Lee, {Yong ho}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

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Kim, SR, Lee, SG, Kim, SH, Kim, JH, Choi, E, Cho, W, Rim, JH, Hwang, I, Lee, CJ, Lee, M, Oh, CM, Jeon, JY , Gee, HY, Kim, JH, Lee, BW, Kang, ES, Cha, BS, Lee, MS, Yu, JW, Cho, JW, Kim, JS & Lee, YH 2020, 'SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease', Nature communications, vol. 11, no. 1, 2127. https://doi.org/10.1038/s41467-020-15983-6

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AU - Kim, So Ra

AU - Lee, Sang Guk

AU - Kim, Soo Hyun

AU - Kim, Jin Hee

AU - Choi, Eunhye

AU - Cho, Wonhee

AU - Rim, John Hoon

AU - Hwang, Inhwa

AU - Lee, Chan Joo

AU - Lee, Minyoung

AU - Oh, Chang Myung

AU - Jeon, Justin Y.

AU - Gee, Heon Yung

AU - Kim, Jeong Ho

AU - Lee, Byung Wan

AU - Kang, Eun Seok

AU - Cha, Bong Soo

AU - Lee, Myung Shik

AU - Yu, Je Wook

AU - Cho, Jin Won

AU - Kim, Jung Sun

AU - Lee, Yong ho

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

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UN SDGs

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