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SGLT2 Inhibition Modulates NLRP3 Inflammasome Activity via Ketones and Insulin in Diabetes With Cardiovascular Disease

Authors
 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 
Citation
 NATURE COMMUNICATIONS, Vol.11(1) : 2127, 2020-05 
Journal Title
 NATURE COMMUNICATIONS 
Issue Date
2020-05
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.
Files in This Item:
T202001636.pdf Download
DOI
10.1038/s41467-020-15983-6
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Eun Seok(강은석) ORCID logo https://orcid.org/0000-0002-0364-4675
Kim, So Ra(김소라)
Kim, Jeong Ho(김정호) ORCID logo https://orcid.org/0000-0003-2479-0548
Kim, Jung Sun(김중선) ORCID logo https://orcid.org/0000-0003-2263-3274
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
Lee, Minyoung(이민영) ORCID logo https://orcid.org/0000-0002-9333-7512
Lee, Byung Wan(이병완) ORCID logo https://orcid.org/0000-0002-9899-4992
Lee, Sang-Guk(이상국) ORCID logo https://orcid.org/0000-0003-3862-3660
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Lee, Chan Joo(이찬주) ORCID logo https://orcid.org/0000-0002-8756-409X
Rim, John Hoon(임정훈) ORCID logo https://orcid.org/0000-0001-6825-8479
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
Cha, Bong Soo(차봉수) ORCID logo https://orcid.org/0000-0003-0542-2854
Hwang, Inhwa(황인화) ORCID logo https://orcid.org/0000-0001-5235-3519
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/176202
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