제1저자 김진희(내과학교실, BK21), 이민영(내과학교실)
교신저자 이용호(내과학교실, BK21)
Diabetes Obes Metab. 2018 Nov 8. doi: 10.1111/dom.13577. [Epub ahead of print]
SGLT2 inhibitor regulates ketone body metabolism via inter-organ crosstalk.
Kim JH1,2, Lee M2,3, Kim SH2, Kim SR2,3,4, Lee BW2,3,5, Kang ES2,3,5, Cha BS2,3,5, Cho JW6, Lee YH1,2,3,5,7,6.
1Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.2Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.3Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea.4Division of Endocrinology and Metabolism, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea.5Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea.6Department of Systems Biology, Glycosylation Network Research Center, Yonsei University, Seoul, Republic of Korea.7Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
Sodium-glucose transporter 2 inhibitors (SGLT2i), a new class of glucose-lowering medications for diabetes, increase serum ketone levels. Recent studies have reported that ketone has an anti-inflammatory function and extends longevity in animal models. However, the mechanisms by which various organs upregulate ketogenesis in response to SGLT2i have not been elucidated. We investigated SGLT2i-induced changes in ketogenic enzymes and transporters in normal and diabetic mice models.
MATERIALS AND METHODS:
Normal mice were randomly assigned to receive either vehicle or SGLT2i (25 mg/kg/day by oral gavage) for 7 days. Diabetic mice were treated with vehicle, insulin (4.5 units/kg/day by subcutaneous injection) or SGLT2i (25 mg/kg/day by intra-peritoneal injection) for 5 weeks. Serum and tissues of ketogenic organs were analyzed.
In both normal and diabetic mice, SGLT2i increased beta-hydroxybutyrate (BHB) content in liver, kidney, and colon tissue, as well as in serum and urine. In these organs, SGLT2i upregulated mRNA expression of ketogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2) and 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HMGCL). Similar patterns were observed in the kidney, ileum and colon for mRNA and protein expression of sodium-dependent monocarboxylate transporters (SMCTs), which mediate the cellular uptake of BHB and butyrate, an important substrate for intestinal ketogenesis. In diabetic mice under euglycemic condition, SGLT2i increased major ketogenic enzymes and SMCTs, while insulin suppressed ketogenesis.
SGLT2i increased systemic and tissue BHB levels by upregulating ketogenic enzymes and transporters in the liver, kidney, and intestine, suggesting the integrated physiological consequences in ketone body metabolism by SGLT2i administration. This article is protected by copyright. All rights reserved.