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Effect of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on gluconeogenesis in proximal renal tubules

Authors
 Jin Hee Kim  ;  Hae Young Ko  ;  Hye Jin Wang  ;  Hyangkyu Lee  ;  MiJin Yun  ;  Eun Seok Kang 
Citation
 DIABETES OBESITY & METABOLISM, Vol.22(3) : 373-382, 2020 
Journal Title
 DIABETES OBESITY & METABOLISM 
ISSN
 1462-8902 
Issue Date
2020
Keywords
SGLT2 inhibitor ; antidiabetic drug ; dapagliflozin ; glycaemic control
Abstract
AIMS: To investigate the effect of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on renal gluconeogenesis in vitro, ex vivo and in vivo. MATERIALS AND METHODS: We treated HK-2 cells (human renal proximal tubule cells) and mouse primary renal proximal tubule cells with dapagliflozin, and evaluated the process of renal gluconeogenesis. We also examined the effect of dapagliflozin on renal gluconeogenesis in normoglycaemic and hyperglycaemic mice. RESULTS: Dapagliflozin enhanced renal gluconeogenesis in vitro, ex vivo and in vivo. It increased phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), peroxisome proliferative activated receptor-gamma co-activator 1α (PGC-1α) and phosphorylated cyclic-AMP response element binding protein (CREB) expression and decreased phosphorylated Forkhead Box O1 (FOXO1) expression in HK-2 cells, mouse primary renal proximal tubule cells, and the mouse renal cortex. Glutamine enhanced the gluconeogenic effect of dapagliflozin in HK-2 cells. Also, dapagliflozin increased 14 C-glutamine utilization in HK-2 cells. Glucagon did not affect dapagliflozin-induced enhancement in renal gluconeogenesis in HK-2 cells. SGLT2 gene knockdown with siRNA resulted in an increase of gluconeogenic gene expression and associated transcription factors in HK-2 cells. Dapagliflozin reduced fasting plasma glucose levels and improved oral glucose tolerance and insulin tolerance in high-fat diet-fed hyperglycaemic mice, although renal gluconeogenesis was enhanced. CONCLUSIONS: Dapagliflozin increased levels of gluconeogenic enzyme in the renal cortex and consequently increased renal gluconeogenesis, which is mediated by SGLT2 inhibition.
Full Text
https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.13905
DOI
10.1111/dom.13905
Appears in Collections:
3. College of Nursing (간호대학) > Dept. of Nursing (간호학과) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 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
Wang, Hye Jin(왕혜진)
Yun, Mi Jin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Lee, Hyang Kyu(이향규) ORCID logo https://orcid.org/0000-0002-0821-6020
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175513
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