Effect of dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on gluconeogenesis in proximal renal tubules
| Autor: | Mijin Yun, Hye Jin Wang, Hyangkyu Lee, Jin Hee Kim, Eun Seok Kang, Hae Young Ko |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_specialty
Endocrinology Diabetes and Metabolism Renal cortex 030209 endocrinology & metabolism FOXO1 030204 cardiovascular system & hematology Glucagon Kidney Tubules Proximal 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology Glucosides Sodium-Glucose Transporter 2 Internal medicine Internal Medicine medicine Benzhydryl Compounds Dapagliflozin Sodium-Glucose Transporter 2 Inhibitors business.industry Sodium Gluconeogenesis Glucose medicine.anatomical_structure Liver chemistry SGLT2 Inhibitor Phosphoenolpyruvate carboxykinase business Ex vivo |
| Zdroj: | Diabetes, Obesity and Metabolism. 22:373-382 |
| ISSN: | 1463-1326 1462-8902 |
| DOI: | 10.1111/dom.13905 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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