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.

中文翻译：

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钠-葡萄糖共转运蛋白2抑制剂dapagliflozin对近端肾小管糖原异生的影响。

目的研究达格列净，一种钠-葡萄糖共转运蛋白2（SGLT2）抑制剂在体外，离体和体内对肾糖原异生的影响。材料与方法我们用达格列净治疗HK-2细胞（人肾近端小管细胞）和小鼠原发性肾近端小管细胞，并评估了肾脏糖异生的过程。我们还检查了达格列净对正常血糖和高血糖小鼠肾糖异生的影响。结果达格列净在体外，离体和体内均可增强肾脏糖异生。它增加了磷酸烯醇丙酮酸羧激酶（PEPCK），葡萄糖6磷酸酶（G6Pase），HK-2细胞，小鼠原发性肾近端肾小管细胞中的过氧化物酶体增殖激活受体-γ共激活物1α（PGC-1α）和磷酸化的环-AMP反应元件结合蛋白（CREB）的表达和磷酸化的Forkhead Box O1（FOXO1）的表达降低，以及老鼠的肾皮质。谷氨酰胺增强达格列净在HK-2细胞中的糖原异生作用。此外，达格列净增加了HK-2细胞中14 C-谷氨酰胺的利用率。胰高血糖素不影响达格列净诱导的HK-2细胞肾糖异生的增强。用siRNA敲低SGLT2基因可导致HK-2细胞中糖异生基因表达及相关转录因子的增加。Dapagliflozin可以降低高脂饮食喂养的高血糖小鼠的空腹血糖水平，并改善口服葡萄糖耐量和胰岛素耐受性，尽管肾糖异生增强。结论Dapagliflozin增加了肾皮质中糖异生酶的水平，并因此增加了由SGLT2抑制介导的肾糖异生。