Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
Nutrients. 2021 Nov 15;13(11):4088. doi: 10.3390/nu13114088.
The prevalence of metabolic syndrome (MetS) is increasing, and patients with MetS are at an increased risk of cardiovascular disease and diabetes. There is a close link between hypomagnesemia and MetS. Administration of sodium-glucose transporter 2 (SGLT2) inhibitors has been reported to increase serum magnesium levels in patients with diabetes. We investigated the alterations in renal magnesium handling in an animal model of MetS and analyzed the effects of SGLT2 inhibitors. Adult rats were fed a fructose-rich diet to induce MetS in the first 3 months and were then treated with either dapagliflozin or magnesium sulfate-containing drinking water for another 3 months. Fructose-fed animals had increased insulin resistance, hypomagnesemia, and decreased urinary magnesium excretion. Dapagliflozin treatment improved insulin resistance by decreasing glucose and insulin levels, increased serum magnesium levels, and reduced urinary magnesium excretion. Serum vitamin D and parathyroid hormone levels were decreased in fructose-fed animals, and the levels remained low despite dapagliflozin and magnesium supplementation. In the kidney, claudin-16, TRPM6/7, and FXDY expression was increased in fructose-fed animals. Dapagliflozin increased intracellular magnesium concentration, and this effect was inhibited by TRPM6 blockade and the EGFR antagonist. We concluded that high fructose intake combined with a low-magnesium diet induced MetS and hypomagnesemia. Both dapagliflozin and magnesium sulfate supplementation improved the features of MetS and increased serum magnesium levels. Expression levels of magnesium transporters such as claudin-16, TRPM6/7, and FXYD2 were increased in fructose-fed animals and in those administered dapagliflozin and magnesium sulfate. Dapagliflozin enhances TRPM6-mediated trans-epithelial magnesium transport in renal tubule cells.
代谢综合征（MetS）的患病率正在上升，患有 MetS 的患者心血管疾病和糖尿病的风险增加。低镁血症与 MetS 密切相关。有报道称，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂可增加糖尿病患者的血清镁水平。我们在 MetS 动物模型中研究了肾脏镁处理的变化，并分析了 SGLT2 抑制剂的作用。成年大鼠在前 3 个月内喂食富含果糖的饮食以诱导 MetS，然后再用达格列净或含硫酸镁的饮用水治疗 3 个月。果糖喂养的动物出现胰岛素抵抗、低镁血症和尿镁排泄减少。达格列净治疗通过降低血糖和胰岛素水平改善胰岛素抵抗，增加血清镁水平，并减少尿镁排泄。果糖喂养的动物血清维生素 D 和甲状旁腺激素水平降低，尽管给予达格列净和镁补充，这些水平仍保持较低水平。在肾脏中，果糖喂养的动物 Claudin-16、TRPM6/7 和 FXDY 的表达增加。达格列净增加细胞内镁浓度，该作用被 TRPM6 阻断和 EGFR 拮抗剂抑制。我们得出结论，高果糖摄入与低镁饮食相结合会导致 MetS 和低镁血症。达格列净和硫酸镁补充均可改善 MetS 特征并增加血清镁水平。Claudin-16、TRPM6/7 和 FXYD2 等镁转运体的表达水平在果糖喂养的动物和给予达格列净和硫酸镁的动物中增加。达格列净增强了肾小管细胞中 TRPM6 介导的跨上皮镁转运。
