Effect of Dapagliflozin and Magnesium Supplementation on Renal Magnesium Handling and Magnesium Homeostasis in Metabolic Syndrome.

Hwee-Yeong Ng,You-Lin Tain,Wei-Hung Kuo,Chien-Te Lee,Foong-Fah Leung,Wen-Chin Lee

doi:10.3390/nu13114088

Hwee-Yeong Ng, You-Lin Tain + Show 4 more

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https://doi.org/10.3390/nu13114088

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Abstract

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.

Highlights

The prevalence and incidence of metabolic syndrome (MetS) are increasing, and MetS has been recognized as an important contributor to diabetes and cardiovascular morbidity [1]
Animals fed a fructose diet for six months had significantly higher fasting glucose, insulin, HOMA-insulin resistance (IR), and triglyceride levels than the control group (p < 0.05)
In animals treated with dapagliflozin and magnesium supplementation, lower glucose, insulin, and HOMA-IR levels were observed compared to those in the fructose group

Summary

Introduction

The prevalence and incidence of metabolic syndrome (MetS) are increasing, and MetS has been recognized as an important contributor to diabetes and cardiovascular morbidity [1]. Serum magnesium levels are closely linked to glucose metabolism and insulin resistance. Several cohort studies have indicated a negative association between dietary magnesium intake and the risk of cardiovascular disease and total mortality [5]. A 0.1 mmol/L decrease in serum magnesium level was associated with an 18% increased risk of diabetes [6]. Low levels of serum magnesium have been observed in large cohorts of patients with type 2 diabetes [7], with a prevalence between 14% and 48%, compared to a prevalence ranging between 2.5% and 15% in healthy control subjects [8]

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