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

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.

Sodium-Glucose Cotransporter 2 Inhibitors and Management of Refractory Hypomagnesemia Without Overt Urinary Magnesium Wasting: A Report of 2 Cases

“…To explain the novel finding of our cases that SGLT2 inhibitors contributed to improving hypomagnesemia in our patients without significantly reducing FEMg, we speculate increased intestinal absorption of magnesium, potentially via increased TRPM6 mediated active transcellular pathway. A group of researchers from Taiwan showed that dapagliflozin enhanced TRPM6-mediated trans-epithelial magnesium transport in renal J o u r n a l P r e -p r o o f 8 tubule cells in an animal model (14). We should note that SGLT2 is expressed primarily in the luminal membrane of the S1 and S2 segments of the proximal tubule, while TRMP6 channels are situated primarily in the distal convoluted tubule of the kidney (12,13).…”

“…A group of researchers from Taiwan showed that dapagliflozin enhanced TRPM6-mediated transepithelial Mg2+ transport in renal tubule cells in an animal model. 12 We should note that SGLT2 is expressed primarily in the luminal membrane of the S1 and S2 segments of the proximal tubule, whereas TRMP6 channels are situated primarily in the distal convoluted tubule of the kidney. 13 , 14 The mechanism of how SGLT2 inhibitors affect TRPM6 channels remains an area of further investigation; however, local or systemic effects could mediate this outcome.…”

“…Data on the impact of SGLT2 inhibitors on hypomagnesemia among patients without type 2 diabetes will be essential to understand this better. The authors of the Taiwanese study suggested further study is needed to assess if dapagliflozin modulates intestinal magnesium absorption by TRPM6 transport (14). If confirmed, such treatment could impact the management of patients with impaired intestinal magnesium absorption, especially in the patients with hypomagnesemia with secondary hypocalcemia (HSH), an autosomal recessive disease with a defect in TRPM6 responsible for poor intestinal absorption of magnesium that leads to catastrophic seizures after weeks to months from birth and requires lifelong oral magnesium supplements (11).…”

“…The authors of the Taiwanese study suggested further study is needed to assess if dapagliflozin modulates intestinal Mg2+ absorption by TRPM6 transport. 12 If confirmed, such treatment could impact the management of patients with impaired intestinal Mg2+ absorption, especially in the patients with hypomagnesemia with secondary hypocalcemia, an autosomal recessive disease with a defect in TRPM6 responsible for poor intestinal absorption of Mg2+ that leads to catastrophic seizures weeks to months after birth and requires lifelong oral Mg2+ supplements. 11 Hereby, we propose that further investigations into the role of SGLT2 inhibitors in patients with hypomagnesemia without significant urinary Mg2+ loss are vital.…”

Kidney-Protective Effects of SGLT2 Inhibitors

“…Restoration of insulin sensitivity following SGLT2i therapy increases expression of the TRPM6 channel, thereby reducing urinary magnesium excretion. In a rodent model of insulin resistance, dapagliflozin decreases urinary magnesium excretion in association with upregulation of TRPM6/7 and claudin 16 (83).…”