Mg(2+) Supplementation Mitigates Metabolic Deficits Associated With TRPM7 Disruption.

Transient receptor potential channel subfamily M member 7 (TRPM7) regulates cellular and systemic Mg(2+) homeostasis through its channel domain and induces protein phosphorylation via its kinase domain. We recently found that mice with selective deletion of Trpm7 in β-cells develop glucose intolerance and declines in insulin secretion, primarily due to the impaired enzymatic activity of this protein. Accumulating evidence suggests that Mg(2+) supplementation effectively mitigates the detrimental effects of TRPM7 disruption in various cell types. However, the impact of Mg(2+) supplementation on metabolic impairments caused by TRPM7 inactivation remains unclear. In the present study, we found that Mg(2+) supplementation significantly ameliorates glucose intolerance observed in high-fat-fed TRPM7 kinase-deficient mice (Trpm7(R/R)). However, our ex vivo analysis of islets isolated from Trpm7(R/R) mice revealed that Mg(2+) supplementation does not enhance glucose-induced insulin secretion. Instead, the improvement appears to be partially driven by enhanced insulin sensitivity and increased β-cell proliferation. The pharmacological analysis in MIN6 cells showed that inhibiting TRPM7 with either NS8593 or VER155008 disrupts β-cell proliferation. These effects mimicked the phenotype seen in Trpm7(R/R) mice. We attribute this impairment to diminished ERK1/2 signaling, which suppressed PDX1 expression, while Mg(2+) supplementation in vitro partially restored ERK1/2 phosphorylation levels. Collectively, Mg(2+) supplementation enhances glucose metabolism in Trpm7(R/R) mice and mitigates the ERK1/2 signaling disruptions and proliferation arrest induced by TRPM7 inactivation in vitro. These findings provide compelling evidence that Mg(2+) supplementation can reverse the adverse metabolic and cellular phenotypes associated with the loss of TRPM7 function.