Mg 2+ Supplementation Mitigates Metabolic Deficits Associated With TRPM7 Disruption

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ABSTRACT 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.

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