Hypomagnesemia in type 2 diabetes: A vicious circle?

Abstract

Over the past decades, hypomagnesemia (serum Mg2+ <0.7 mmol/L) has been strongly associated with type 2 diabetes mellitus (T2DM). Patients with hypomagnesemia show a more rapid disease progression and have an increased risk for diabetes complications. Clinical studies demonstrate that T2DM patients with hypomagnesemia have reduced pancreatic βb-cell activity and are more insulin resistant. Moreover, dietary Mg2+ supplementation for patients with T2DM improves glucose metabolism and insulin sensitivity. Intracellular Mg2+ regulates glucokinase, KATP channels, and L-type Ca2+ channels in pancreatic b-cells, preceding insulin secretion. Moreover, insulin receptor autophosphorylation is dependent on intracellular Mg2+ concentrations, making Mg2+ a direct factor in the development of insulin resistance. Conversely, insulin is an important regulator of Mg2+ homeostasis. In the kidney, insulin activates the renal Mg2+ channel transient receptor potential melastatin type 6 that determines the final urinary Mg2+ excretion. Consequently, patients with T2DM and hypomagnesemia enter a vicious circle in which hypomagnesemia causes insulin resistance and insulin resistance reduces serum Mg2+ concentrations. This Perspective provides a systematic overview of the molecular mechanisms underlying the effects of Mg2+ on insulin secretion and insulin signaling. In addition to providing a review of current knowledge, we provide novel directions for future research and identify previously neglected contributors to hypomagnesemia in T2DM.