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Over the past decades, hypomagnesemia (serum Mg(2+) <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 β-cell activity and are more insulin resistant. Moreover, dietary Mg(2+) supplementation for patients with T2DM improves glucose metabolism and insulin sensitivity. Intracellular Mg(2+) regulates glucokinase, KATP channels, and L-type Ca(2+) channels in pancreatic β-cells, preceding insulin secretion. Moreover, insulin receptor autophosphorylation is dependent on intracellular Mg(2+) concentrations, making Mg(2+) a direct factor in the development of insulin resistance. Conversely, insulin is an important regulator of Mg(2+) homeostasis. In the kidney, insulin activates the renal Mg(2+) channel transient receptor potential melastatin type 6 that determines the final urinary Mg(2+) excretion. Consequently, patients with T2DM and hypomagnesemia enter a vicious circle in which hypomagnesemia causes insulin resistance and insulin resistance reduces serum Mg(2+) concentrations. This Perspective provides a systematic overview of the molecular mechanisms underlying the effects of Mg(2+) 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.

Original publication

DOI

10.2337/db15-1028

Type

Journal article

Journal

Diabetes

Publication Date

01/2016

Volume

65

Pages

3 - 13

Keywords

Blood Glucose, Calcium Channels, L-Type, Diabetes Mellitus, Type 2, Dietary Supplements, Disease Progression, Glucokinase, Glycogen, Glycolysis, Humans, Inflammation, Insulin, Insulin Resistance, Insulin-Secreting Cells, KATP Channels, Liver, Magnesium, Magnesium Deficiency, Obesity, Potassium Channels, Inwardly Rectifying, Sodium Chloride Symporters, Sodium-Potassium-Exchanging ATPase, Water-Electrolyte Imbalance