Mk 14 vicious circle10/29/2023 Defective insulin receptor phosphorylation is therefore regarded as the main mechanism by which hypomagnesemia contributes to insulin resistance in T2DM patients. Altogether, Mg 2+ seems to be an important factor in insulin receptor autophosphorylation. However, the value of this study can be questioned because insulin phosphorylation was normal in rats with the same serum Mg 2+ levels at 6 weeks or in muscle tissue. In contrast, increased insulin receptor phosphorylation was shown in liver tissue of rats fed Mg 2+-deficient diets for 11 weeks ( 28). Indeed, rats with hypomagnesemia have reduced levels of insulin receptor phosphorylation, mimicking a state of insulin resistance ( 26, 27). Here, Mg 2+ enhances tyrosine kinase activity by increasing the receptor’s affinity for ATP ( 24, 25). The role of this Mg 2+ binding has been shown by in vitro studies using isolated insulin receptors. The crystal structure of the insulin receptor tyrosine kinase shows that two Mg 2+ ions can bind to the tyrosine kinase domain ( 23). It is widely accepted that Mg 2+ is essential for autophosphorylation of the β-subunits of the insulin receptor. An overview of the main insulin signaling pathways is provided in Fig. Alternatively, the insulin receptor can activate IRS-independent pathways via Src homology 2 domain containing transforming protein causing the activation of mitogen-activated protein kinase signaling and regulation of cell proliferation ( 16, 19). These IRSs, in turn, phosphorylate downstream signaling pathways leading to glucose uptake, glycogenesis, lipid synthesis, and other insulin-dependent actions. Depending on the target tissue, direct substrates of the insulin receptor may be recruited to the receptor, of which insulin receptor substrates (IRSs)-1–4 are the most studied. Specifically, upon insulin binding, the tyrosine residues of the β-subunits become autophosphorylated, activating a wide signaling network in the cell ( Fig. Insulin resistance is often the consequence of reduced sensitivity of the insulin receptor that is composed of two insulin-binding α-subunits and two β-subunits. In healthy subjects, insulin increases glycogen production in the liver, lipid synthesis by adipose tissue, and glucose uptake in muscle ( 5, 13– 18). Increased insulin resistance is the major pathophysiological cause for the development of T2DM. 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. This Perspective provides a systematic overview of the molecular mechanisms underlying the effects of Mg 2+ on insulin secretion and insulin signaling. Consequently, patients with T2DM and hypomagnesemia enter a vicious circle in which hypomagnesemia causes insulin resistance and insulin resistance reduces serum Mg 2+ concentrations. In the kidney, insulin activates the renal Mg 2+ channel transient receptor potential melastatin type 6 that determines the final urinary Mg 2+ excretion. Conversely, insulin is an important regulator of Mg 2+ homeostasis. Moreover, insulin receptor autophosphorylation is dependent on intracellular Mg 2+ concentrations, making Mg 2+ a direct factor in the development of insulin resistance. Intracellular Mg 2+ regulates glucokinase, K ATP channels, and L-type Ca 2+ channels in pancreatic β-cells, preceding insulin secretion. Moreover, dietary Mg 2+ supplementation for patients with T2DM improves glucose metabolism and insulin sensitivity. Clinical studies demonstrate that T2DM patients with hypomagnesemia have reduced pancreatic β-cell activity and are more insulin resistant. Patients with hypomagnesemia show a more rapid disease progression and have an increased risk for diabetes complications. Over the past decades, hypomagnesemia (serum Mg 2+ <0.7 mmol/L) has been strongly associated with type 2 diabetes mellitus (T2DM).
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