The role of metal ion metabolism in the pathogenesis of diabetes and associated complications

Abstract

Diabetes is a growing health concern, accompanied by significant complications like cardiovascular disease, kidney disease, and retinopathy. Metal ions, including iron, zinc, and copper, play a crucial role in maintaining human health through their balance within the body. Disruptions in metal ion balance can intensify diabetic conditions. For instance, iron overload induces oxidative stress, which harms islet β cells and impacts vascular complications of diabetes. Abnormal copper levels heighten insulin resistance, and zinc deficiency has a strong connection with type 1 diabetes. Future in - depth exploration of the association between metal metabolism and diabetes holds the potential to uncover novel treatment avenues, enhancing both the quality of life and health prognosis for patients.

Keywords: complications; copper ion; diabetes; iron ion; metabolism; metal ion.

Figure 1

Metal ion metabolism. The main components involved in metal ion metabolism and homeostatic regulation include transporters, metal-blinding chaperones, and metalloproteins.

Figure 2

Relationship between iron metabolism disorder and diabetes and its complications. Plasma iron and ferritin levels increase in T2DM patients. Iron accumulates in liver cells and leads to insulin resistance and reduced secretion through oxidative stress pathways. In addition, free iron can induce iron death of beta cells by activating the ASK1/P-P38/CHOP signaling pathway. Besides, an iron influx in the retina, through the Fenton/Haber-Weiss reaction, causes the generation of a series of hydroxyl radicals, aggravates oxidative stress, propagates lipid peroxidation, and damages neurons, retinal endothelial cells (REC) and retinal pigment epithelium (RPEC), which may catalyze the induction of ferroptosis, and lead to diabetic retinopathy (DR). Renal damage in patients with diabetes nephropathy leads to abnormal iron metabolism, including decreased absorption, increased release and decreased utilization of iron, which aggravates iron deficiency and leads to anemia.

Figure 3

Relationship between copper metabolism disorder and diabetes and its complications. Wilson's disease protein (ATP7B) is mainly present in the liver, and Wilson's disease can damage this protein, leading to the accumulation of Cu. ATP7A is present in extrahepatic tissues, which can be damaged by Menkes disease and hinder the absorption of Cu in the intestinal mucosa, leading to systemic copper deficiency. Copper overload will lead to diabetes and diabetes complications through oxidative stress, in which diabetes small vessel disease is closely related to EDRF-dependent arterial relaxation. In diabetic patients, the internal elastic layer of the arteries (composed of elastin) accumulates glycated proteins that bind Cu, and the Cu enriched in the arterial wall catalyzes the destruction of NO or NO adducts, which is EDRF, by the metal catalysis, which prevents normal EDRF-mediated diastole, leading to arterial diastolic defects and impaired peripheral blood flow. And SOD can protect against NO^-mediated vasodilation. Superoxide (O^2-) is produced by mitochondrial enzymes, lipoxygenase, nitric oxide synthase (NOS), xanthine oxidase and NADPH oxidase. Superoxide dismutase (SOD) converts superoxide to H₂O₂. Then, peroxide reductase (Prx), glutathione peroxidase (GPx), and catalase reduce H₂O₂ to water. Nitric oxide (NO) is rapidly deactivated through reacting with O^2-, resulting in the generation of the peroxynitrite (ONOO^-), which is a strong oxidant. Therefore, SOD is the first line of defense against the toxicity of superoxide anion radicals. Moreover, this enzyme protects NO and its ability to mediate vasodilation.