The Role of Zinc Homeostasis in the Prevention of Diabetes Mellitus and Cardiovascular Diseases

Abstract

Zinc is an essential micronutrient for human health and is involved in various biological functions, such as growth, metabolism, and immune function. In recent years, research on intracellular zinc dynamics has progressed, and it has become clear that zinc transporters strictly control intracellular zinc localization, zinc regulates the functions of various proteins and signal transduction pathways as a second messenger similar to calcium ions, and intracellular zinc dyshomeostasis is associated with impaired insulin synthesis, secretion, sensitivity, lipid metabolism, and vascular function. Numerous animal and human studies have shown that zinc deficiency may be associated with the risk factors for diabetes and cardiovascular diseases (CVDs) and zinc administration might be beneficial for the prevention and treatment of these diseases. Therefore, an understanding of zinc biology may help the establishment of novel strategies for the prevention and treatment of diabetes and CVDs. This review will summarize the current knowledge on the role of zinc homeostasis in the pathogenesis of diabetes and atherosclerosis and will discuss the potential of zinc in the prevention of these diseases.

Keywords: Atherosclerosis; Cardiovascular diseases; Diabetes; Endothelial function; Insulin resistance; Zinc; Zinc transporter.

Fig.1. Subcellular localization of a zinc transporter in mammalian cells (modified from reference (10)).

ER, endoplasmic reticulum

Fig.2. Proposed mechanisms for the participation of zinc transporters (ZnT3, ZnT7, ZnT8, and Zip5) in the regulation of insulin processing, secretion, and clearance

Sirt1, sirtuin 1; PGC-1, peroxisome proliferator-activated receptor γ coactivator-1; GLUT2, glucose transporter 2

Fig.3. Role of zinc in the regulation of insulin signaling (modified from reference (34))

PTPase, protein tyrosine phosphatase; IRS, Insulin receptor substrate; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4, 5-bisphosphate; PIP3, phosphatidylinositol 3, 4, 5-bisphosphate; PDK, phosphoinositide dependent kinase; PTEN, phosphatase and tensin homolog: Akt, protein kinase B; GSK-3β, glycogen synthase kinase 3β; FoxO1, forkhead box protein O1; GLUT4, glucose transporter 4

Fig.4. Proposed mechanisms of the protective action of zinc in endothelial function

MT, metallothionein; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; TNF-α, tumor necrosis factor-alpha; NF-κB, nuclear factor-κB; AGEs, advanced glycation end products