Reappraisal of metallothionein: Clinical implications for patients with diabetes mellitus

Abstract

Reactive oxygen and nitrogen species (ROS and RNS, respectively) are byproducts of cellular physiological processes of the metabolism of intermediary nutrients. Although physiological defense mechanisms readily convert these species into water or urea, an improper balance between their production and removal leads to oxidative stress (OS), which is harmful to cellular components. This OS may result in uncontrolled growth or, ultimately, cell death. In addition, ROS and RNS are closely related to the development of diabetes and its complications. Therefore, numerous researchers have proposed the development of strategies for the removal of ROS/RNS to prevent or treat diabetes and its complications. Some molecules that are synthesized in the body or obtained from food participate in the removal and neutralization of ROS and RNS. Metallothionein, a cysteine-rich protein, is a metal-binding protein that has a wide range of functions in cellular homeostasis and immunity. Metallothionein can be induced by a variety of conditions, including zinc supplementation, and plays a crucial role in mediating anti-OS, anti-apoptotic, detoxification, and anti-inflammatory effects. Metallothionein can modulate various stress-induced signaling pathways (mitogen-activated protein kinase, Wnt, nuclear factor-κB, phosphatidylinositol 3-kinase, sirtuin 1/AMP-activated protein kinase and fibroblast growth factor 21) to alleviate diabetes and diabetic complications. However, a deeper understanding of the functional, biochemical, and molecular characteristics of metallothionein is needed to bring about new opportunities for OS therapy. This review focuses on newly proposed functions of a metallothionein and their implications relevant to diabetes and its complications.

Endothelial Overexpression of Metallothionein Prevents Diabetes-Induced Impairment in Ischemia Angiogenesis Through Preservation of HIF-1α/SDF-1/VEGF Signaling in Endothelial Progenitor Cells

“…Metallothionein (MT) is a cysteine-rich protein that binds metals such as zinc (Zn). As a potent antioxidant, MT is highly efficient in scavenging or quenching various reactive oxygen species (ROS) that play critical roles in the onset and development of diabetes and diabetic complications (7). The importance of MT in diabetic complications has been demonstrated in previous studies in MT transgenic mice.…”

Long non-coding RNA metallothionein 1 pseudogene 3 promotes p2y12 expression by sponging miR-126 to activate platelet in diabetic animal model

“…Metallothionein can be induced by a variety of conditions including high glucose (17,18), and plays a crucial role in mediating anti-apoptosis and anti-inflammation. By modulating stress- induced signaling pathways of Wnt, NF-kB, and PI3K, Metallothionein can alleviate diabetes and diabetic complications (19). Fasting resulted in a significant increase in metallothionein 1 gene expressions in retroperitoneal, epididymal, and inguinal white adipose tissue of rats, and this effect was reversed by refeeding.…”

Zinc Homeostasis in Diabetes Mellitus and Vascular Complications

“…Concurrently, the overexpression of MT in streptozotocin-induced diabetic mice caused lower levels of β-cell DNA damage and oxidative stress. While this classical view of MT as an antioxidant has been confirmed, a review by Park et al (2018) suggests new mechanisms of action for MT [ 34 ].…”

“…First, the authors proposed that MT may counteract oxidative stress by reversing mitochondrial dysfunction, which is the main source of ROS. Mitochondrial dysfunction is a primary contributor to many diabetic issues including β-cell impairment, IR, endothelial dysfunction, and vascular damage [ 6 , 34 ]. The precise mechanism surrounding MT’s effects on the respiratory chain are unclear, but studies have demonstrated that MT protects against mitochondrial superoxide (O 2 •− ) over-production and exerts myocardial anti-apoptotic effects induced by mitochondrial dysfunction [ 34 , 35 , 36 ].…”

“…Mitochondrial dysfunction is a primary contributor to many diabetic issues including β-cell impairment, IR, endothelial dysfunction, and vascular damage [ 6 , 34 ]. The precise mechanism surrounding MT’s effects on the respiratory chain are unclear, but studies have demonstrated that MT protects against mitochondrial superoxide (O 2 •− ) over-production and exerts myocardial anti-apoptotic effects induced by mitochondrial dysfunction [ 34 , 35 , 36 ]. Other promising diabetic MT protective mechanisms suggested by Park et al (2018) include: the mitigation of oxidative-induced ER stress via the suppression of signaling pathways, the maintenance of cellular autophagy to prevent apoptosis, and the possible anti-inflammatory action of extracellular MTs in the immune system and neuronal health.…”