Zinc Transporters, Mechanisms of Action and Therapeutic Utility: Implications for Type 2 Diabetes Mellitus

Abstract

Zinc is an essential trace element that plays a vital role in maintaining many biological processes and cellular homeostasis. Dysfunctional zinc signaling is associated with a number of chronic disease states including cancer, cardiovascular disease, Alzheimer's disease, and diabetes. Cellular homeostasis requires mechanisms that tightly control the uptake, storage, and distribution of zinc. This is achieved through the coordinated actions of zinc transporters and metallothioneins. Evidence on the role of these proteins in type 2 diabetes mellitus (T2DM) is now emerging. Zinc plays a key role in the synthesis, secretion and action of insulin in both physiological and pathophysiological states. Moreover, recent studies highlight zinc's dynamic role as a “cellular second messenger” in the control of insulin signaling and glucose homeostasis. This suggests that zinc plays an unidentified role as a novel second messenger that augments insulin activity. This previously unexplored concept would raise a whole new area of research into the pathophysiology of insulin resistance and introduce a new class of drug target with utility for diabetes pharmacotherapy.

Differential expression of zinc transporters accompanies the differentiation of C2C12 myoblasts

“…ZnT3 is located mainly in synaptic vesicles of glutamatergic neurons located in the hippocampus, but is proposed to also modulate insulin production in pancreatic β cells [65–67]. ZnT8 activity has important implications in diabetes mellitus [68]. ZnT8 knock-out mice fed a high-fat diet became glucose intolerant or diabetic, and islet cells became less responsive to glucose.…”

Comparative Study of Serum Copper, Iron, Magnesium, and Zinc in Type 2 Diabetes-Associated Proteinuria

“…Hypozincemia may retard insulin release and its deficiency enhances insulin resistance resulting to hyperglycemia. Zn(II)T8 is a well-known zinc transporter, for insulin secretion from β cells [36].…”

Biochemical Alterations in Zinc Deficient Sheep Associated by Hyperlactatemia

“…Plasma lactate levels in zinc deficient animals were significantly higher than those in control one (Myers et al, 2012). The blood lactate concentration reflects a balance between production and uptake of lactate in tissues.…”