Zinc transporters and insulin resistance: therapeutic implications for type 2 diabetes and metabolic disease
Norouzi et al. Journal of Biomedical Science
Zinc transporters and insulin resistance: therapeutic implications for type 2 diabetes and metabolic disease
Shaghayegh Norouzi 0
John Adulcikas 0
Sukhwinder Singh Sohal 0
Stephen Myers 0
0 Faculty of Health, School of Health Sciences, University of Tasmania , Newnham Campus, Launceston, TAS 7250 , Australia
Background: Zinc is a metal ion that is essential for growth and development, immunity, and metabolism, and therefore vital for life. Recent studies have highlighted zinc's dynamic role as an insulin mimetic and a cellular second messenger that controls many processes associated with insulin signaling and other downstream pathways that are amendable to glycemic control. Main body: Mechanisms that contribute to the decompartmentalization of zinc and dysfunctional zinc transporter mechanisms, including zinc signaling are associated with metabolic disease, including type 2 diabetes. The actions of the proteins involved in the uptake, storage, compartmentalization and distribution of zinc in cells is under intense investigation. Of these, emerging research has highlighted a role for several zinc transporters in the initiation of zinc signaling events in cells that lead to metabolic processes associated with maintaining insulin sensitivity and thus glycemic homeostasis. Conclusion: This raises the possibility that zinc transporters could provide novel utility to be targeted experimentally and in a clinical setting to treat patients with insulin resistance and thus introduce a new class of drug target with utility for diabetes pharmacotherapy.
Zinc ions; Skeletal muscle; Cell signaling; Glycemic control
Background
Insulin resistance (IR) is a common pathophysiological
condition in which patients present with reduced insulin
sensitivity and thus glucose intolerance, particularly in
liver, adipose tissue and skeletal muscle [
1
]. This has
significant implications for the patient, as they are unable
to obtain to process the required energy from glucose to
maintain cellular metabolic processes. IR is of major global
concern as it is well-established as underpinning many
chronic health conditions including type 2 diabetes mellitus
(T2DM), obesity, cardiovascular disease polycystic ovary
syndrome (PCOS), liver cirrhosis [
2
] atherosclerosis,
hypertension, and stroke [
3
]. Moreover, given that IR
usually precedes the development of T2DM and
contributes to the progressive nature of this challenging and
devastating disease, understanding the molecular mechanisms
that lead to IR will help facilitate the development of
novel therapeutic strategies to prevent or lessen disease
progression. However, despite extensive ongoing research
into IR, its molecular mechanism(s) of action remains
largely elusive.
Recently, research on metabolic processes associated
with IR and T2DM has revealed an exciting role for the
biochemical and physiological role of zinc and the proteins
that transport zinc in cells in diseases associated with
abnormal cellular signaling [
4
]. Accordingly, zinc and the
proteins that transport this metal ion have emerged as
potential therapeutic targets for disease states associated
with dysfunctional metabolism. For example, zinc in the
diet and zinc transporter proteins that influence/regulate
zinc metabolism are implicated in metabolic homeostasis in
peripheral tissues (e.g. skeletal muscle and liver) that
respond to insulin [
4
].
Zinc is ubiquitous in physiological systems, albeit, within
tightly controlled parameters, and therefore suggests that
atypical levels are likely to have significant biological and
clinical effects on disease processes. Knowing how zinc
transporter proteins and the storage of zinc in cells are
involved in metabolic processes implicated in IR for example,
may present opportunities to develop novel drugs targeting
these transporters to prevent or treat IR and T2DM disease
progression.
Type 2 diabetes mellitus
Type 2 diabetes mellitus (T2DM) is devastating disorder
characterised by hyperinsulinemia, hyperglycaemia,
compromised energy metabolism and expenditure, and the
progression of chronic illness and disease. T2DM is high
complex involving both genetic predisposition and
environmental factors. A major factor involved in a person’s
susceptibility to T2DM can be linked through family
history of diabetes. For example, Pacific Islander peoples
are a unique population with especially high rates of T2DM
[
5
]. The environment also plays a major role in the
development of IR and T2DM with inactivity and poor
nutritional status being two key factors [
6
].
Development of T2DM
The development of T2DM is preceded by IR, a disorder
associated with hyperinsulinemia, glucose intolerance
and dysfunctional energy metabolism [
7
]. A leading
concern for people with IR is the progressive failure of
pancreatic β-cell function (a major determinant of T2DM
progression) and thus, compromised insulin secretion
[
8
]. T2DM oc (...truncated)