Zinc transporters and insulin resistance: therapeutic implications for type 2 diabetes and metabolic disease

Journal of Biomedical Science, Nov 2017

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. 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. 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.

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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)


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Shaghayegh Norouzi, John Adulcikas, Sukhwinder Singh Sohal, Stephen Myers. Zinc transporters and insulin resistance: therapeutic implications for type 2 diabetes and metabolic disease, Journal of Biomedical Science, pp. 87,