Zinc and diabetes mellitus: understanding molecular mechanisms and clinical implications

Diabetes mellitus is a leading cause of morbidity and mortality worldwide, with an estimated 387 million adults being affected in year 2014, a figure which is expected to increase by nearly 40 % by year 2035 [1]. Ninety to ninety five percent of those with the disease have type-2 diabetes. In a patho-physiologic sense, type-2 diabetes is a multi-organ, multi-factorial condition characterized primarily by insulin resistance, hyper insulinaemia and β-cell dysfunction, which ultimately leads to β-cell failure [2]. Type-1 diabetes has historically been most prevalent in populations of European origin, and the latest edition of the Diabetes Atlas estimates that 490,100 children below the age of 15 years are living with type-1 diabetes [1]. Currently 77 % of those with diabetes live in low- and middle-income countries of the African, Asian, and South American regions [1, 3, 4]. In 2014, diabetes was responsible for 4.9 million deaths worldwide and at least US$ 612 billion in global healthcare expenditures (11 % of the total global healthcare expenditures in adults) [1]. Recent cost estimates, include those for Brazil (US$ 3.9 billion), Argentina (US$ 0.8 billion) and Mexico (US$ 2.0 billion) [5]. Each of these is an annual figure and is rising as diabetes prevalence increases. Overall, direct health care costs of diabetes ranges from 2.5 to 15 % annual health care budgets, depending on local diabetes prevalence and the sophistication of the treatment available [5]. Diabetes is also associated with a host of potentially disabling macro- and micro-vascular complications. Hence, there is also a much larger burden in the form of lost productivity as a result of restricted daily activity. This rapidly increasing prevalence is attributable to population growth, aging, urbanization, unhealthy dietary habits, increasing prevalence of obesity and physical inactivity [6].

Although comprehensive diabetes management guidelines are readily available, even in developed countries like the US 30–50 % adults with diabetes do not meet individualized targets for glycaemic, blood pressure, or lipid control [7]. Reasons for failure to achieve glycaemic control includes the progression of underlying β-cell dysfunction, incomplete adherence to treatment (often due to adverse effects of medication) and reluctance of clinicians to intensify therapy [8]. Anti-diabetic agents currently in use can directly or indirectly enhance the functioning of β-cells. However, reducing the decline and the eventual failure of β-cells is crucial in preventing type-2 diabetes in those at risk and halting disease progression in the affected patients [8]. The increasing worldwide prevalence of type-2 diabetes and the progressive loss of metabolic control in patients are clear demonstrations that the current therapeutic strategies aimed at protecting the β-cells are largely inadequate. Hence there is an urgent need for anti-diabetic agents targeting the intimate mechanisms of β-cell damage and optimizing its function at cellular level.

Insulin, is stored as a hexamer containing two Zinc ions in β-cells of the pancreas and released into the portal venous system at the time of β-cell de-granulation [9]. In-vitro and in-vivo studies in animals and humans have shown that Zinc has numerous beneficial effects in both type-1 and type-2 diabetes [10–14]. A recent meta-analysis confirmed these findings, and concluded that Zinc supplementation in patients with diabetes improves glycaemic control and promotes healthy lipid parameters [15]. Hence, it is evident that Zinc has a promising potential as a novel therapeutic agent in diabetes. Studies have also shown that diabetes is commonly accompanied by hypozincemia and hyperzincuria [16, 17]. Furthermore the high prevalence of Zinc deficiency in developing countries could be contributing towards driving the current diabetes epidemic encountered by them [4, 18]. Numerous research studies have been conducted to clarify the molecular mechanisms underlying the action of Zinc in diabetes. Understanding the molecular mechanisms of action of Zinc will help to further develop targeted therapy and guide future research. The present study aims to systematically evaluate the literature on the mechanisms and molecular level effects of Zinc on glycaemic control, β-cell function, pathogenesis of diabetes and its complications.