Elsevier

Medical Hypotheses

Volume 84, Issue 5, May 2015, Pages 451-455
Medical Hypotheses

The protection conferred by chelation therapy in post-MI diabetics might be replicated by high-dose zinc supplementation

https://doi.org/10.1016/j.mehy.2015.01.038Get rights and content

Abstract

The recent Trial to Assess Chelation Therapy (TACT) study, enrolling subjects who had previously experienced a myocardial infarction, has provided strong evidence that intravenous chelation therapy can markedly reduce risk for mortality and vascular events in diabetics, whereas no discernible benefit was observed in non-diabetics. It has plausibly been suggested that this reflects a role for transition metal ions – iron or copper – in the genesis of advanced glycation end products, key mediators of diabetic complications that can destabilize plaque. Since phlebotomy therapy fails to prevent vascular events in diabetics, we hypothesize that labile copper may be the chief culprit whose removal by chelation mediated the benefit observed in TACT. If so, strategies less time and labor intensive than chelation therapy might provide comparable benefit. A number of recent studies report that the copper-specific orally-active chelator trientine can reduce risk for range of diabetic complications in rodents; a clinical trial with this agent demonstrated some decrease in left ventricular mass in diabetics with ventricular hypertrophy. However, until this agent becomes less expensive, supplementation with high-dose zinc may represent a more feasible alternative. Zinc opposes the absorption and redox activity of copper via induction of the antioxidant protein metallothionein, which binds copper tightly. A great many studies demonstrate that increased expression of metallothionein decreases risk for tissue damage in diabetic rodents, and in some of these studies metallothionein expression was boosted by supplemental zinc. Zinc supplementation also modestly improves glycemic control in type 2 diabetics, and might reduce risk for diabetes by protecting pancreatic beta cells from oxidative stress. A long term study assessing the impact of supplementing diabetics with high-dose zinc, assessing risk for mortality, vascular events, and diabetic complications, may be warranted. Histidine, which readily forms complexes with copper that possess superoxide dismutase activity, also has potential for alleviating the contribution of loosely bound copper to AGE formation; moreover, in a recent clinical study, supplemental histidine improved insulin sensitivity and exerted anti-inflammatory and antioxidant effects in women with metabolic syndrome. Since ascorbate can reduce labile copper and thereby enhance its pathogenicity, the impact of high-dose ascorbate supplementation on cardiovascular risk in diabetics should receive further study.

Section snippets

Chelation therapy decreases vascular events in diabetics – a role for AGE reduction?

IN the Trial to Assess Chelation Therapy (TACT), subjects who had previously experienced a myocardial infarction were randomized to receive intravenous EDTA or placebo solutions 40 times over approximately one year, and were followed for five years; primary endpoints assessed were death, re-infarction, stroke, coronary revascularization, or hospitalization for angina [1]. Somewhat surprisingly, a major reduction in the primary endpoints was observed in the 633 diabetic subjects (hazard ratio

Copper, rather than iron, may be the key target of chelation therapy

If this formulation is essentially correct, is either iron or copper the primary culprit whose removal was protective in the TACT study? A previous study may cast some light on this issue. The Iron and Atherosclerosis Study (FeAST) randomized 1277 patients with stable symptomatic peripheral arterial disease to a control group or a group receiving repeated phlebotomies [6]. In treated patients who were reasonably compliant, baseline ferritin levels were reduced by approximately half, whereas

Supplemental zinc, via metallothionein induction, prevents diabetic complications

What alternative strategies might be feasible? It is well known that high intakes of supplemental zinc can be employed in the treatment of Wilson’s disease (often as maintenance therapy after an initial course of trientine), owing to the fact that high-dose zinc promotes induction of the protein metallothionein [21], [22], [23], [24]. This protein, an antioxidant rich in cysteine groups, binds not only to zinc, but also copper and cadmium; in this bound form, copper and cadmium are innocuous.

Alternative copper chelators – focus on histidine

A number of agents – drugs and natural metabolites – have moderate affinity for copper, and their copper chelates have limited redox activity. Although these agents do not boost urinary loss of copper as trientine does, they have the potential to compete for the loosely bound copper affiliated with AGE-modified proteins, and hence may render this copper less pathogenic [2], [76], [77]. Baynes and colleagues have noted that a number of commonly used drugs can suppress copper-catalyzed oxidation

A caution on vitamin C

If labile extracellular copper does indeed increase risk for mortality and cardiovascular events in diabetics, then it is reasonable to suspect that chemical agents capable of reducing this copper to its cuprous superoxide-generating form could exacerbate its pathogenicity. In this regard, vitamin C comes to mind, as it readily reduces free copper and iron [90]. (This is the basis of the utility of mega-dose intravenous ascorbate in cancer therapy [91], [92]). Indeed, some practitioners of

Conflict of interest

The authors have no conflicts of interest.

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      The antioxidant property of MTs has been elucidated by Helal and Helal (2009), who showed that MTs reduce oxidative stress in rats. Zinc protects cell membranes from oxidative damage, is normally bound to MTs (Krizkova et al., 2010), and is suggested to boost antioxidant MT protein expression via antagonism to redox activity (McCarty and DiNicolantinio, 2015). In the current study, the reduction in serum Zn concentration corresponds well with the lowered levels of MT1 in the metal treatment groups.

    Financial support provided to MFM by Catalytic Longevity, a non-profit organization.

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