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.