Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma

Abstract

Evidence in support of this hypothesis included the observation that many drugs used in the treatment of diabetes are chelators, that advanced glycation end product (AGE) inhibitors and AGE breakers lack carbonyl-trapping or AGE-breaker activity but are potent chelators, and that simple copper chelators inhibit vascular pathology in diabetes and aging. In the present article, we extend this hypothesis, proposing the interplay between copper and iron in the development of pathology in diabetes and other chronic age-related diseases, including atherosclerosis and neurodegenerative diseases. We also discuss the need and provide a framework for the development of a clinical laboratory test to assess plasma autoxidative catalytic activity and transition metal homeostasis in vivo.

Chelation Therapy: Overlooked in the Treatment and Prevention of Diabetes Complications?

“…The half-life of ascorbate (1 mM) is over a year in metal-free buffer, but less than 30 min in the presence of 1 µM copper. Using this assay, a wide range of antihypertensive agents, including ACE inhibitors, angiotensin receptor blockers, thiazides and hydralazine are potent inhibitors of copper-catalyzed ascorbate oxidation, with IC 50 values commonly in the 1-10 µM range [5,6]. Similar chelating activity is demonstrable for other drugs used for treatment of diabetes and CVD, including aldose reductase inhibitors, statins, b-blockers and metformin [5,6].…”

“…We also discuss the role of metal ions in the pathogenesis of other chronic inflammatory disease of aging, methods for evaluating the chelating activity of drugs, the therapeutic potential for new chelators, and relevant methods for assessing metal ion homeostasis in chronic disease. Some aspects of this work are discussed in greater detail in previous publications from our laboratory [5,6].…”

“…Brewer has argued that low-level copper toxicity, following adoption of copper plumbing, has contributed to the increase in Alzheimer's disease in the western world; b-amyloid protein, which accumulates in Alzheimer's plaque, chelates copper in a catalytically active form [13,14]. Both CVD and diabetes, which are associated with increases in copper and/or iron in tissues [5,6], are risk factors for both neurodegenerative disease and stroke, consistent with a contribution of metal ion-catalyzed tissue damage in these diseases.…”

“…Using this assay, a wide range of antihypertensive agents, including ACE inhibitors, angiotensin receptor blockers, thiazides and hydralazine are potent inhibitors of copper-catalyzed ascorbate oxidation, with IC 50 values commonly in the 1-10 µM range [5,6]. Similar chelating activity is demonstrable for other drugs used for treatment of diabetes and CVD, including aldose reductase inhibitors, statins, b-blockers and metformin [5,6]. Significantly, a wide range of drugs designed as AGE inhibitors are also chelators, inhibiting the formation of AGE and ALEs in vitro and strongly suggesting that chelation is a primary mechanism of action of these drugs.…”

Frontiers in research on the Maillard reaction in aging and chronic disease

“…Monnier et al focus on glucosepane, the major Maillard crosslink in tissue proteins [4], and Arsov et al discuss the clinical application of skin autofluorescence measurements in studies of end-stage renal disease [5]. Frizzell and Baynes propose the development of a clinical assay to assess the level of oxidative stress in plasma, which is a catalyst of Maillard reactions [6]. Several more targeted mini-reviews address the site specificity of AGE modification of proteins [7], glycation of blood lipids [8], the health impact of dietary Maillard reaction products [9] and the relevance of the Maillard reaction to food allergies [10].…”