Therapeutic potential of copper chelation with triethylenetetramine in managing diabetes mellitus and Alzheimers disease.
This article reviews recent evidence, much of which has been generated by my groups research programme, which has identified for the first time a previously unknown copper-overload state that is central to the pathogenesis of diabetic organ damage. This state causes tissue damage in the blood vessels, heart, kidneys, retina and nerves through copper-mediated oxidative stress. This author now considers this copper-overload state to provide an important new target for therapeutic intervention, the objective of which is to prevent or reverse the diabetic complications. Triethylenetetramine (TETA) has recently been identified as the first in a new class of anti-diabetic molecules through the original work reviewed here, thus providing a new use for this molecule, which was previously approved by the US FDA in 1985 as a second-line treatment for Wilsons disease. TETA acts as a highly selective divalent copper (Cu(II)) chelator that prevents or reverses diabetic copper overload, thereby suppressing oxidative stress. TETA treatment of diabetic animals and patients has identified and quantified the interlinked defects in copper metabolism that characterize this systemic copper overload state. Copper overload in diabetes mellitus differs from that in Wilsons disease through differences in their respective causative molecular mechanisms, and resulting differences in tissue localization and behaviour of the excess copper. Elevated pathogenetic tissue binding of copper occurs in diabetes. It may well be mediated by advanced-glycation endproduct (AGE) modification of susceptible amino-acid residues in long-lived fibrous proteins, for example, connective tissue collagens in locations such as blood vessel walls. These AGE modifications can act as localized, fixed endogenous chelators that increase the chelatable-copper content of organs such as the heart and kidneys by binding excessive amounts of catalytically active Cu(II) in specific vascular beds, thereby focusing the related copper-mediated oxidative stress in susceptible tissues. In this review, summarized evidence from our clinical studies in healthy volunteers and diabetic patients with left-ventricular hypertrophy, and from nonclinical models of diabetic cardiac, arterial, renal and neural disease is used to construct descriptions of the mechanisms by which TETA treatment prevents injury and regenerates damaged organs. Our recent phase II proof-of-principle studies in patients with type 2 diabetes and in nonclinical models of diabetes have helped to define the pathogenetic defects in copper regulation, and have shown that they are reversible by TETA. The drug tightly binds and extracts excess systemic Cu(II) into the urine whilst neutralizing its catalytic activity, but does not cause systemic copper deficiency, even after prolonged use. Its physicochemical properties, which are pivotal for its safety and efficacy, clearly differentiate it from all other clinically available transition metal chelators, including D-penicillamine, ammonium tetrathiomolybdate and clioquinol. The studies reviewed here show that TETA treatment is generally effective in preventing or reversing diabetic organ damage, and support its ongoing development as a new medicine for diabetes. Trientine (TETA dihydrochloride) has been used since the mid-1980s as a second-line treatment for Wilsons disease, and our recent clinical studies have reinforced the impression that it is likely to be safe for long-term use in patients with diabetes and related metabolic disorders. There is substantive evidence to support the view that diabetes shares many pathogenetic mechanisms with Alzheimers disease and vascular dementia. Indeed, the close epidemiological and molecular linkages between them point to Alzheimers disease/vascular dementia as a further therapeutic target where experimental pharmacotherapy with TETA could well find further clinical application.