Demonstration of a Hyperglycemia-Driven Pathogenic Abnormality of Copper Homeostasis in Diabetes and Its Reversibility by Selective Chelation

Abstract

We recently showed that treatment with the Cu II -selective chelator, trientine, alleviates heart failure in diabetic rats, improves left ventricular hypertrophy in humans with type 2 diabetes, and increases urinary Cu excretion in both diabetic rats and humans compared with nondiabetic control subjects. In this study, we characterized the homeostasis of Cu and eight other nutritionally essential elements in diabetes under fully residential conditions in male subjects with type 2 diabetes and age-matched control subjects. We then probed elemental balance with oral trientine in a parallel-group, placebo-controlled study in these subjects. Before treatment, there were no detectable between-group differences in the balance of any element, although urinary output of several elements was greater in diabetic subjects. Mean extracellular superoxide dismutase (EC-SOD) activity was elevated in diabetic subjects, and its activity correlated strongly with the interaction between [Cu] serum and HbA 1c . Trientine caused the Cu balance to become negative in diabetic subjects through elevated urinary Cu losses and suppressed elevated EC-SOD. Basal urinary Cu predicted urinary Cu losses during treatment, which caused extraction of systemic Cu II . We suggest that cardiovascular complications in diabetes might be better controlled by therapeutic strategies that focus on lowering plasma glucose and loosely bound systemic Cu II .

Copper(II)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments

“…Human urine collection Urine samples were collected during a previously reported clinical study [1,32]. Six healthy male volunteers and seven men with type 2 diabetes (aged between 30 and 70 years) completed that study.…”

“…Triethylenetetramine (TETA) is a potent and highly selective Cu(II) chelator [1]. It is an orphan drug used in the treatment of the Wilson's disease [2] and has also shown beneficial effects in the experimental treatment of cardiac/vascular and renal disease in diabetes [3][4][5][6][7].…”

“…Arterial tissue-bound EC-SOD is decreased in diabetic individuals, promoting increased susceptibility to superoxide-mediated damage via NO depletion and endothelial dysfunction [19]. Elevation of plasma EC-SOD in patients with type 2 diabetes is strongly correlated with an interaction between plasma HbA 1c and total Cu levels [1]. Furthermore, high concentrations of Cu(II) suppress EC-SOD secretion from cultured vascular smooth muscle cells [20].…”

“…Excessive accumulation of ECM proteins and associated myocardial fibrosis are implicated as pathogenic mechanisms in diabetic heart disease [28]. Increased fibrous ECM proteins provide the excess Cu-binding sites responsible for the accumulation of elevated loosely bound/chelatable Cu(II) in diabetes [1,3,29]. In a rat model of diabetic complications TETA treatment normalised cardiac and aortic fibrosis, and suppressed elevations of aortic and renal TGF-β1 production and urinary albumin/creatinine ratio (uACR) [3,4,30].…”

“…The numbers of rats assigned to each treatment were as stated below for the individual studies. Dosages of TETA were based on those found to be efficacious in diabetic rats and patients [1][2][3][4][5]. Dosages of Pen, Def and ZnA were equivalent to those reported to be efficacious in animals and patients, and drug dosing was verified by measurement of disappearance of the drinking water in all studies.…”