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

Quantitative Comparisons Between the Biology of Copper and Eight Other Nutritionally Essential Elements in Normal and Diabetic Individuals

¹ School of Biological Sciences, Faculty of Science, University of Auckland, New Zealand
² Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, New Zealand
³ Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
⁴ Human Nutrition Unit, University of Auckland, New Zealand
⁵ South Auckland Diabetes Service, Middlemore Hospital, Otahuhu, New Zealand
⁶ School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
⁷ Department of Medicine, Christchurch Clinical School, University of Otago, Christchurch, New Zealand

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.

Abbreviations: EC-SOD, extracellular superoxide dismutase; FPG, fasting plasma glucose; IBC, iron-binding capacity; PABA, p-aminobenzoic acid; REML, restricted maximum likelihood; RIGLS, restrictive iterative generalized least squares; ROS, reactive oxygen species

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