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. Garth J.S. Cooper1234,
  2. Yih-Kai Chan14,
  3. Ajith M. Dissanayake5,
  4. Fiona E. Leahy146,
  5. Geraldine F. Keogh14,
  6. Chris M. Frampton7,
  7. Gregory D. Gamble3,
  8. Dianne H. Brunton1,
  9. John R. Baker5 and
  10. Sally D. Poppitt34
  1. 1School of Biological Sciences, Faculty of Science, University of Auckland, New Zealand
  2. 2Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, New Zealand
  3. 3Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
  4. 4Human Nutrition Unit, University of Auckland, New Zealand
  5. 5South Auckland Diabetes Service, Middlemore Hospital, Otahuhu, New Zealand
  6. 6School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
  7. 7Department of Medicine, Christchurch Clinical School, University of Otago, Christchurch, New Zealand
  1. Address correspondence and reprint requests to Garth J.S. Cooper, Level 4, Thomas Bldg., School of Biological Sciences, University of Auckland, Private Bag 92019 Auckland, New Zealand. E-mail: g.cooper{at}auckland.ac.nz

Abstract

We recently showed that treatment with the CuII-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 HbA1c. 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 CuII. We suggest that cardiovascular complications in diabetes might be better controlled by therapeutic strategies that focus on lowering plasma glucose and loosely bound systemic CuII.

Footnotes

  • G.J.S.C. is a stock shareholder in, has served on an advisory panel or board of, and has received grant research support from Protemix. Y.-K.C. is employed by and has received grant/research support from Protemix. G.D.G. has received fees for providing statistical support to Protemix. J.R.B. is employed by, has served on the advisory panel or board of, and is a stock shareholder in Protemix. D.H.B. has been paid a consulting fee for statistical analysis by Protemix. S.D.P. has received grant/research support from Protemix. C.M.F. is associated with Protemix. Protemix is not affiliated with Anstead U.K., Ltd.

    • Accepted February 2, 2005.
    • Received December 9, 2004.
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