A HRC-funded programme co-led by Professor Garth Cooper at The University of Auckland’s School of Biological Sciences has uncovered one of the main causes of heart failure and other complications in patients with diabetes. Not only that, but Professor Cooper and his diabetes research group have now developed a new treatment that can restore diabetic patients’ damaged hearts and other organs back to normal.
This ground-breaking research is part of a recently completed HRC programme with The University of Auckland’s Professors Garth Cooper and Mark Cannell (now Chair of Cardiac Cell Biology at the University of Bristol), which set out to improve our understanding of the relationship between structure and function in heart failure.
Professor Cooper, who is also Professor of Discovery and Experimental Medicine at the University of Manchester in the UK (co-appointed to The University of Auckland), focused on researching the molecular mechanisms that cause heart failure, particularly in patients with diabetes. His group’s earlier HRC-funded research had suggested that defects in the mechanism for maintaining adequate levels of copper in the body (called copper homeostasis) were the main culprits responsible for causing diabetic-induced heart failure – not defects in calcium homeostasis as previously thought(1).
To test this, the group undertook extensive molecular analysis of the copper regulation pathways in tissues that are known to be adversely affected by diabetes.
“We have now identified two distinct molecular pathways by which diabetes causes copper imbalance. These are defects in the mitochondria of cells and defects in the organs’ antioxidant defences. I believe that these defects in copper regulation can lead to all of the complications associated with diabetes, including damage to the heart, aorta, kidneys, retina and nerves,” says Professor Cooper.
The group have also proven in phase I and II clinical trials carried out in the US, and in New Zealand and Australia respectively, that treatment with triethylenetetramine (TETA), a copper-selective chelator, can restore both these defective molecular pathways back to normal, effectively reversing the organ damage caused by diabetic complications (2,3,4, 5).
“In the heart, TETA has been found to restore function of the left ventricle, restore the structure and function of the mitochondria, and repair fibrosis in the wall of the heart,” says Professor Cooper.
Group member Dr Linda Zhang, who carried out research in diabetic animal models, says the copper drug treatment appears to have a role in protecting the muscle structure of the heart.
“In our diabetic animal models, we observed that the copper treatment can prevent or reverse cardiac dysfunction. The results from our animal models are a very good reflection of the results that we’ve seen in type 2 diabetic patients, and provide strong support for ongoing studies of treatment in diabetic patients with heart failure,” says Dr Zhang.
This work from the Cooper laboratories was performed under the guidance of the US Food and Drug Administration (FDA) who awarded it “fast track” status, a special designation that accelerates the approval process for a new treatment for a serious or life-threatening disease that has no current treatment.
Professor Cooper says this is pivotal in the development of an experimental medicine for the treatment of diabetic heart disease and other diabetic complications, and they are now working on getting the copper chelation treatment to phase III trials.
1 Zhang L, Cannell MB, Phillips AR, Cooper GJS, Ward ML: Altered calcium homeostasis does not explain the contractile deficit of diabetic cardiomyopathy. Diabetes 2008, 57(8):2158-2166.
2 Cooper GJS, Young AA, Gamble GD, Occleshaw CJ, Dissanayake AM, Cowan BR, Brunton DH, Baker JR, Phillips AR, Frampton CM et al: A copper(II)-selective chelator ameliorates left-ventricular hypertrophy in type 2 diabetic patients: a randomised placebo-controlled study. Diabetologia 2009, 52(4):715-722.
3 Lu J, Gong D, Choong SY, Xu H, Chan YK, Chen X, Fitzpatrick S, Glyn-Jones S, Zhang S, Nakamura T … Cooper GJS: 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.Diabetologia 2010, 53(6):1217-1226.
4 Cooper GJS: Therapeutic potential of copper chelation with triethylenetetramine in managing diabetes and Alzheimer’s disease. Drugs 2011, 71:1281-1320.
5 Lu J, Pontré B, Pickup S, Choong SY, Li M, Xu H, Gamble GD, Phillips ARJ, Cowan BR, Young AA et al: Treatment with a copper-selective chelator causes substantive improvement in cardiac function of diabetic rats with left-ventricular impairment. 2012: Accepted for publication in Cardiovasc Diabetol (2013, 12:28).
• For a full list of all publications relating to the research of Professor Cooper’s group on this programme, please contact Group Research Manager Cynthia Tse.