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Regeneration of the heart in diabetes by selective copper chelation
Garth J S Cooper1, Anthony R J Phillips, Soon Y Choong
1Level 4, Thomas Building, School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. g.cooper@auckland.ac.nz
Insights
Copper chelation therapy using trientine shows promise for treating heart disease in diabetes. This treatment improved heart function and structure in diabetic rats and humans without affecting blood glucose levels.
Area of Science:
- Cardiovascular Medicine
- Endocrinology
- Toxicology
Background:
- Heart disease is a leading cause of mortality in diabetic patients.
- The role of transition metal metabolism, specifically copper, in diabetic heart disease is not fully understood.
- Previous research has explored altered systemic regulation of transition metals in diabetes.
Purpose of the Study:
- To investigate if altered transition metal metabolism contributes to heart disease in diabetes.
- To determine if metal chelation therapy can reverse cardiac complications in diabetes.
- To explore the efficacy of copper-selective chelation in managing diabetic cardiomyopathy.
Main Methods:
- Administration of the copper-selective chelator trientine to rats with streptozotocin-induced diabetes.
- Analysis of urinary copper excretion and identification of copper-trientine complexes.
- Assessment of cardiac function, cardiomyocyte structure, and left ventricular collagen and beta(1) integrin levels in treated diabetic rats.
- Evaluation of trientine's effects on copper excretion and left ventricular mass in human patients with type 2 diabetes.
Main Results:
- Trientin administration increased urinary copper excretion in diabetic rats, forming a detectable copper-trientine complex.
- In diabetic rats with heart failure, trientine therapy significantly alleviated cardiac dysfunction and improved cardiomyocyte structure.
- Trientin treatment reversed elevated left ventricular collagen and beta(1) integrin in diabetic rats.
- In humans with type 2 diabetes, oral trientine increased copper excretion and significantly reduced elevated left ventricular mass.
Conclusions:
- Elevated levels of loosely bound copper contribute to cardiac damage in diabetes.
- Selective copper chelation with trientine is a potential therapeutic strategy for diabetic heart disease.
- Trientin therapy can improve cardiac structure and function in diabetes independently of blood glucose control.
Abstract:
Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.
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