Article,
Regeneration of the Heart in Diabetes by Selective Copper Chelation
Diabetes, 53 (9): 2501-2508 (2004)
DOI: 10.2337/diabetes.53.9.2501
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
CuII-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 beta1 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.
