Title:Selective Divalent Copper Chelation for the Treatment of Diabetes Mellitus
Volume: 19
Issue: 17
Author(s): G. J.S. Cooper
Affiliation:
Keywords:
Atherosclerosis, copper deficiency, copper overload, copper-selective chelation, diabetes mellitus, diabetic arteriopathy, diabetic
cardiomyopathy, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, divalent copper, hydroxyl radical, iron regulation,
mitochondrial dysfunction, oxidative stress, organ regeneration, experimental therapeutics, experimental pharmacology, heart failure,
randomized clinical trials, superoxide anion, superoxide dismutase, triethylenetetramine (TETA), zinc regulation
Abstract: Oxidative stress and mitochondrial dysfunction have been identified by many workers as key pathogenic mechanisms in
ageing-related metabolic, cardiovascular and neurodegenerative diseases (for example diabetes mellitus, heart failure and Alzheimer’s
disease). However, although numerous molecular mechanisms have been advanced to account for these processes, their precise nature
remains obscure. This author has previously suggested that, in such diseases, these two mechanisms are likely to occur as manifestations
of a single underlying disturbance of copper regulation. Copper is an essential but highly-toxic trace metal that is closely regulated in
biological systems. Several rare genetic disorders of copper homeostasis are known in humans: these primarily affect various proteins
that mediate intracellular copper transport processes, and can lead either to tissue copper deficiency or overload states. These examples
illustrate how impaired regulation of copper transport pathways can cause organ damage and provide important insights into the impact
of defects in specific molecular processes, including those catalyzed by the copper-transporting ATPases, ATP7A (mutated in Menkes
disease), ATP7B (Wilson’s disease), and the copper chaperones such as those for cytochrome c oxidase, SCO1 and SCO2. In diabetes,
impaired copper regulation manifests as elevations in urinary CuII excretion, systemic chelatable-CuII and full copper balance, in
increased pro-oxidant stress and defective antioxidant defenses, and in progressive damage to the blood vessels, heart, kidneys, retina and
nerves. Linkages between dysregulated copper and organ damage can be demonstrated by CuII-selective chelation, which simultaneously
prevents/reverses both copper dysregulation and organ damage. Pathogenic structures in blood vessels that contribute to binding and
localization of catalytically-active CuII probably include advanced glycation endproducts (AGEs), as well as atherosclerotic plaque: the
latter probably undergoes AGE-modification itself. Defective copper regulation mediates organ damage through two general processes
that occur simultaneously in the same individual: elevation of CuII-mediated pro-oxidant stress and impairment of copper-catalyzed
antioxidant defence mechanisms. This author has proposed that diabetes-evoked copper dysregulation is an important new target for
therapeutic intervention to prevent/reverse organ damage in diabetes, heart failure, and neurodegenerative diseases, and that
triethylenetetramine (TETA) is the first in a new class of anti-diabetic molecules, which function by targetting these copper-mediated
pathogenic mechanisms. TETA prevents tissue damage and causes organ regeneration by acting as a highly-selective CuII chelator which
suppresses copper-mediated oxidative stress and restores anti-oxidant defenses. My group has employed TETA in a comprehensive
programme of nonclinical studies and proof-of-principle clinical trials, thereby characterizing copper dysregulation in diabetes and
identifying numerous linked cellular and molecular mechanisms though which TETA exerts its therapeutic actions. Many of the results
obtained in nonclinical models with respect to the molecular mechanisms of diabetic organ damage have not yet been replicated in
patients’ tissues so their applicability to the human disease must be considered as inferential until the results of informative clinical
studies become available. Based on evidence from the studies reviewed herein, trientine is now proceeding into the later stages of
pharmaceutical development for the treatment of heart failure and other diabetic complications.
