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 end products (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.