This article reviews recent evidence, much of which has been generated by my group's research programme, which has identified for the first time a previously unknown
copper-overload state that is central to the pathogenesis of diabetic organ damage. This state causes tissue damage in the blood vessels, heart, kidneys, retina and nerves through
copper-mediated oxidative stress. This author now considers this
copper-overload state to provide an important new target for therapeutic intervention, the objective of which is to prevent or reverse the
diabetic complications.
Triethylenetetramine (TETA) has recently been identified as the first in a new class of anti-diabetic molecules through the original work reviewed here, thus providing a new use for this molecule, which was previously approved by the US FDA in 1985 as a second-line treatment for
Wilson's disease. TETA acts as a highly selective divalent
copper (Cu(II))
chelator that prevents or reverses diabetic
copper overload, thereby suppressing oxidative stress. TETA treatment of diabetic animals and patients has identified and quantified the interlinked defects in
copper metabolism that characterize this systemic
copper overload state.
Copper overload in
diabetes mellitus differs from that in
Wilson's disease through differences in their respective causative molecular mechanisms, and resulting differences in tissue localization and behaviour of the excess
copper. Elevated pathogenetic tissue binding of
copper occurs in diabetes. It may well be mediated by
advanced-glycation endproduct (AGE) modification of susceptible
amino-acid residues in long-lived
fibrous proteins, for example, connective tissue
collagens in locations such as blood vessel walls. These AGE modifications can act as localized, fixed endogenous
chelators that increase the chelatable-
copper content of organs such as the heart and kidneys by binding excessive amounts of catalytically active Cu(II) in specific vascular beds, thereby focusing the related
copper-mediated oxidative stress in susceptible tissues. In this review, summarized evidence from our clinical studies in healthy volunteers and diabetic patients with
left-ventricular hypertrophy, and from nonclinical models of diabetic cardiac, arterial, renal and neural disease is used to construct descriptions of the mechanisms by which TETA treatment prevents injury and regenerates damaged organs. Our recent phase II proof-of-principle studies in patients with
type 2 diabetes and in nonclinical models of diabetes have helped to define the pathogenetic defects in
copper regulation, and have shown that they are reversible by TETA. The
drug tightly binds and extracts excess systemic Cu(II) into the urine whilst neutralizing its catalytic activity, but does not cause systemic
copper deficiency, even after prolonged use. Its physicochemical properties, which are pivotal for its safety and efficacy, clearly differentiate it from all other clinically available transition
metal chelators, including
D-penicillamine,
ammonium tetrathiomolybdate and
clioquinol. The studies reviewed here show that TETA treatment is generally effective in preventing or reversing diabetic organ damage, and support its ongoing development as a new medicine for diabetes.
Trientine (TETA dihydrochloride) has been used since the mid-1980s as a second-line treatment for
Wilson's disease, and our recent clinical studies have reinforced the impression that it is likely to be safe for long-term use in patients with diabetes and related metabolic disorders. There is substantive evidence to support the view that diabetes shares many pathogenetic mechanisms with
Alzheimer's disease and
vascular dementia. Indeed, the close epidemiological and molecular linkages between them point to
Alzheimer's disease/
vascular dementia as a further therapeutic target where experimental
pharmacotherapy with TETA could well find further clinical application.