Copper overload in diabetes mellitus differs from that in Wilson’s disease through differences in their respective Screening Library molecular weight causative molecular mechanisms, and resulting differences in tissue localization and behaviour of the excess copper.\n\nElevated 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.\n\nIn this review, summarized evidence from our clinical studies in healthy volunteers BIX 01294 datasheet 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.\n\nThe 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 VX-680 inhibitor 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.