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 Cu II -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 ␤ 1 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.

Summary Objective  To explore the mechanism underlying severe hypomagnesaemia in long‐term users of proton‐pump inhibitors (PPIs). Patients  Two cases of severe hypomagnesaemia in adult long‐term users of the PPI omeprazole, presenting with hypocalcaemic seizures. Measurements  We studied renal magnesium handling during an incremental intravenous magnesium infusion, and assessed total body magnesium status by the 24‐h retention of the parenteral load. We also observed the effects of oral magnesium supplements whilst continuing the PPI, and the effect of withdrawal of the PPI. Results  Both patients were severely magnesium‐depleted and had avid renal magnesium retention, implicating a failure of intestinal magnesium absorption. There was no evidence of generalized malabsorption. The hypomagnesaemia could be partially corrected by high dose oral magnesium supplementation, and resolved on withdrawal of PPIs. Conclusions  PPI use can inhibit active magnesium transport in the intestine, though it is not clear if this is an idiosyncratic effect. Long‐term PPI users who are highly adherent to treatment can eventually deplete total body magnesium stores and present with severe complications of hypomagnesaemia.

We recently showed that treatment with the Cu II -selective chelator, trientine, alleviates heart failure in diabetic rats, improves left ventricular hypertrophy in humans with type 2 diabetes, and increases urinary Cu excretion in both diabetic rats and humans compared with nondiabetic control subjects. In this study, we characterized the homeostasis of Cu and eight other nutritionally essential elements in diabetes under fully residential conditions in male subjects with type 2 diabetes and age-matched control subjects. We then probed elemental balance with oral trientine in a parallel-group, placebo-controlled study in these subjects. Before treatment, there were no detectable between-group differences in the balance of any element, although urinary output of several elements was greater in diabetic subjects. Mean extracellular superoxide dismutase (EC-SOD) activity was elevated in diabetic subjects, and its activity correlated strongly with the interaction between [Cu] serum and HbA 1c . Trientine caused the Cu balance to become negative in diabetic subjects through elevated urinary Cu losses and suppressed elevated EC-SOD. Basal urinary Cu predicted urinary Cu losses during treatment, which caused extraction of systemic Cu II . We suggest that cardiovascular complications in diabetes might be better controlled by therapeutic strategies that focus on lowering plasma glucose and loosely bound systemic Cu II .

Aims/hypothesis Cu(II)-selective chelation with trientine ameliorates cardiovascular and renal disease in a model of diabetes in rats. Here, we tested the hypothesis that Cu(II)-selective chelation might improve left ventricular hypertrophy (LVH) in type 2 diabetic patients. Methods We performed a 12 month randomised placebocontrolled study of the effects of treatment with the Cu (II)-selective chelator trientine (triethylenetetramine dihydrochloride, 600 mg given orally twice daily) on LVH in diabetic patients (n=15/group at baseline) in an outpatient setting wherein participants, caregivers and those assessing outcomes were blinded to group assignment. Using MRI, we measured left ventricular variables at baseline, and at months 6 and 12. The change from baseline in left ventricular mass indexed to body surface area (LVM bsa ) was the primary endpoint variable.Results Diabetic patients had LVH with preserved ejection fraction at baseline. Trientine treatment decreased LVM bsa by 5.0± 7.2 g/m 2 (mean ±SD) at month 6 (when 14 trientine-treated and 14 placebo-treated participants were analysed; p=0.0056 compared with placebo) and by 10.6± 7.6 g/m 2 at month 12 (when nine trientine-treated and 13 placebo-treated participants were analysed; p=0.0088), whereas LVM bsa was unchanged by placebo treatment. In a multiple-regression model that explained~75% of variation (R 2 =0.748, p=0.001), cumulative urinary Cu excretion over 12 months was positively associated with trientine-evoked decreases in LVM bsa . Conclusions/interpretation Cu(II)-selective chelation merits further exploration as a potential pharmacotherapy for diabetic heart disease.

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