**4. Copper in T2D pathogenesis**

Plasma Cu concentrations have been reported in some studies to be altered in diabetic humans compared to non-diabetics [4], particularly in diabetic patients with microvascular disease complications [48] and proteinuria [49]. Similarly, serum ceruloplasmin has been noted to be higher in T2D subjects compared to non-diabetics in numerous studies [50]. Alterations in Cu metabolism coupled with an increase in glycated proteins [4] may contribute to the progression of diabetes-related pathologies. Several lines of evidence support a role of Cu in diabetesinduced oxidative stress. Several previous studies have showed that ceruloplasmin can be fragmented following non-enzymatic glycosylation [51]. Secondly, glycation of CuZn-SOD in humans with diabetes leads to a site-specific fragmentation resulting in its inactivation [52] as well as the release of Cu, which can further exacerbate oxidative stress. Glycation of CuZn-SOD increases the formation of DNA damage in vitro, which suggests that the release of Cu2+ from glycated SOD can participate in cleavage of nuclear DNA [53]. As CuZn-SOD accounts for 90% of the total SOD activity of the mouse lens [54], the excessively high concentrations of glycated CuZn-SOD in diabetic rat lenses are postulated to be involved in lens pathology [55]. Cu can increase the rate advanced glycated end (AGE) products formation, which is associated with the pathogenesis of secondary complications in diabetes [56]. Agents used to prevent or reduce AGE formation typically have potent Cu chelating [57].
