Role of Copper Ion in the Pathogenesis of Type 2 Diabetes

Abstract

Abstract. reactive oxygen species (ros) are induced under diabetic conditions and are likely associated with the development of type 2 diabetes. it is also known that ros production is facilitated in the presence of copper ion through the Fenton reaction. The aim of this study was to examine the involvement of copper ion in the pathogenesis of type 2 diabetes and to evaluate the potential usefulness of a copper chelating agent for the treatment of type 2 diabetes. First, both serum copper ion and ROS levels in diabetic C57BL/KsJ-db/db mice were significantly higher compared to those in nondiabetic mice. second, we treated diabetic db/db mice with a copper chelating agent tetrathiomolybdate and examined the effects on the development of type 2 diabetes. As the results, both serum copper ion and ROS levels were significantly decreased by the treatment, which were equivalent to those in non-diabetic mice. consequently, the treatment with a copper chelating agent reduced insulin resistance and ameliorated glucose intolerance in diabetic db/db mice. in addition, serum triglyceride levels were also decreased by the treatment. in conclusion, our present results suggest that copper ion is involved in the development of type 2 diabetes and thereby a potential therapeutic target for diabetes.

Metal ions affect insulin-degrading enzyme activity

“…We carried out enzymatic digestions of B20-30, in the presence or absence of copper(II), aluminum(III) and zinc(II), metals chosen for their important role in neurodegenerative diseases [24,26,66,67]. Moreover, since copper enters the cell as copper(I) through high-affinity plasma membrane copper transporters or low affinity permeases [68] and IDE is mainly cytosolic [1], it is interesting to analyze the effect of both oxidation states on B (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) processing. Furthermore, as silver belongs to the same group of copper and silver(I) has the same chemistry of copper(I), we have also performed studies using this ion, in order to have a replication of the copper(I) results without any possible invalidation due to copper(I) oxidation problems (although we worked in a reducing environment, copper(I) could be oxidized to copper(II) during the incubation with the enzyme).…”

“…To assess how metal ions affect the IDE enzymatic activity, steady state kinetics on the B (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) peptide in the presence and in the absence of the above mentioned ions were performed. Fig.…”

“…It is also interesting to outline that if we compare these parameters with those obtained for the amyloid peptides Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and Aβ [16][17][18][19][20][21][22][23][24][25][26][27][28] several similarities and some differences emerge [54]. In particular, the overall proteolytic activity toward the main cleavage sites (i.e., Phe 24 [16][17][18][19][20][21][22][23][24][25][26][27][28] ) is somewhat higher in the case of the B20-30 peptide due to a slightly more efficient cleavage rate-limiting step (see Table 2), whereas the substrate affinity of B20-30 appears intermediate between that of Aβ [1][2][3]…”

“…Recently, zinc [27] and copper [28] have been identified to have a crucial role on insulin action and, ultimately, in diseases such as DM2. In particular, zinc deficiency seems to facilitate diabetes mellitus and its cardiovascular complications [29,30].…”

“…Although some studies have demonstrated antidiabetogenic properties of zinc supplementation in both animal models and humans, the efficacy is still controversial and the observation that all patients could benefit from ion administration is too simplistic [31][32][33][34]. Interestingly, it has also been shown that copper chelating agents might be useful for the treatment of glucose and lipid dismetabolism in DM2 mouse model [28].…”