**5. Manganese in T2D pathogenesis**

The manganese status in T2D is still unclear and the few studies that have addressed this issue in humans are controversial. However, Mn acts as a cofactor in several metalloenzymes including those involved in glucose homeostasis (*Pyruvate carboxylase, GTP oxaloacetate carboxylase, Isocitrate dehydrogenase, Malate dehydrogenase, Phosphoenolpyruvate carboxykinase*). These enzymes play a critical role in the blood glucose regulation via glycolysis, gluconeogenesis, Krebs cycle [58]. Mn is required for insulin synthesis [59], and to regulate of glucose utilization and lipogenesis in adipose tissue [60]. Previous studies have shown that blood manganese levels are unchanged in plasma, not significantly (approx. 15%) reduced in whole blood [61], or decreased in erythrocytes [62], from diabetic patients as compared to controls. In healthy subjects, manganese is very present in tissues rich in mitochondria (12–16 mg), in particular skeletal muscle, liver, pancreas and kidney. Mn is necessary for the synthesis, secretion and action of insulin. Mn is also indispensable for the maturation of bones and cartilage. Mn plasma levels are essentially regulated via the bile excretion pathway. Mn also participates in vitamins E and B1 synthesis [63]. Mn is found mainly in quinoa, rye, whole rice, soybeans, avocado, egg yolk, green beans, spinach, walnuts, olive oil, oysters, green tea and provence herbs [64].

Our recently diabetes investigation [65], we found Mn blood concentrations are significantly increased (23%) in diabetic patients compared to controls. The correlation is positive with hyperglycemia and HbA1C. Our data suggest that Mn play a crucial role in antioxidant capacity and we hypothesize that antioxidant defense is preserved in the cytosol (superoxide dismutase Cu/Zn-SOD), whereas it is impaired in mitochondria (Mn-SOD), which makes this cell organelle a true therapeutic target in diabetes. In our recent study, we showed the competitive effect between the manganese and iron in T2D. However, when the iron was in the free form and reduced, it was constantly a pro-oxidant, whereas Mn was an anti-oxidant. Several studies suggesting that transferrin (Tf)/Tf receptor (TfR) transport system is the major transport of manganese and iron in plasma. The Mn bioavailability is reduced due to altered Tf/TfR transport system [66–69]. Consequently, the Mn (III) forms a more stable with Tf than the Mn (II) form [70]. The more complex questions related to the regulation of each by Mn and Fe might affect the insulin secretion and glucose homeostasis. Probably the increased Mn levels would affect the availability or concentration of both various transporters and finally bêta cell Mn distribution [71]. The interactions of Mn, Fe and ferritin are closely related in the following manner; and can lead to hyperglycemia associated to mitochondrial Fe, Mn, copper, and zinc levels [72], demonstrating the interrelationship with glycemia homeostasis. Probably, that the heightened β-cell oxidative stress may result from occurring Tf/Tf receptor system, and elevated manganese is produced via an extracellular Tf-manganese redox mechanism, rather than simply the presence of elevated tissue manganese per se. In this context, the plasma manganese accumulation was associated to iron plasma depletion and ferritin increased, suggesting that mitochondrial iron accumulation resulting in generation of ROS by Fenton chemistry [73]. The Mn is confined to the cytosol where it is associated with decreased mitochondrial SOD-Mn due the lack of mitochondrial manganese. The finding that DT2 pathogenesis are able to regulate manganese transport into, and/or export from, mitochondria and maintain a normal pool of mitochondrial manganese, despite the presence of a two-fold increase in cytosolic manganese content. Among possible explanations for this result, the upregulation of mitochondrial manganese transporters in situations of large changes in metal availability, or a heretofore undescribed function for the transferrin in regulation of mitochondrial metal accumulation. At last, in diabetes vascular complications, Mn is involved in Arginine production, precursor to nitric oxide (NO) formation as endothelial vasodilator [74].
