*6.2. Anti-Diabetic Activity of PTS*

Diabetes is a disease characterized by uncontrolled sugar levels due to insufficient secretion and the improper action of insulin, usually disturbing the metabolism of fats, carbohydrates, or proteins [99]. Various rodent models have demonstrated the anti-diabetic effect of PTS (Table 2). The compound has been reported to strongly influence glucose homeostasis by decreasing systemic glucose levels while increasing insulin concentrations [3,100]. Indeed, the findings from our lab indicated that PTS treatment markedly regulated blood glucose by improving insulin secretion in STZ-induced diabetic mice [37]. In particular, we observed that PTS-mediated glucose regulation is achieved by regulating glucose metabolism enzymes in the liver of STZ-induced diabetic mice [37]. The oral administration of PTS to diabetic rats elevated the levels of the hepatic glycolytic enzyme hexokinase, reduced the levels of glycogenic enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatase, and thereby improved the peripheral utilization of glucose [72]. PTS also improved the antioxidant capacity in diabetic rats by upregulating GST, SOD, GPX, and catalase levels and counteracting ROS accumulation [100]. These mechanisms protect renal and hepatic cells from the deleterious effects of hyperglycemia-induced oxidative stress. Hence, PTS exhibits anti-diabetic activity by reducing hyperglycemia, but it also protects liver and kidney cells from hyperglycemia-associated damage [100].

While investigating PTS-mediated protection against β-cell apoptosis in STZ-induced diabetic rodents, our lab demonstrated that PTS treatment improved glucose homeostasis while attenuating the pro-inflammatory cytokine response. The cytoprotection of β-cells by PTS treatment was conferred by an Nrf2-mediated mechanism, as evidenced by the attenuation of caspase-3 activity and the BAX/Bcl-2 ratio (Figure 2). We also found the inhibition of iNOS and reduced nitric oxide (NO) synthesis in the diabetic pancreas. PTS significantly alleviated the function of pancreatic β-cell cells and improved their survival in the background of cytokine stress, thereby preventing the pathogenic features of STZinduced diabetes [36]. Furthermore, our proteomic study demonstrated the molecular mechanisms involved following PTS administration in diabetic rodents by employing electrospray ionization tandem mass spectrometry (LC-MS/MS). Our findings indicated that the administration of PTS normalized the levels of 315 proteins that were modulated in diabetic mice. Outstandingly, a major proportion of these proteins were involved in the regulation of redox imbalance, the antioxidative stress response, the unfolded protein response, and ER degradation pathways, indicating that PTS treatment plays a crucial role in the rehabilitation of defective metabolic processes and stress sensors in diabetes [101].

Lipid peroxidation is a characteristic of diabetes, and lipid peroxidation products can damage DNA and contribute to extra-pancreatic tissue damage in diabetes. PTS significantly reduced lipid peroxidation levels and was reported to scavenge DPPH free radicals and peroxyl radicals (ROO\*). In a tertiary-butyl hydroperoxide (TBHP)-induced oxidative damage rodent model, free radicals, including hydroxyl, superoxide, and hydrogen peroxide, were attenuated by PTS in a concentration-dependent manner [102]. Notably, in diabetic-nephropathy-induced rats, PTS ameliorated renal damage by dampening the NF-κB inflammatory signaling pathway and inhibiting oxidative stress [73]. Diabetic retinopathy is associated with pathogenic alterations in the structure of the retina, mediated through high glucose levels. PTS was observed to reduce ROS generation while increasing the SOD levels to scavenge free radicals and thereby suppress diabetic retinopathy [38].
