Sodium-Glucose Cotransporter-2 Inhibitor Suppresses Endoplasmic Reticulum Stress and Oxidative Stress in Diabetic Nephropathy Through Nrf2 Signaling: A Clinical and Experimental Study.

Diabetic nephropathy (DN), a severe complication of type 2 diabetes mellitus (T2DM), is marked by heightened endoplasmic reticulum stress (ERS) and oxidative stress (OS) due to protein misfolding and free radical generation. We investigated the sodium-glucose co-transporter-2 inhibitor (SGLT2i), canagliflozin (Cana), in alleviating ERS and OS in DN patients and THP-1 cells under hyperglycemic condition. A total of 120 subjects were divided into four groups, with 30 subjects in each group: healthy controls, T2DM individuals, DN patients receiving standard treatment, and those treated with Cana. The control group had no history of diabetes, cardiovascular or renal diseases, or other comorbidities. Cana was administered at doses of either 100 or 300 mg per day based on the estimated glomerular filtration rate (eGFR) value of DN individuals, with a mean follow-up of 6 months. Additionally, THP-1 monocytes were exposed to HGM (33.3 mM glucose with a cytokine cocktail of TNF-α and IFN-γ at 50 ng/mL each) to evaluate the relative levels of ERS, OS markers, and nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor regulating cellular redox, which is downregulated in diabetes. Our results revealed that ERS markers GRP78 and PERK, as well as OS markers TXNIP and p22phox, were elevated in both DN patients and HGM-treated THP-1 monocytes and were reduced by Cana intervention. Furthermore, Cana regulated the phosphorylation of Nrf2, Akt, and EIF2α in HGM-treated monocytes. In conclusion, our findings highlight the role of Cana in activating Nrf2, thereby attenuating ERS and OS to mitigate DN progression.

Dysfunctions, molecular mechanisms, and therapeutic strategies of pancreatic ß-cells in diabetes.

Pancreatic beta-cell death has been established as a critical mediator in the progression of type 1 and type 2 diabetes mellitus. Beta-cell death is associated with exacerbating hyperglycemia and insulin resistance and paves the way for the progression of DM and its complications. Apoptosis has been considered the primary mechanism of beta-cell death in diabetes. However, recent pieces of evidence have implicated the substantial involvement of several other novel modes of cell death, including autophagy, pyroptosis, necroptosis, and ferroptosis. These distinct mechanisms are characterized by their unique biochemical features and often precipitate damage through the induction of cellular stressors, including endoplasmic reticulum stress, oxidative stress, and inflammation. Experimental studies were identified from PubMed literature on different modes of beta cell death during the onset of diabetes mellitus. This review summarizes current knowledge on the crucial pathways implicated in pancreatic beta cell death. The article also focuses on applying natural compounds as potential treatment strategies in inhibiting these cell death pathways.