Insulinotropic and Anti-Inflammatory Effects of Rosiglitazone in Experimental Autoimmune Diabetes

Abstract

Cytokines and nitric oxide (NO) are involved in the pathogenesis of autoimmune diabetes mellitus (DM). Rosiglitazone is an insulin-sensitizing drug that is a ligand for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The anti-inflammatory and immunomodulating properties of PPAR-gamma have been documented. The aim of this study is to investigate the effectiveness of rosiglitazone in autoimmune DM and to clarify the possible mechanism(s) involved. Autoimmune DM was induced in adult male Balb/c mice by co-administration of cyclosporin A and multiple low doses of streptozotocin. Diabetic mice were treated daily with rosiglitazone (7 mg/kg, p.o.) for 21 days. Blood glucose level (BGL), serum insulin level and pancreatic levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and NO were measured. Histopathological examination and immunohistochemical determination of CD4 and CD8 T lymphocytes in the pancreatic islets were performed. In addition, analysis of pancreatic protein expression was carried out. The results showed that rosiglitazone treatment resulted in a significant decrease in the BGL and the pancreatic levels of TNF-alpha, IFN-gamma and NO compared to diabetic mice. The serum insulin level was significantly increased after rosiglitazone treatment compared to diabetic mice. The destroyed pancreatic islets were regenerated and became free from both CD4 and CD8 T cells after treatment. Furthermore, many changes in pancreatic protein expression were observed. These results suggest that rosiglitazone has a beneficial effect in the treatment of autoimmune diabetes, an effect that seemed to be a secondary consequence of its anti-inflammatory and immunomodulating properties and might be reflected at the level of protein expression.

In-vivo antioxidant and anti-inflammatory activity of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists in animal model of bronchial asthma

“…Starting on the second day of immunization to avoid dampening sensitization, the first immunized group was treated with 5 mg/kg/day per oral (PO) of rosiglitazone ( Figure 1) according to previous studies [24,25] for 21 days (treated group), while the second immunized group received from the second day oral saline for the same period (asthma group). [26] On day 21, the two immunized groups (asthma and treated groups) were challenged with another dose of ovalbumin, injected by the IP and SC routes. The control group underwent the same schedule for challenge, but received saline rather than ovalbumin ( Table 1).…”

Modulatory Effects of 6‐Carboxymethylthiopurine on Activated Murine Macrophages

“…As observed on NO production, potential anti-inflammatory effects of the 6-CMMP were also pronounced when IFN-c stimulus was applied. This cytokine is involved in the regulation of immune and inflammatory responses and its inappropriate production can lead to autoimmune disorders (35). Interestingly, 6-CMMP was shown to have no effect on J774A.1 cells submitted to IFN-c plus BCG stimuli.…”

PPARγAgonists in Adaptive Immunity: What Do Immune Disorders and Their Models Have to Tell Us?

“…PPAR γ agonists decrease lupus-related nephritis through decreased IFN- γ and nitric oxide production in MRL/lpr mice in vivo [21]. Treatment of diabetic mice with rosiglitazone resulted in a significant decrease in the pancreatic level of TNF- α and IFN- γ compared to untreated diabetic mice [22]. …”