Effects of Rosiglitazone Treatment on Visfatin and Insulin resistance in streptozotocin induced obesed diabetic rats

Abstract

Obesity is a chronic metabolic disorder that along with insulin resistance has become leading cause of type2 diabetes mellitus (T2DM). Type2 diabetes mellitus usually cluster with insulin resistance, poor glycaemic control, physical inactivity, smoking, and disturbed adipokines. The possible mechanism of diabetic complications is hyperglycaemia induced cellular damage by cytotoxic oxygen free radicals that are endanger through various metabolic pathways in all the cells. Oxidative stress also impairs insulin action. Various enzymatic and non-enzymatic antioxidant mechanisms involving catalase, SOD, GSH, copper and zinc can eliminate reactive oxygen species (ROS). Increased ROS generation in adipose tissues and other insulin sensitive tissue is the leading cause of inflammatory cytokines production including visfatin and other adipokines that disturbed insulin signaling and increased insulin resistance. It also increased production of advanced glycation end products and Paraoxonase-1 (PON-1). Electrolytes and trace elements dysregulation play an important role in progression of obesity and diabetes complications in insulin sensitive tissues. All above alterations cause deleterious effects on microvascular and macrovascular functions. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a nuclear receptor and act by binding with specific agonists, can modulate the oxidative stress pathway and improve the endothelial function. The prospective of the research is to evaluate the insulin sensitizing role of PPAR-γ activation via agonist on different diagnostic biomarkers of insulin resistance and type 2 diabetes mellitus and to test the hypothesis that PPAR-γ activation can altered the detrimental effects of obesity and HFD/STZ induced T2DM. Following Institutional Animal Ethics Committee permission, the study was performed in male Wistar rats (180-220 g), categorized into five experimental groups. Group 1: Control animals remain fed on a normal rat diet Group 2: HFD fed obese group (fed on HFD for 8 week) Group 3: HFD fed obese treated group, fed on HFD for 8 week and treated with Rosiglitazone (RSG) (3 mg/kg in water) via oral gavage for 7 days Group 4: HFD/STZ induced T2DM group Group 5: HFD/STZ induced T2DM treated group, treated with RSG (3 mg/kg in water) via oral gavage for 7 days. ABSTRACT xxxiii The experimental model of T2DM was developed by previously used HFD/STZ induced T2DM model. Animal were fed with high fat diet over a period of 8 weeks. Diet manipulated rats were injected with a low dose of Streptozotocin (i.p. 35 mg/ml/kg body weight in 0.1 M citrate buffer, pH 4.5) after 4 week and further animals were feeding on HFD for another 4 week. Anthropometric indices and insulin resistance were assessed by estimation of body weight, BMI, lee index, blood glucose and serum insulin levels, HOMA-IR, HOMA-β and QUICKI. Serum visfatin, AGEs, PON-1 and insulin levels were estimated as an emerging biomarkers for early detection of diabetes risk and complications by using ELISA (Enzyme-Linked Immuno-Sorbent Assay). Renal, hepatic and cardiac tissue damage and oxidative stress were analyzed by plasma urea and creatinine level, tissue malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and glutathione Reductase (GSH) respectively. However, serum and tissues electrolytes were estimated by Flame photometer and trace elements in renal, hepatic and cardiac tissues were determined by atomic absorption spectroscopy. Pearson correlation was analyzed among serum visfatin and all above mentioned parameters to find the association among them. HFD and T2DM demonstrated a significant increased anthropometric indices, blood glucose, serum insulin levels and insulin resistance while the insulin sensitivity was markedly reduced in comparison with control. There was a marked increase serum visfatin, AGEs and Paraoxonase-1 in HFD fed and T2DM groups in comparison with control. HFD induce obesity and HFD/STZ induced T2DM caused an increased plasma urea, creatinine, renal, hepatic and cardiac tissues MDA whereas a decreased CAT, SOD and GSH were observed in all tissues. Increased copper and iron levels, however decreased zinc and selenium levels were in HFD and HFD/STZ induced T2DM. PPAR-γ activation via agonist Rosiglitazone altered these changes. Strong association was observed among serum visfatin and above parameters. The results suggested that insulin resistance mediated by HFD and HFD/STZ induced T2DM restored and reversed by using PPAR- agonist (RSG). It also decreased serum levels of visfatin, AGEs and PON-1, oxidative stress biomarkers and restored electrolytes and trace elements. The results of the study could serve as a basis for further studies for the prevention, better cure and management of diabetic complications.