Effect And Mechanism Of Rosiglitazone On Prevention Of Diabetes In OLETF Rats

BACKGROUD:Type 2 diabetes mellitus has become one of chronic incommucable disease damaged human health seriously. The incidence rate of diabetes mellitus roars up year by year. It brings enormous economic burden for individual and society. With the knowledge of insulin, the development and application of drugs stimulating secretion of insulin and insulin-sensitizing drugs etc, more methods are available in the treatment of diabetes. However, although progress has been made in the treatment of diabetes, we still can't control the development of diabetes and its complications. So preventing diabetes becomes one of the most important issues in order to solve the problem radically. Whether diabetes can be prevented and what is the most economical, safe, effective way to prevent diabetes becomes a must to tackle this problem. The evidence-based research of DPP and stop-NIDDM showed type 2 diabetes mellitus which accounts for 90% of all patients with type 2 diabetes can be prevented and the risk of development of diabetes can be decreased by 31%-58%. in pharmacological interventions.The mechanism of type 2 diabetes mellitus has not been acknowleged yet.Insulin resistance and β -cell dysfunction are the most two important reasons for the onset of type 2 diabetes mellitus. Insulin resistance play a key role in onset of type 2 diabets mellitus and run through the whole process of diabetes mellitus. So it is important to improve insulin resistance for prenvtion and therapy of type 2 diabetes meillitus.It is now generally recognized diabetes will get through the stage of IGT in which stage insulin resistance is the main character. Insulin resistance is apathophysiologic condition that the reactivity of organ to insulin is decreased. It is the congenerous risk of many clinical diseases (such as hypertension and atherosclerosis), especially in endocrine and metabolism diseases. Researches show that many hormone and cytokines secreted by adipose tissue play a very important role in insulin resistance. As one of cytokines secreted by adipocytes, adiponectin was found in 1994, and many experiments show that it plays an important role in energy metabolism and insulin resistance. Many research show that there is a negative correlation between plasma adiponectin concentration and constituent ratio of body fat, waist-to-hip ratio, fasting blood glucose, postprandial 2h blood glucose, and there is a positive correlation between plasma adiponectin concentration and insulin sensitivity. Plasma adiponectin level had decreased in earlier period of obesity and decreased continuously after type 2 diabetes mellitus happened. The decrease of plasma adiponectin has a close affinity to insulin resistance. Adiponectin may become a valid medicine for curing insulin resistance and DM. So it is necessary to study the effects of prophylactic agent on insulin resistance and the expression of adiponectin mRNA to elucidate the pathogenesis of insulin resistance and type 2 DM and the mechanism of prophylactic agent.As one of new type thiazonediones, rosiglitazone has been used widely in clinic for therapy of insulin resisntance and type 2 diabetes mellitus. Rosiglitazone can improve the insulin sensitivity of muscle and adipose tisus by activating PPAR- y . The studies show that rosiglitazone can derease blood glucose, ameliorate lipid metabolism, improve hyperinsulinsm and insulin resistance.We think rosiglitazone may have some effects on intervention of type 2 diabets mellitus.OLETF (Otsuka Long- Evans Tokushima Fatty) rats were used in this study to observe the effects of Rosiglitazone on incidence rate of diabetes, and explore the probable mechanism, such as insulin resistance in order to provide theoretical and experimental proofs.Part 1 Effects of Rosiglitzone on prevention of diabetes in OLETF ratsOBJECTIVE:To study the effects of rosiglitazoen on preventing diabetes in OLETF (Otsuka Long-Evans Tokushima Fatty) rats explores the probability of rosiglitazone in preventing diabetes in laboratory animals.METHODS:1 OLETF rats, spontaneous NIDDM model rats, with their lean nondiabetic counterparts, Long-Evans Tokushima Otsuka (LETO) rats, were supplied at 4 weeks of age. Forty male OLETF rats were randomly divided into two groups, Rosigltazone treated group (Group RSG) and the control group (Group Control). Ten male LETO rats were in normal control group (Group LETO). Rats of Group RSG were given Rosiglitazone (3mg ? kg'd"1) by intragastric administration from 8 weeks of age on. Except for Group Liuwei rats, all rats were given distilled water by intragastric administration.2 The blood glucose was determined by OGTT (oral glucose tolerance test) to diagnose diabetes. 15 hours before OGTT (5:00 PM, the day before), food was removed from the cage. 2g/kg glucose was administered intragastricly to conscious rats. Blood was obtained from the tail before and 30, 60, 90 and 120 min after the administration of glucose and was analyzed for glucose with life scan ultra glucose photometer. Diabetes was diagnosed when both peak blood glucose > 16.7 mmol/L and 120 min blood glucose > 11.1 mmol/L. IGT (impaired glucose tolerance) was diagnosed when either was determined.3 Body weight and food intake were monitored every week. Rats were sacrificed at the age of 8, 32 and 40 weeks. Blood glucose, serum triglyceride, serum cholesterol, surm FFA (free fatty acid), plasma insulin were determined.RESULTS:1 The food intake in both OLETF rats groups are significantly higher than group LETO rats (p<0.01). The food intake of Rosiglitazone treated rats was not different with that of group control. Body weight was significantly greater in OLETF rats compared with LETO rats since 6 weeks of age (p<0.05). Body weight was significantly higher in Group RSG compared with Group LETO since 28 week-old (p<0.05).2 The 2hPG of rats in Group Control rise at 23 weeks of age (10. 1 ± 1. 8mmol/L), whereas it rise at 30 weeks of age in Group RSG. 2hPG of Group RSG was significantly lower than that of Group Control (p<0.01) and same with the glucose area under curve (AUC) (p<0. 05). AUC in both Group OLETF rats are higher than that of Group LETO.3 OLETF rats in Group Control developed diabetes since 23 weeks of age and the incidence rate of diabetes became higher with the time goes by until got to 92.9% at 40 weeks of age when the research came to the end. Rats in Group RSG developed diabetes since 30 weeks of age and incidence rate was 6.7% at 40 weeks, significantly lower than Group Control (p<0.01). No rats have developed diabetes or IGT in Group LETO.4 The serum triglyceride, serum cholesterol, plasma FFA was significantly lower in Group Liuwei than that of Group Control (p<0.05).CONCLUSIONS:1 Rosiglitazone can decrease the extent of and delay the occurrence of hyperglycemia in OLETF rats.2 Rosiglitazone can decrease the incidence rate of type 2 diabetes significantlywhich doesn't depend on the loss of body weight.3 Rosiglitazone can decrease the serum triglyceride, serum cholesterol, serum FFA and plasma insulin.Part 2 Effects of Rosiglitazone on insulin resistance in OLETF rats OBJECTIVE:To study the effects of Rosiglitazone on insulin resistance in OLETF rats, and observe the influence on plasma adiponectin level and the expression level of adiponectin mRNA in adipose tissue of OLETF rats. Other indexes related to insulin sensitivity were measured to identify the effects of Rosiglitazone and to provide beneficial evidence of Rosiglitazone on prevention of diabetes mellitus.METHODS:1. Greater omentunK epididymidis fat and perirenal fat were removed and weighed with water absorbed away by filter paper after rats were sacrificed. Visceral fat weight was calculated by the sum weight of greater omentunu epididymidis fat and perirenal fat..2. Fasting blood glucose and plasma adiponectin concentration were determined.3. Insulin sensitivity index (ISI) was calculated according to the fasting blood glucose and fasting plasma insulin concentration.4. The adiponectin mRNA expression level in adipose tissue was tested by RT-PCR.5.The correlation between plasma adiponectin level and other related indexes were analyzed.RESULTS:l.Body weight(BW), visceral fat weight(VF) and VF/BW in Control group weresignificant higher than in LETO group from 8 week-old(p<0.01). RSG group had higher BW than Control group in 32 week-old. Compared with LETO group , RSG group had higher BW, VF and VF/BW in 40 week-old(p<0.01).2. The FBG, FINS and ISI had no significant difference among each group at 8 weeks(p>0.05). From 32 week-old, RSG group had lower FENS and higher ISI,compared with Control group.3. Rats of Group Control had significantly lower serum adiponectin and the expression level of adiponectin mRNA in adipose tissue decreased compared with rats of Group LETO. The plasma adiponectin concentration and the expression level of adiponectin mRNA in adipose tissue in Group RSG were obvious higher than those of Group Control.4. There was a positive correlation between plasma adiponectin concentration and ISI, while there was a negative correlation between plasma adiponectin level and body weight, visceral fat weight, fasting plasma insulin, serum TG, FFA, CHOL.CONCLUSIONS:1. Rosiglitazone can decrease visceral fat weight and BW/VF, and ameliorate insulin resistance in OLETF rats.2. Rosiglitazone can increase the plasma level of adiponectin and the expression level of adiponectin mRNA in adipose tissue.3.Plasma adiponectin level is positively correlated to insulin sensitivity in OLETF rats. The level of adiponectin is negatively correlated to visceral fat weight, fasting plasma insulin, serum FFA and triglyceride.4.1mproving insulin resistance is one of mechanisms of rosiglitazone preventing onset of type 2 diabetes mellitus.