The Effect And Preliminary Mechanism Of OA And Jiangzhitong On Improving Insulin Resistance

【Background】 Diabetes(DM) is a kind of widespread metabolic disorder all over the world and about 80-85% diabeticpatients are Type 2 Diabetes(T2DM). As a result, 12% of global public health expenditures are paid for the treatment of T2 DM and its complications. Therefore, the prevention and control of T2 DM have become one of the central issues of international public health community. The typical feature of T2 DM is insulin resistance(IR), which is especially reflect as the decreased insulin sensitivity in liver, fat and muscle, so that insulin can’t maintain normal glucose homeostasis. The insulin resistance in liver plays a key role in the pathophysiology of diabetes. The mechanism of IR is still debetable now, but there are many canonical theories including oxidative stress, lipid toxicity and the impairment of transduction of insulin signal which play leading roles in the pathogenesis of IR. Simulating the risk factors of diabetes in the real life and the rapid establishing of the rats model of IR by high-fat, high fructose and tert butyl hydroperoxide(t BHP) can be benefit to clarify the occurrence and the development of IR and lay the experimental foundation for the T2 DM research and its prevention.Currently, there are no effective drugs for the treatment of T2 DM. The commonly used drugs for the therapy of T2 DM are still mainly chemical synthesis, which are with serious side effects. Therefore, it has become a hot spot in the research of diabetes to find a new natural drug for T2 DM.The research group extracts Jiangzhitong from the traditional Chinese medicine after preliminary screening and applys nano on oleanolic acid(OA) of natural pentacyclictriterpenoid compound, then studies if they can improve IR. It is very important for the discovery of natural medicines which a new drug with high efficiency, low toxicity in the treatment of IR and T2 DM.【Aims】 1. To establish the IR-rat model with high fat, high fructose and t BHP. 2. To investigate the effect and preliminary mechanism of Jiangzhitong on IR in rats. 3. To study the effect of nano OA on the improvement of IR in rats.【Methods】 1. High fat and high fructose with t BHP induce IR in the rat. After with a high fat and high fructose diet for 4 weeks, all animals were injected t BHP for 2 weeks by abdominal, and then detected fasting blood glucose, serum insulin, insulin sensitive index, glucose tolerance and insulin tolerance, to determine the IR model of rats. 2. The improvement effect and mechanism of Jiangzhitong on IR in rats need to be investigated. After with Jiangzhitong of 50 mg/kg and 200 mg/kg for 6 weeks, it is determined the following index including index related to insulin resistance, such as body weight, blood glucose, serum insulin, insulin sensitive index, blood lipid, glucose tolerance and insulin tolerance. And including index related to oxidative stress, such as MDA, NO, CAT and SOD. The pathological changes were observed in liver and in pancreas by microscope and electron microscope. The oil red stain in liver was observed the content of lipid droplet. The protein expression of CAT、SOD-1、GPx1and PPARγ、p-Akt in liver was determined as well. 3. On a high fat high fructose diet and injected t BHP by abdominal, IR was happened in rats. After treated with 25 mg/kg OA and nano OA for 6 weeks by gavage, body weight,blood glucose, serum insulin, insulin sensitive index, blood lipid, intraperitoneal injections of glucose tolerance and insulin tolerance were determined. The content of MDA、NO and the activity of SOD、CAT were determined. The pathological changes in liver and pancreas, the content of lipid droplets were observed by light microscope and electron microscope. The oil red stain in liver was observed the content of lipid droplet.【Results】 1. Injection with high fat, high fructose diet and t BHP, caused increasing of fasting blood glucose significantly and serum insulin levels, decreasing of insulin sensitivity index, damage of glucose tolerance and insulin resistance. 2. Jiangzhitong alleviated the gain of the body weight in IR rats and reduced blood glucose and serum insulin, increased insulin sensitivity index, relieved glucose intolerance and insulin intolerance. It reduced MDA and NO in serum, elevated the activity of SOD, CAT in serum and their protein expression, reduced the triglyceride in serum and the lipid droplets in liver, and reversed pathological process in liver and pancreas, up-regulated the expression of the PPARγ、p-Akt. Compared to rosiglitazone, the effects of jiangzhitong were better in the following index, including increasing the activity SOD, CAT in serum, decreasing the level of MDA, the gain body weight, the level of triglyceride in serum and the content of lipid droplets in liver. 3. Nano OA slowed down the gain of the weight in IR rats and reduced blood glucose and the levels serum insulin, increased insulin sensitivity index, reduced the content MDA and NO in serum, elevated the activity SOD and CAT in serum, reduced the content of triglyceride in serum and the content of lipid droplets in liver, relieved the damage of hepatic, pancreatic in the pathological and ultrastructural pathology. 4. Nano OA significantly reduced the fasting blood glucose, the content of MDA, and increased the activity of SOD significantly in IR rats, but OA No changing of the above indicators in OA group rats. Oil red O staining in liver showed that, compared to OA, the effect of nano OA on reducing the content of lipid droplets in liver was the higher. The morphology in liver showed that nano OA made hepatic cells arrangement more neatly than those in OA group.【Conclusions】 1. High fat, high fructose and t BHP can induce the rat model of IR successfully2. Jiangzhitong alleviats IR by blocking metabolic disorder of the glucose. and the lipid, increasing insulin sensitivity, reducing the accumulation of lipid in liver the oxidative damage, improving the antioxidant level., reducing 3. Nano OA plays a role of improving IR by alleviating metabolic disorder of the glucose and the lipid, increasing insulin sensitivity, improving the antioxidant ability and reducing the oxidative damage. 4. The effect of nano OA on improving the IR is the better than OA.