| Diabetes is a metabolic disorder characterized by resistance to the action of insulin, insufficience of insulin secretion, or both. The major clinical manifestation of the diabetic state is hyperglycemia. 90% of diabetes patients suffer from type 2 diabetes, and the prevalence of type 2 diabetes increases dramatically worldwide in recent years. Although the pathogenesis of type 2 diabetes is unclear, obesity is considered to be a major causative factor. Amelioration of obesity has been a strategy to treat type 2 diabetes.The purpose of our studies is to elucidate the mechanism of obesity, identify the causative factor(s), and consequently find potential therapeutic intervention point(s) on obesity and type 2 diabetes.OLETF and LETO rats were used as model animals in our studies. OLETF rat, a spontaneous type 2 diabetic rat with mild obesity, was established by Tokushima Research Institute Otsuka Pharmaceutical in Japan. The clinical and pathological features of the disease state in OLETF rat closely resemble those of human type 2 diabetes, which suggested that OLETF rat provides a useful animal model for analyzing the pathogenesis of obesity and type 2 diabetes and for developing new drugs to regulate those diseases. LETO rat, the diabetes-resistant counterparts of OLETF rat, was established from the same colony as OLETF rat, and was used as normal control.The OLETF rat displays obvious hyperphagia, so we restricted the daily amount of food of OLETF rat firstly. After the hyperphagia behavior was corrected, thepreventive effects on the development of obesity and type 2 dibetes were investigated. Animals were allocated to food-satiated OLETF group, food-restricted OLETF group and LETO group. In food-restricted group, rats were given the same amount of food daily as LETO rats ranging since 5 to 21 weeks of age. At the end of the experiment, changes in body weight, body fat, intraabdominal fat weight, triglyceride (TG) content in heptic tissue, plasma TG and plasma fatty free acid level were determined to investigate the amelioration of obesity; changes in glucose tolerance, plasma insulin, plasma glucose and plasma leptin level were measured to value the improvement of diabetes. The results showed that compared with food-satiated OLETF rat, the obesity and insulin resistance in food-restricted OLETF rat were significantly ameliorated, while compared with LETO rat, although the body weight was similar, the body fat, intraabdominal fat weight were still significantly increased, and insulin resistance still displayed. From the results above it is suggested that hyperphagia may be a crucial factor leading to obesity, and other potentical factors can not be excluded.In order to elucidate other causative factors, further studies were performed using food-resitried OLETF rat. With focus on lipid metabolism, the activities of key enzymes including lipoprotein lipase (LPL), monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) were assayed. The LPL is the TG hydrolase, MGAT is a key enzyme that controls the absorption of exogenous lipid in the intestinal mucosa, and DGAT is believed to catalyze one common step in the synthesis of TG in all tissues. The results showed that the activity of LPL decreased significantly in food-satiated group, and no abnormalities was found in food-restricted group, so it was suggested that the decreased LPL activity was caused by hyperphagia, which is the result of obesity in stead of the causation of obesity. There was no significant difference of activity of DGAT in the three groups. The activity of MGAT was markedly higher in both food-restricted OLETF group and food-satiated OLETF group than that in LETO group, which indicated that the increased activity of MGAT may be a causative factor independent of hyperphagia lead to obesity and diabetes in OLETF rats, and may become apotential therapeutic intervention point on obesity and type 2 diabetes.The existing methods to assay MGAT activity are complicated and time-consuming, and incompete...
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