The Pathogenesis Research Of Experimental Type1Diabetic Models And Its Application In Preclinical Safety Evaluation

Animal disease models are not widely used in preclinical safety evaluation and the main purpose for them is applied in pharmacological researches. However, when it refers to the evaluation about the safety in special pharmacological effects (drugs for hypertension and diabetes), they may have the great advantage on the safety evaluation. In this paper, it reviews the progress of type1diabetic models researches on its own characteristics as well as the advantages, application prospects and problems in preclinical safety evaluation.Type1diabetic rat models were constructed by injection of streptozotocin (STZ) into healthy SD rats followed with a six-month investigation about their viability. Then a one-month toxicity experiment in model rats was carried out. The model rats were randomly divided into four groups as high, medium, low dose group and control group. The four groups of rats were administered protamine recombinant human insulin injection with30U/kg,12U/kg,5U/kg and blank solution (10mL/kg). The insulin, C-peptide, glycosylated hemoglobin of all the autopsies were examined with the addition of blood biochemistry, hematological profile, histopathology. All the rats were judged if it was a successful model on the basis of glucose levels. The success rate of our modeling was91.7%and the survival rate was82%after6months; in the long term toxicity experiments, there were4dead rats in the high dose group. When compared with other three groups, t he glycosylated hemoglobin in high dose group decreased (p<0.01), the insulin and C-peptide levels in high dose group increased (p<0.05p<0.01) on the day after administration and in the end of the recovery period. The albumin and blood platelet in high dose group increased (p<0.05), the lymphocytes in high dose group decreased (p<0.05), the red and white blood cells in high dose group female rats decreased (p<0.05). These indicators in the four groups had no difference in the end of the recovery period. The mortality of type1diabetic rats was low, and type1diabetic rats exhibited higher tolerance to hypoglycemia than the healthy rats. When compared to healthy rats, their pathophysiological characteristics are more close to the diabetic patients, and there is value in long term toxicity experiments about the recombinant human insulin protamine which has special pharmacological effects.Type1diabetic rat models were constructed by injection of streptozotocin (STZ) into healthy SD rats. The model (12) and healthy (12) rats were randomly divided into two groups as model and healthy groups. When all the signs of type1diabetes met the requirements, half of the rats of both groups were sacrificed to get the thymus, spleen and peripheral. All samples we got were dealt with flow cytometry to see their levels of CD4+CD25+Foxp3+. All the remaining rats were sacrificed to get their spleens, the CD4+CD25+T cells were isolated to detect the immunosuppressive function. No difference was found among the three groups about the levels and function of regulatory T cells (p>0.05).The mortality of type1diabetic rats was low, and type1diabetic rats exhibited higher tolerance to hypoglycemia than the healthy rats. When compared to healthy rats, their pathophysiological characteristics are more close to the diabetic patients, and there is value in long term toxicity experiments about the recombinant human insulin protamine which has special pharmacological effects.The pathogenesis of type1diabetic rats (using streptozotocin for modeling) has little relationship with regulatory T cells.