| Objectives:To investigate the association between intrauterine growth retardation(IUGR)and type 2 diabetes by studying pancreatic isletβcell function and insulin sensitivity at different stages of lifetime in rats born with IUGR.Methods:1.The IUGR rat model was established by maternal nutrition restriction(50%calorie restriction of the normal)during the 11th to 21st days of pregnancy.Male offsprings at different stages(newborn,3 weeks, 7 weeks,10 weeks,15 weeks and 36 weeks)were selected as research subjects.Body and pancreas weights were assessed and the ratio of pancreas weight to body weight was calculated in order to evaluate the growth and development status of rats.2.Immunohistochemistry analysis of pancreas was used to evaluate the changes of islet morphology and the expression of insulin in islets at different stages in IUGR rats.3.On the basis of intraperitoneal glucose tolerance test(IPGTT)and insulin releasing test(IRT),plasma glucose and serum insulin were detected after a glucose load to investigate the changes of isletβcell function at different stages in IUGR groups.4.Pancreatic islets of IUGR rats at different stages were isolated and purified.On the basis of glucose-stimulated insulin secretion(GSIS)test, supernatant insulin was tested by radioimmunoassay to investigate the changes of islet secretory function in vitro as age grows.5.RT-PCR was applied to detect the expression of pancreas genes relevant to insulin synthesis of IUGR rats at age 36 weeks in order to elucidate the mechanism of pancreatic islet dysfuncion.6.On the basis of insulin tolerance test(ITT),plasma glucose levels were detected after insulin load to study the changes of insulin sensitivity at different stages in IUGR rats.Results:1.Body weight,pancreas weight and pancreas/body weight of the newborns in IUGR group were much lower than those in normal group (P＜0.001).While body weight of IUGR rats caught up with normal rats after birth,pancreas weight and pancreas/body weight remained lower at all stages of lifetime(P＜0.05).2.The areas of insulin-expression positive cells and positive rate of cells staining with insulin in IUGR newborns were less than normal pups (P＜0.01).Insulin-staining positive areas were enlarged as age grows. There was no significant difference of insulin-staining positive areas in two groups,while the average photodensity of islets was remarkably decreased in IUGR rats at 36 weeks of age(P＜0.05).3.The fasting glucose and insulin levels of IUGR newborns were both lower than those of normal controls,whereas glucose levels at 120min and 180min after glucose load were significantly higher in IUGR group(P＜0.05).Glucose tolerance was impaired with time in IUGR rats, which was manifested as elevated glucose levels and compensatory increment of insulin secretion after glucose administration at early stage, especially at age 15 weeks(P＜0.05),while insulin secretion decreased at later stage(36 weeks).4.Compared with normal group,the stimulating index of pancreatic islets in vitro of IUGR rats was significantly decreased form 15 weeks of age(P＜0.01),indicating the impaired pancreatic islet function.5.Although no significant differences were observed in gene expression of insulin2 and PDX-1,the expressions of insulin1 were reduced markedly in IUGR rats(P＜0.05)at 36 weeks of age.6.There was a significantly blunted glycemic response of IUGR group to insulin load compared with normal group(P＜0.05)from 10 weeks of age,which was impaired gradually as age grows.Conclusions:1.IUGR rats have both impaired pancreatic development and isletβcell dysfunction.Glucose tolerance and insulin sensitivity deteriorate with age.2.Decreased gene expression of insulinl in pancreas may be responsible for the reduced secretion of insulin in IUGR rats at later stages of life.
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