Long-term Consequences Of Paternal Diabetes On Glucose Regulation In The Offspring

Background: Diabetes has been one of the major chronic diseases. Itwas estimated that by2030,366million people will have this diseaseworldwide. Genetic factors play important roles in the development andprogression of diabetes, and many genes responsible for diabetessusceptibility were studied. Researches suggested that intrauterinehyperglycemia environment significantly increases the risk of offspringdeveloping diabetes. However, there has been little discussion about theinfluence of paternal diabetes. The main abnormality in the early stages oftype2diabetes is insulin resistance. Liver, muscle and adipose tissue arethe main target organs of insulin functions, and liver is the most importantorgan regulating glucose and lipid metabolism, maintaining fasting bloodglucose level through regulation of hepatic glucose output. The livergluconeogenesis and blood glucose was elevated when insulin resistanceoccurs. Therefore, this study was designed to investigate the long-termconsequences of paternal diabetic condition on the regulation of hepaticgluconeogenesis in the offspring. Methods: Model of paternal diabetes was established by usingintraperitoneal injection of streptozotocin (35mg/kg). The offspring fromdiabetic male rats breeding with female rats were set as STZ-O group,while the offspring from healthy male and female rats were set as CON-Ogroup. The birth weights of the offspring were recorded right after delivery.Serum insulin level was determined by using ELISA toolkit. To evaluatethe condition of insulin resistance, glucose tolerance tests (GTT) andinsulin tolerance tests (ITT) were carried out at18weeks. Pyruvitetolerance test（PTT） and real-time PCR were performed to assess livergluconeogenesis. Periodic acid-schiff staining was performed to assessglycogen deposition in the liver tissue.Results: The birth weights of STZ-O group were significantly lowerthan those of CON-O group（6.63±0.46VS5.72±0.31，P=0.0013）. Therewas no difference of random blood glucose level between the two groups,however a significant difference of serum insulin level was observed（49.47±15.63uIU/ml in STZ-O group and18.55±2.59uIU/ml in CON-Ogroup, P=0.011）. There were also significant differences of GTT, ITT, PTTand PAS staining results between the two groups. The mRNA expressionlevels of two key enzymes involving in hepatic gluconeogenesis, PEPCKand G-6-P, were upregulated in STZ-O group.Conclusion: The results of this study indicate that paternal diabeteswould lead to low birth weight and oppose long-term consequences on the offspring, including insulin resistance and abnormal elevation of hepaticgluconeogenesis.