Objective: Numerous methods for modeling gestational diabetes mellitus (GDM) in rats exist. However, their repeatability and stability are unclear. This study aimed to compare the effects of high-fat and high-sugar (HFHS) diet, HFHS diet combined with streptozotocin (STZ) administration, and HFHS diet combined with movement restriction (MR) modeling methods on rat models to confirm the best method for constructing a rat model of GDM.
Method: Forty female Sprague-Dawley rats were randomly divided into four groups (n = 10): the normal control (NC), HFHS, HFHS+STZ, and HFHS+MR groups. The rats in the NC group were fed with a standard diet, and those in the remaining groups were fed with a HFHS diet. The rats in the HFHS+STZ group received 25 mg/kg STZ on their first day of pregnancy, and those in the HFHS+MR group were subjected to MR during pregnancy. Bodyweight, food intake, water intake, fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of insulin sensitivity (HOMA-IS), homeostasis model assessment of β-cell function, pancreatic and placental morphology, and the expression levels of glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3) in placentas were then quantified. Moreover, iTRAQ was used to identify placental proteomics.
Results: During pregnancy, the rats in the HFHS+STZ group showed FBG levels that were kept stable in a state of moderate hyperglycemia; the typical GDM symptoms of polydipsia, polyphagia, polyuria, and increased body weight; and the modeling rate of 87.5%. On the first and 19th days of pregnancy, the rats in the HFHS group showed higher FBG than that of the NC group, increasing body weight and food intake and the modeling rate of 50%. On the 19th day of pregnancy, the FBG of the rats in the HFHS+MR group was higher than that of the rats in the NC group, and the modeling rate of 42.9%. Comparison with the NC group revealed that the three modeling groups exhibited increased FINS and HOMA-IR, decreased HOMA-IS, and different degrees of pathological changes in pancreases and placentas. Among the groups, the HFHS+STZ group displayed the greatest changes with significant reductions in the numbers of pancreatic and placental cells and appeared cavitation. The expression levels of GLUT1 and GLUT3 in the placentas of the HFHS+STZ and HFHS+MR groups were higher than those in the placentas of the NC and HFHS groups. The above results indicated that the rats in the HFHS+STZ group showed the best performance in terms of modeling indicators. After the changes in placental proteomics in the HFHS+STZ group were compared with those in the NC group, we found that in the HFHS+STZ group, five proteins were up-regulated and 18 were down-regulated; these proteins were enriched in estrogen signaling pathways.
Conclusion: HFHS combined with the intraperitoneal injection of 25 mg/kg STZ was the best modeling method for the nonspontaneous model of experimentally induced GDM, and its modeling rate was high. The pathological characteristics of the constructed GDM rat model were similar to those of human patients with GDM. Moreover, the model was stable and reliable. The modeling method can provide a basis for constructing a GDM rat model for subsequent research on the prevention and treatment of GDM.