ABSTRACT. Six pregnant rats were made mildly hyperglycemic by intraperitoneal injection of streptozotocin on d 5 of gestation. Four control rats were injected with citrate buffer. Thirty pups born to experimental dams who had increased birth weight (birth weight >1.7 SD of mean birth weight of pups from control dams) maintained accelerated growth through 10 wk of age. At 10 wk, oral glucose tolerance tests showed higher glucose and insulin levels than the controls (n = 37). In addition to the higher body weight, the experimental rats also had higher fat weight to body weight ratios. Adipocytes of epididymal fat from obese males and periovarian fat from obese females had higher lipid content with significantly larger cell size than the adipocytes of the controls. The adipocytes of macrosomic rats showed attenuated response to insulin-stimulated glucose conversion to total lipid and fatty acid when compared with the responses seen in the adipocytes of the control rats. Interestingly, although the insulin-stimulated glucose conversion to COz was similar in macrosomic and control males, the response in the macrosomic female was blunted when compared with that of the control females. Insulin receptor binding capacities of the macrosomic rats were lower than those of the controls, which is consistent with a phenomenon of down-regulation. However, the receptor affinities were higher in the experimental animals than in controls. Therefore, a postreceptor defect may account for the abnormality in glucose metabolism in the obese rats. In conclusion, the abnormal response to oral glucose loading in these experimental obese, hyperinsulinemic rats is due to peripheral tissue insulin resistance that is probably postreceptor in nature. (Pediatr Res 28: 641-645,1990)Infants of diabetic mothers are at greater risk for perinatal complications than those born to nondiabetic mothers. Specifically, diabetic mothers tend to give birth to abnormally large babies (1, 2). Infants with increased birth size have also been shown to be predisposed to the development of obesity in adolescence and early adulthood (3, 4). Adolescent obesity has been associated with the manifestation of diabetes mellitus in adulthood (5). Prevention of obesity in these subjects to minimize the incidence of adult-onset diabetes is an important public health problem.Obesity is characterized anatomically by excessive adipose tissue mass. Glucose utilization studies of obese subjects have C demonstrated a reduction in the rate of uptake of glucose from the blood (6). It is now generally believed that this abnormal carbohydrate metabolism may be related to the development of insulin resistance of peripheral tissue. We have previously shown that the macrosomic rat pups of mildly hyperglycemic diabetic dams maintain accelerated growth through 12 wk of age and have abnormal glucose tolerance when compared with pups of control dams. The difference in weight between the two groups was shown to be due to increased fat storage in the macrosomic pups (7). We hypothesize tha...

ABSTRACT. To study the cross-generation effect of enhanced growth in macrosomic newborn rats, we induced mild hyperglycemia in 15 pregnant Sprague Dawley rats by intraperitoneal injection of streptozotocin, 35 mg/kg body weight, on the 5th d of gestation. As reported previously, we produced hyperinsulinemia and accelerated growth in the fetuses of hyperglycernic dams. We also showed that the macrosomic female pups (second generation) continued to have a higher growth rate through the first 12 wk of life. In this study, the second-generation female rats were mated with macrosomic second-generation males; they demonstrated glucose intolerance during late pregnancy and delivered pups (third generation) with higher birth weight and plasma insulin levels than the pups from control second-generation rats. When the macrosomic third-generation pups were raised under identical nutritional and environmental conditions as controls, the macrosomic rats showed accelerated growth and higher fat tissue weight during the first 12 wk of life. Furthermore, the macrosomia was associated with glucose intolerance and higher insulin to glucose ratios compared to controls. We also mated the offspring of second-generation streptozotocin-injected nonmacrosomic as well as the offspring of macrosomic pups of buffer-injected dams; none of the pups from these matings were significantly macrosomic. Therefore. we conclude that the ueruetuation of obesity and -.. .possibly glucose intolerance across generations in this rat model is predominantly a result of abnormal intrauterine metabolic environment rather than genetic factor driven. (Pediatr Res 29: 606-610, 1991) According to Pedersen's hypothesis (1), poorly controlled pregnant diabetics will have maternal hyperglycemia, which in turn induces fetal hyperglycemia and hyperinsulinemia. This abnormal metabolic and hormonal milieu results in several neonatal morbidities including neonatal macrosomia (2). Macrosomia is a result of accelerated fetal growth in the presence of an abundance of substrates and anabolic hormones such as insulin and somatomedin-c (3-5). In the human (6, 7) and experimental models (8), neonatal macrosomia is associated with accelerated postnatal growth through adulthood resulting in an increased propensity toward obesity. In the experimental model (8), the obesity is further associated with glucose intolerance, particularly in female subjects. An intriguing question is: "Will the rnacrosomic female offspring of diabetic mothers become glucose in- tolerant during pregnancy and will their fetuses show accelerated fetal growth and abnormal glucose metabolism?" The purpose of our study is to use an experimental model to answer this question. Our hypotheses are: 1 ) the female offspring of streptozotocin-induced mild hyperglycemic rats will exhibit glucose intolerance when they attain adulthood and become pregnant; 2) these second-generation macrosomic females will produce offspring (third generation) of higher birth weight; and 3) the third-generation macrosomic offsprin...