Abstract 1633 Neonatal Nutrition and Metabolism I Poster Symposium, Saturday, 5/1

Gestational diabetes has been linked to the later development of obesity and type II diabetes in the offspring. The mechanisms underlying this phenomenon are unknown. We have developed a model for gestational diabetes in rats that produces overgrown offspring that remain obese and later develop diabetes (by 3-4 months of age). These animals have a β-cell defect that leads to impaired insulin secretion. Because defects in both insulin secretion and peripheral insulin sensitivity are thought to contribute to the pathogenesis of type II diabetes, the aims of this study were to determine: 1) if insulin resistance occurs in these rats, 2) the cellular mechanisms underlying the defect in insulin signaling, and 3) whether insulin resistance occurs in the newborn period which indicates a primary defect. Bilateral uterine artery ligation was performed on 8 pregnant rats at d19 (term= 22d). The animals were allowed to deliver spontaneously. The resultant offspring were growth retarded (IUGR) compared to offspring of sham operated control rats. When the IUGR female offspring reached sexual maturity they were bred (to normal male rats), and during pregnancy they developed diabetes. Their offspring (F2) were fostered to normal postpartum rats. Time-dated pregnant rats and their resultant offspring served as controls (C). Insulin stimulated glucose uptake and Glut 4 protein levels in muscle of newborn and young adult rats were measured. At delivery, F2 newborns (n= 8 litters) were significantly heavier (p <0.05) than controls (8 litters) and remained heavier (p<0.05) throughout adulthood. At birth, and in early adulthood (35d), serum glucose and insulin levels in F2's were similar to those of controls. By 3 months of age insulin and glucose levels were significantly elevated in F2's (p <0.05). Animals were sacrificed at day 4 and day 35 of life and muscle tissue harvested. Glut 4 protein levels were measured by Western Blot analysis. On day 4 of life there was no significant difference between Glut 4 protein levels in F2's vs controls. However, at 35 days of age, Glut 4 protein levels in F2 muscle were almost one-third those of controls (p<0.05). Muscle strips were isolated from 35 day old animals and basal and insulin stimulated glucose uptake were measured. Basal glucose uptake did not differ between the two groups. However, insulin (1,000 µU) stimulated glucose uptake was severely blunted in F2's (0.39 vs 0.91 µM/min/mg protein, F2's vs C, respectively, p <0.05). These findings suggest that a reduction in Glut 4 leads to a decrease in insulin stimulated glucose uptake in offspring of diabetic rats. However, this does not appear to be a primary defect as Glut 4 levels are not reduced in the newborn period. We speculate that the altered maternal metabolic milieu that occurs during gestational diabetes induces subtle changes in metabolism that lead to the later development of insulin resistance and type II diabetes