Fetal pancreatic beta-cell development and insulin secretion in ovine maternal over-nutrition and under-nutrition models

The number of overweight and obese people has significantly increased in both developing and developed countries in recent years, and has been called the global epidemic of obesity. Obesity is commonly associated with insulin resistance and pancreatic beta-cell exhaustion which commonly leads to hyperglycemia and type II diabetes. Interestingly, both maternal over-nutrition and nutrient restriction in pregnancy are associated with increased risk for obesity and type II diabetes. This dissertation presents studies using the sheep as a biomedical model to investigate the effects of both maternal overnutrition and nutrient restriction on fetal pancreatic growth and development, with specific emphasis on beta-cell development and insulin secretory capacity, as well as the postnatal risk of developing insulin resistance and type II diabetes. In the first experiment, ewes were either fed an obesogenic diet to achieve obesity at conception or were fed to requirements to achieve a normal weight at conception and then both groups were maintained on these diets during the first half of gestation. Maternal obesity in these ewes resulted in maternal and fetal hyperglycemia and hyperinsulinemia, over-growth of the pancreatic islets and accelerated fetal beta-cell development (due to hyperplasia) at midgestation. In the second experiment, maternal obesity was induced by conception using the same protocol and obesogenic diet fed in the first experiment, but the diet was fed throughout gestation. The initial acceleration in fetal pancreatic growth and beta-cell numbers observed at mid-gestation in OB ewes in experiment one were followed by marked reduction in pancreatic growth and development from mid- to late gestation. This reduction in pancreatic size at late gestation was associated with markedly decreased numbers of beta-cells as a result of increased apoptosis, and resulting in reduced circulating insulin concentrations at term compared to control ewes. In the third experiment, ewes were fed either 50% of requirements (nutrient restricted) or 100% of requirements (controls) from day 28 of gestation to day 78 of gestation (midgestation) and then all ewes were fed the control diet through late gestation. The fetuses gestated by nutrient restricted ewes resulted in higher fetal pancreatic beta-cell mass and accelerated beta-cell mitosis at midgestation, whereas reductions in pancreatic growth and beta-cell numbers (due to lower cell proliferation and a trend of higher apoptosis) were observed by late-gestation, which lead to pancreatic dysfunction in postnatal life. Overall, both maternal obesity and nutrient restriction induced similar changes in fetal pancreatic growth and development, and beta-cell numbers and function throughout gestation. The similarity of fetal beta-cell changes in these models of maternal overnutrition and undernutrition may partially explain the predisposition of offspring from obese and undernourished women to similar metabolic disease.