Effects of Preterm Birth and Neonatal Hyperglycaemia on the Developing Pancreas and Liver

Abstract

Preterm birth increases risk of impaired glucose tolerance (IGT) in adulthood. It is not known whether preterm birth per se or complications thereof such as hyperglycaemia, a common complication occurring at a time comparable to that of fetal hyperglycaemia which is known to predispose offspring to IGT, are responsible. Insulin is commonly used to treat hyperglycaemia in preterm babies, but the effects of this treatment on the developing pancreas and liver are unknown. IGT is characterised by reduced insulin secretion and reduced insulin sensitivity. The aims of this thesis were to investigate in sheep the effects of preterm birth, neonatal hyperglycaemia and the treatment of hyperglycaemia with insulin on the developing pancreas, responsible for insulin secretion, and liver, which contributes to insulin sensitivity. Results demonstrate that preterm birth in sheep, induced through maternal glucocorticoid exposure, results in a 50% reduction in pancreatic β cell mass in early adulthood. However, exposure to antenatal glucocorticoids appears to ameliorate the impact of preterm birth on β cell mass, as in neonatal lambs in which preterm birth was induced through progesterone blockade the reduction in β cell mass was significantly greater (75% reduction compared with term controls). The reduced β cell mass is associated with reduced insulin gene expression which persisted to early adulthood. In contrast, although pancreatic gene expression of pdx1, igf1, glut2 and glucokinase were increased in young preterm-born lambs compared with term controls, by adulthood expression of these genes was normalised or even reversed. Neonatal hyperglycaemia has short-term effects on β cell parameters and pancreatic gene expression in ways which may limit insulin secretory capacity of β cells in later life, although few effects persisted through to adulthood. Insulin treatment of hyperglycaemia ameliorated some, but not all of the short-term pancreatic effects which were induced by hyperglycaemia. In contrast to these findings in the pancreas, there were few significant effects of preterm birth and hyperglycaemia on insulin-responsive hepatic glucose and fatty acid metabolic pathways. These findings suggest that preterm birth itself may result in significantly reduced β cell mass in adulthood and indicate mechanisms which may underlie these findings. Maternal glucocorticoids may ameliorate, but do not abolish, these effects. If preterm-born adults also have reduced β cell mass, this may contribute to their increased risk of IGT. Future research should explore neonatal interventions to mitigate these long-term effects on the pancreas.