Glucocorticoid-Induced Preterm Birth and Neonatal Hyperglycemia Alter Ovine β-Cell Development

Abstract

Adults born preterm are at increased risk of impaired glucose tolerance and diabetes. Late gestation fetuses exposed to high blood glucose concentration also are at increased risk of impaired glucose tolerance as adults. Preterm babies commonly become hyperglycemic and are thus exposed to high blood glucose concentration at an equivalent stage of pancreatic maturation. It is not known whether preterm birth itself, or complications of prematurity, such as hyperglycemia, alter later pancreatic function. To distinguish these, we made singleton preterm lambs hyperglycemic (HYPER) for 12 days after birth with a dextrose infusion and compared them with vehicle-treated preterm and term controls and with HYPER lambs made normoglycemic with an insulin infusion. Preterm birth reduced β-cell mass, apparent by 4 weeks after term and persisting to adulthood (12 mo), and was associated with reduced insulin secretion at 4 months (juvenile) and reduced insulin mRNA expression in adulthood. Hyperglycemia in preterm lambs further down-regulated key pancreatic gene expression in adulthood. These findings indicate that reduced β-cell mass after preterm birth may be an important factor in increased risk of diabetes after preterm birth and may be exacerbated by postnatal hyperglycemia. Preterm babies are at increased risk of type 2 diabetes in later life (1). They have decreased insulin sensitivity (SI) in childhood, with a compensatory increase in acute insulin secretion (2, 3), and evidence of insulin resistance (4). Young adults born preterm are more likely to require prescriptions for diabetes than term-born controls, with most of these being for insulin, indicating that there is impaired β-cell function after preterm birth (5). However, it is not known which factors associated with preterm birth are responsible for later impaired glucose homeostasis. Preterm birth may be a marker for an adverse fetal environment; for example, periconceptional undernutrition in sheep can cause both preterm birth (6) and insulin resistance in the offspring (7). Alternatively, premature exposure to the ex utero environment or complications associated with preterm birth may alter development of physiological systems in ways that predispose to disease risk (8). Hyperglycemia is common in preterm babies, with 80% of extremely low birth weight (ELBW) babies experiencing high blood glucose concentrations (BGCs) (9). The etiology is multifactorial, including relative insulin resistance and immature processing of proinsulin to insulin (10), persistent endogenous glucose production (11), and an iatrogenic component due to a large iv glucose load (12). Neonatal hyperglycemia is associated with increased short-term mortality and morbidity, such as sepsis, retinopathy of prematurity and necrotizing enterocolitis (NEC) (13–16). We have replicated some of these findings in preterm lambs with experimentally induced hyperglycemia (17). However, there are no data on the long-term metabolic effects of hyperglycemia after preterm birth. Exposure of fetuses to hyperglycemia in late gestation results in decreased insulin secretion in response to secretagogues in fetal sheep (18) and in response to a glucose challenge in adult rat offspring (19), and offspring of women with diabetes have an increased rate of type 2 diabetes beyond that expected from genetic or environmental factors alone (20) which may be due to impaired insulin secretion (21). These data indicate that the pancreas in late gestation, at an equivalent stage of maturity to that of the preterm baby, is susceptible to altered development in response to prevailing glucose concentrations. If early exposure to high BGC in preterm babies alters pancreatic development and contributes to an increased risk of type 2 diabetes in later life, it is possible that this could be reversed by neonatal insulin treatment, a common management for neonatal hyperglycemia (22), with benefits for long-term health. However, there are few data on the relative risks and benefits of this treatment (23, 24) and none on the long-term effects on later pancreatic function. We, therefore, studied preterm lambs, to investigate the effect of: 1) preterm birth itself, 2) exposure to neonatal hyperglycemia, and 3) treatment of neonatal hyperglycemia with insulin, on insulin secretion, glucose tolerance, β-cell mass and expression of key genes involved in pancreatic development and insulin secretion in later life. Our findings suggest that preterm birth itself can have long-term effects on pancreatic β-cell mass and gene expression and also provide evidence that a complication of preterm birth, hyperglycemia, can exacerbate these long-term metabolic consequences