Insights Into the Progression of β-Cell Dysfunction Caused by Preterm Birth.

Abstract

One of the most significant problems in perinatology is preterm birth, which has a worldwide incidence of approximately 10% and accounts for a quarter of the neonatal deaths (1, 2). In the past 20 years, mortality rates have declined due to improvements in clinical practices, including the administration of antenatal corticosteroid to prevent respiratory distress (3, 4). However, surviving infants born premature have increased shortand long-term morbidity that burdens health-care resources. Short-term complications include transient neonatal hyperglycemia, which is common in extremely preterm infants receiving parenteral nutrition and appears to result from -cell defects in proinsulin to insulin processing (5). Several epidemiological studies establish long-term effects that include greater prevalence of glucose intolerance and type 2 diabetes mellitus in adults who were preterm compared with adults that were born at term (6–8). The increased incidence of metabolic dysfunction in infants and adults who were born preterm indicates impaired -cell function after preterm delivery. However, no information for premature delivery or early hyperglycemic stress is available for -cell mass and its regulation, until now. In this issue of Endocrinology, Bansal et al (9) present a series of elegant experiments that investigated the consequences of preterm birth on -cell mass and function. Using a newly established sheep model for preterm delivery, the authors show that -cell mass was lower at 4 weeks after term as a result of preterm delivery (10). The deficiency in -cell mass persisted into adulthood and was supported by parallel reductions in pancreatic insulin mRNA concentration. As newborns, -cell mass deficiency was not attributed to decreased -cell proliferation or apoptosis. Interestingly, deficiencies in -cell maintenancedevelop inpreterm lambswithageasapoptotic rates increased and proliferation rates decreased after the first year of life in preterm animals. Although the deficit in -cell mass reaches 65% at 12 months of age, only modest declines in second phase insulin secretion were apparent at 4 months, demonstrating compensatory adaptations in the remaining -cell population (11). The subclinical effect on glucose homeostasis seen in preterm lambs is similar to reports inamodelwithpartial pancreatectomy (12). Bansal et al also show that transient bout of neonatal hyperglycemia decreases the expression of key pancreatic genes and increases apoptotic rates in adult animals, which was partially improved with exogenous insulin. A smaller yet more active -cell pool in preterm lambs likely increases the vulnerability of the endocrine pancreas to oxidative stress, which may speed the transition from a dwindling -cell population to full-fledged type 2 diabetes (13). Also, in the face of increasing insulin resistance due to normal aging, it is presumed that the compensatory -cell response will fail leading to overt diabetes. This body of work contributes significantly to our understanding on the progressive dysfunction of pancreatic -cells and the development of glucose intolerance and diabetes in subjects born preterm (Figure 1). From this detailed investigation of preterm lambs it is apparent that there is early loss in -cell mass. The absence of alterations in apoptosis and proliferation at this age indicate that the decline in -cell mass is a consequence of early maturation cause by either preterm birth itself or antenatal corticosteroid administration. Cortisol has been shown to inhibit the formation of new -cells (14, 15). Another possibility is that premature delivery results in the loss of placental derived hormones or growth factors that promote -cell mass, such as placental lactogen (16). A second phenotype of -cell dysfunction that becomes apparent in adulthood