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-Cell Replication Contributes to Reduced -Cell Mass in Fetal Sheep with Intrauterine Growth Restriction
1 Perinatal Research Center, Department of Pediatrics, University of Colorado Health Sciences Center, Aurora, CO, USA
2 Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: sean.limesand{at}uchsc.edu.
Human fetuses with severe intrauterine growth restriction (IUGR) have less pancreatic endocrine tissue and exhibit 
-cell dysfunction, which may limit -cell function in later life and contribute to their increased incidence of non-insulin dependent diabetes mellitus. Three factors, replication, apoptosis, and neoformation, contribute to fetal -cell mass. We studied an ovine model of IUGR to understand whether nutrient deficits lead to decreased rates of fetal pancreatic -cell replication, increased rates of apoptosis, or lower rates of differentiation. At 90% of term gestation, IUGR fetal and pancreatic weights were 58% and 59% less than pair fed control, respectively. We identified a selective impairment of -cell mass compared to other pancreatic cell types in IUGR fetuses. Insulin and insulin mRNA contents were less than other pancreatic endocrine hormones in IUGR fetuses, as were pancreatic insulin positive area (42%) and -cell mass (76%). Pancreatic -cell apoptosis was not different between treatments. -cell capacity for cell cycling, determined by proliferating cell nuclear antigen (PCNA) immunostaining, was not different between treatment groups. However, the percentage of -cells actually undergoing mitosis was 72% lower in IUGR fetuses. These results indicate that in utero nutrient deficits decrease the population of pancreatic -cells by lengthening G1, S, and G2 stages of interphase and decreasing mitosis near term. Diminished -cell mass in IUGR infants at birth, if not adequately compensated for after birth, may contribute to insufficient insulin production in later life and, thus, a predisposition to non-insulin dependent diabetes.
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