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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Diminished -cell replication contributes to reduced -cell mass in fetal sheep with intrauterine growth restriction

¹Perinatal Research Center, Department of Pediatrics, University of Colorado Health Sciences Center, Aurora Colorado; and ²Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado

Submitted 23 July 2004 ; accepted in final form 6 January 2005

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 noninsulin-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 with 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 noninsulin-dependent diabetes.

pregnancy; fetal endocrine pancreas; cell cycle

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