Diminished beta-cell replication contributes to reduced beta-cell mass in fetal sheep with intrauterine growth restriction.
Human fetuses with severe intrauterine growth restriction (IUGR) have less pancreatic endocrine tissue and exhibit beta-cell dysfunction, which may limit beta-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 beta-cell mass. We studied an ovine model of IUGR to understand whether nutrient deficits lead to decreased rates of fetal pancreatic beta-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 beta-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 beta-cell mass (76%). Pancreatic beta-cell apoptosis was not different between treatments. beta-cell capacity for cell cycling, determined by proliferating cell nuclear antigen (PCNA) immunostaining, was not different between treatment groups. However, the percentage of beta-cells actually undergoing mitosis was 72% lower in IUGR fetuses. These results indicate that in utero nutrient deficits decrease the population of pancreatic beta-cells by lengthening G1, S, and G2 stages of interphase and decreasing mitosis near term. Diminished beta-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.
Limesand
Sean W
SW
Perinatal Research Center, Dept. of Pediatrics, Univ. of Colorado Health Sciences Center, P.O. Box 6508, F441, Aurora CO 80045, USA. Sean.Limesand@UCHSC.edu
Jensen
Jan
J
Hutton
John C
JC
Hay
William W
WW
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D005317:Fetal Growth Retardation / Q000473:pathology / Q000503:physiopathology*; D005333:Fetus / Q000502:physiology; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology* / Q000473:pathology; D008938:Mitosis / Q000502:physiology*; D009929:Organ Size / Q000502:physiology; D010927:Placental Insufficiency; D011247:Pregnancy; D012756:Sheep