Limesand, S., Chen, X., Rozance, P. J., Hay, W. W., & Limesand, S. W. (2012). Insulin-like growth factor and fibroblast growth factor expression profiles in growth-restricted fetal sheep pancreas. Experimental biology and medicine (Maywood, N.J.), 237(5).
Placental insufficiency results in intrauterine growth restriction (IUGR), impaired fetal insulin secretion and less fetal pancreatic β-cell mass, partly due to lower β-cell proliferation rates. Insulin-like growth factors (IGFs) and fibroblast growth factors (FGFs) regulate fetal β-cell proliferation and pancreas development, along with transcription factors, such as pancreatic and duodenal homeobox 1 (PDX-1). We determined expression levels for these growth factors, their receptors and IGF binding proteins in ovine fetal pancreas and isolated islets. In the IUGR pancreas, relative mRNA expression levels of IGF-I, PDX-1, FGF7 and FGFR2IIIb were 64% (P 0.01), 76% (P 0.05), 76% (P 0.05) and 52% (P 0.01) lower, respectively, compared with control fetuses. Conversely, insulin-like growth factor binding protein 2 (IGFBP-2) mRNA and protein concentrations were 2.25- and 1.2-fold greater (P 0.05) in the IUGR pancreas compared with controls. In isolated islets from IUGR fetuses, IGF-II and IGFBP-2 mRNA concentrations were 1.5- and 3.7-fold greater (P 0.05), and insulin mRNA was 56% less (P 0.05) than control islets. The growth factor expression profiles for IGF and FGF signaling pathways indicate that declines in β-cell mass are due to decreased growth factor signals for both pancreatic progenitor epithelial cell and mature β-cell replication.
Frost, M. S., Zehri, A. H., Limesand, S. W., Hay, W. W., & Rozance, P. J. (2012). Differential effects of chronic pulsatile versus chronic constant maternal hyperglycemia on fetal pancreatic β-cells. Journal of pregnancy, 2012.
Constant maternal hyperglycemia limits, while pulsatile maternal hyperglycemia may enhance, fetal glucose-stimulated insulin secretion (GSIS) in sheep. However, the impact of such different patterns of hyperglycemia on the development of the fetal β-cell is unknown. We measured the impact of one week of chronic constant hyperglycemia (CHG, n = 6) versus pulsatile hyperglycemia (PHG, n = 5) versus controls (n = 7) on the percentage of the fetal pancreas staining for insulin (β-cell area), mitotic and apoptotic indices and size of fetal β-cells, and fetal insulin secretion in sheep. Baseline insulin concentrations were higher in CHG fetuses (P 0.05) compared to controls and PHG. GSIS was lower in the CHG group (P 0.005) compared to controls and PHG. PHG β-cell area was increased 50% (P 0.05) compared to controls and CHG. CHG β-cell apoptosis was increased over 400% (P 0.05) compared to controls and PHG. These results indicate that late gestation constant maternal hyperglycemia leads to significant β-cell toxicity (increased apoptosis and decreased GSIS). Furthermore, pulsatile maternal hyperglycemia increases pancreatic β-cell area but did not increase GSIS, indicating decreased β-cell responsiveness. These findings demonstrate differential effects that the pattern of maternal hyperglycemia has on fetal pancreatic β-cell development, which might contribute to later life limitation in insulin secretion.
Kelly, A., Bidwell, C., Camacho, L., McCarthy, F., & Limesand, S. (2016). Transcriptome Expression Profiles Identify Increased Metabolic Capacity in Adipose Tissue from Fetal Sheep with Intrauterine Growth Restriction.. REPRODUCTIVE SCIENCES, 23, 225A-226A.
Chen, X., Rozance, P., Hay, J. W., & Limesand, S. (2012). Insulin-like Growth Factor and Fibroblast Growth Factor Expression Profiles in Growth Restricted Fetal Sheep Pancreas. Experimental Biology and Medicine, 237(5), 524-529.
Camacho, L. E., Yates, D. T., Allen, R. E., & Limesand, S. W. (2016). Reduced Insulin-Stimulated Glucose Uptake in Skeletal Muscle Strips from Intrauterine Growth Restricted Lambs.. REPRODUCTIVE SCIENCES, 23, 312A-312A.
