Sean W Limesand

Sean W Limesand

Chair, Institutional Animal Care-USE Committee
Director, Agriculture Research Complex
Professor, Animal and Comparative Biomedical Sciences
Professor, BIO5 Institute
Professor, Obstetrics and Gynecology
Professor, Physiological Sciences - GIDP
Department Affiliations
Contact
(520) 626-8903

Work Summary

Work Summary
Our current research program use an integrative approach at the whole animal, isolated organ, cellular and molecular levels to investigate developmental adaptations in pancreatic β-cells and insulin sensitivity that result from early life risk factors, such as intrauterine growth restriction, and increase risk of glucose intolerance and Diabetes in later life.

Research Interest

Research Interest
Sean W. Limesand, PhD, is an Associate Professor in the School of Animal and Comparative Biomedical Sciences at the University of Arizona in the College of Agriculture and Life Sciences. He is also a member of the UA’s BIO5 Institute and Department of Obstetrics and Gynecology. Dr. Limesand is nationally and internationally recognized for his work studying fetal endocrinology and metabolism in pregnancy and in pregnancies compromised by pathology such as intrauterine growth restriction and diabetes. His research is focused on defining developmental consequences resulting from a compromised intrauterine environment. Specifically, he is focused on fetal adaptations in insulin secretion and action that when altered in utero create lifelong metabolic complications. Dr. Limesand has lead the charge on prenatal origins of –cell dysfunction as the Principal Investigator for a number of federal and foundation grant awards and published more than 40 peer-reviewed articles on topics related to this research. Keywords: Diabetes, Pregnancy, Perinatal Biology

Publications

Cole, L., Anderson, M., Antin, P. B., & Limesand, S. W. (2009). One process for pancreatic beta-cell coalescence into islets involves an epithelial-mesenchymal transition. The Journal of endocrinology, 203(1), 19-31.
BIO5 Collaborators
Parker B Antin, Sean W Limesand

Islet replacement is a promising therapy for treating diabetes mellitus, but the supply of donor tissue for transplantation is limited. To overcome this limitation, endocrine tissue can be expanded, but this requires an understanding of normal developmental processes that regulate islet formation. In this study, we compare pancreas development in sheep and human, and provide evidence that an epithelial-mesenchymal transition (EMT) is involved in beta-cell differentiation and islet formation. Transcription factors know to regulate pancreas formation, pancreatic duodenal homeobox factor 1, neurogenin 3, NKX2-2, and NKX6-1, which were expressed in the appropriate spatial and temporal pattern to coordinate pancreatic bud outgrowth and direct endocrine cell specification in sheep. Immunofluorescence staining of the developing pancreas was used to co-localize insulin and epithelial proteins (cytokeratin, E-cadherin, and beta-catenin) or insulin and a mesenchymal protein (vimentin). In sheep, individual beta-cells become insulin-positive in the progenitor epithelium, then lose epithelial characteristics, and migrate out of the epithelial layer to form islets. As beta-cells exit the epithelial progenitor cell layer, they acquire mesenchymal characteristics, shown by their acquisition of vimentin. In situ hybridization expression analysis of the SNAIL family members of transcriptional repressors (SNAIL1, -2, and -3; listed as SNAI1, -2, -3 in the HUGO Database) showed that each of the SNAIL genes was expressed in the ductal epithelium during development, and SNAIL-1 and -2 were co-expressed with insulin. Our findings provide strong evidence that the movement of beta-cells from the pancreatic ductal epithelium involves an EMT.

Harris, S. E., De Blasio, M. J., Davis, M. A., Kelly, A. C., Davenport, H. M., Wooding, F. B., Blache, D., Meredith, D., Anderson, M., Fowden, A. L., Limesand, S. W., & Forhead, A. J. (2017). Hypothyroidism in utero stimulates pancreatic beta cell proliferation and hyperinsulinaemia in the ovine fetus during late gestation. The Journal of physiology, 595(11), 3331-3343.

Thyroid hormones are important regulators of growth and maturation before birth, although the extent to which their actions are mediated by insulin and the development of pancreatic beta cell mass is unknown. Hypothyroidism in fetal sheep induced by removal of the thyroid gland caused asymmetric organ growth, increased pancreatic beta cell mass and proliferation, and was associated with increased circulating concentrations of insulin and leptin. In isolated fetal sheep islets studied in vitro, thyroid hormones inhibited beta cell proliferation in a dose-dependent manner, while high concentrations of insulin and leptin stimulated proliferation. The developing pancreatic beta cell is therefore sensitive to thyroid hormone, insulin and leptin before birth, with possible consequences for pancreatic function in fetal and later life. The findings of this study highlight the importance of thyroid hormones during pregnancy for normal development of the fetal pancreas.

Andrews, S. E., Brown, L. D., Thorn, S. R., Limesand, S. W., Davis, M., Hay, W. W., & Rozance, P. J. (2015). Increased adrenergic signaling is responsible for decreased glucose-stimulated insulin secretion in the chronically hyperinsulinemic ovine fetus. Endocrinology, 1(1), 367-76.

Insulin may stimulate its own insulin secretion and is a potent growth factor for the pancreatic β-cell. Complications of pregnancy, such as diabetes and intrauterine growth restriction, are associated with changes in fetal insulin concentrations, secretion, and β-cell mass. However, glucose concentrations are also abnormal in these conditions. The direct effect of chronic fetal hyperinsulinemia with euglycemia on fetal insulin secretion and β-cell mass has not been tested. We hypothesized that chronic fetal hyperinsulinemia with euglycemia would increase glucose-stimulated insulin secretion (GSIS) and β-cell mass in the ovine fetus. Singleton ovine fetuses were infused with iv insulin to produce high physiological insulin concentrations, or saline for 7-10 days. The hyperinsulinemic animals also received a direct glucose infusion to maintain euglycemia. GSIS, measured at 133 ± 1 days of gestation, was significantly attenuated in the hyperinsulinemic fetuses (P

Yates, D. T., Clarke, D. S., Macko, A. R., Anderson, M. J., Shelton, L. A., Nearing, M., Allen, R. E., Rhoads, R. P., & Limesand, S. W. (2014). Myoblasts from intrauterine growth-restricted sheep fetuses exhibit intrinsic deficiencies in proliferation that contribute to smaller semitendinosus myofibres. The Journal of physiology, 592(Pt 14), 3113-25.

Intrauterine growth restriction (IUGR) reduces skeletal muscle mass in fetuses and offspring. Our objective was to determine whether myoblast dysfunction due to intrinsic cellular deficiencies or serum factors reduces myofibre hypertrophy in IUGR fetal sheep. At 134 days, IUGR fetuses weighed 67% less (P

Limesand, S. W., Regnault, T. R., & Hay Jr., W. W. (2004). Characterization of glucose transporter 8 (GLUT8) in the ovine placenta of normal and growth restricted fetuses. Placenta, 25(1), 70-77.

PMID: 15013641;Abstract:

Facilitated glucose transporters (GLUTs) in the chorionic epithelium are primary conduits for glucose delivery to placental and fetal tissues. The objective of this study was to characterize GLUT8 in the ovine placenta and determine if differences in mRNA and protein concentrations occur in an ovine model of intrauterine growth restriction (IUGR). A GLUT8 partial mRNA was generated, which shares 95 per cent identity with bovine GLUT8 nucleotide sequence. Northern hybridization identified a 2.1 kilobase transcript. GLUT8 mRNA concentrations normalized to β-actin mRNA concentrations increased during late gestation. Western immunoblots with an affinity-purified anti-mouse GLUT8 antiscrum detected GLUT8 in late gestation ovine placenta plasma membranes. GLUT8 was immunolocalized to the chorionic epithelial layer and uterine epithelial cells from mid to late gestation. GLUT8 mRNA and protein concentrations at 135 days gestational age were decreased by 34.8 per cent and 21.8 per cent, respectively (P