Sean W Limesand

Sean W Limesand

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


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.

Limesand, S., Leos, R. A., Anderson, M. J., Chen, X., Pugmire, J., Anderson, K. A., & Limesand, S. W. (2010). Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufficiency and intrauterine growth restriction. American journal of physiology. Endocrinology and metabolism, 298(4).

In this study, we examined chronic norepinephrine suppression of insulin secretion in sheep fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR). Glucose-stimulated insulin secretion (GSIS) was measured with a square-wave hyperglycemic clamp in the presence or absence of adrenergic receptor antagonists phentolamine (alpha) and propranolol (beta). IUGR fetuses were hypoglycemic and hypoxemic and had lower GSIS responsiveness (P

Rozance, P. J., Limesand, S. W., Barry, J. S., Brown, L. D., & Hay Jr., W. W. (2009). Glucose replacement to euglycemia causes hypoxia, acidosis, and decreased insulin secretion in fetal sheep with intrauterine growth restriction. Pediatric Research, 65(1), 72-78.

PMID: 18704001;PMCID: PMC2678008;Abstract:

Nutritional interventions for intrauterine growth restriction (IUGR) have raised concerns for fetal toxicity, the mechanisms of which are unknown. Most of these attempts did not aim to normalize fetal metabolic conditions. Therefore, we used a model of IUGR to determine whether normalization of fetal hypoglycemia for 2 wks would be tolerated and increase insulin concentrations and pancreatic β-cell mass. IUGR fetuses received either a direct saline infusion (Sal, the control group) or a 30% dextrose infusion (Glu) to normalize glucose concentrations. Neither insulin concentrations (0.11 ± 0.01 Glu vs. 0.10 ± 0.01 ng/mL Sal) nor β-cell mass (65.2 ± 10.3 Glu vs. 74.7 ± 18.4 mg Sal) changed. Glucose stimulated insulin secretion (GSIS) was lower in the Glu group. Glu fetuses became progressively more hypoxic: O 2 content 1.4 ± 0.5 Glu vs. 2.7 ± 0.4 mM Sal, p 2) (53.6 ± 0.8 Glu vs. 51.6 ± 0.8 Sal, p

Limesand, S. W., Jeckel, K. M., & Anthony, R. V. (2004). Purα, a Single-Stranded Deoxyribonucleic Acid Binding Protein, Augments Placental Lactogen Gene Transcription. Molecular Endocrinology, 18(2), 447-457.

PMID: 14645500;Abstract:

Placental lactogen (PL) is thought to alter maternal metabolism to increase the pool of nutrients available for the fetus and to stimulate fetal nutrient uptake. The ovine (o) PL gene is expressed in chorionic binucleate cells (oBNC) and cis-elements located within the proximal promoter (-124 to +16 bp) are capable of trophoblast-specific expression in human (BeWo) and rat (Rcho-1) choriocarcinoma cells. Protein-DNA interactions were identified with oBNC nuclear extracts, and mutational analysis of these regions revealed a previously undefined cis-element from -102/-123 bp that enhances promoter activity in BeWo cells but not Rcho-1 cells. Characterization of this region identified the nucleotide sequence CCAGCA (-105/ -110; o110) as the responsible cis-acting element. Southwestern analysis with this element identified a binding protein with an apparent Mr of approximately 41,000. Expression screening of an ovine placental cDNA library identified six homologous cDNAs, which shared identity with human (97%) and mouse (95%) Purα, a single-stranded DNA binding protein. The Purα-o110 interaction was confirmed by electrophoretic mobility-supershift assays with oBNC and BeWo extracts but was absent with Rcho-1 extracts. Furthermore, overexpression of ovine Purα enhanced transactivation of the oPL gene proximal promoter in both choriocarcinoma cell lines through this novel cis-element. This study identified a previously undefined cis-element, which interacts with Purα to augment PL gene transcription.

Macko, A. R., Yates, D. T., Chen, X., Shelton, L. A., Kelly, A. C., Davis, M. A., Camacho, L. E., Anderson, M. J., & Limesand, S. W. (2016). Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose-Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction. ENDOCRINOLOGY, 157(5), 2104-2115.