Sean W Limesand

PMID: 18333795;Abstract:

Islet transplantation for the purpose of treating insulin-sensitive diabetes is currently limited by several factors, including islet survival posttransplantation. In the current study, a tissue-engineered prevascularized pancreatic encapsulating device (PPED) was developed. Isolated islets were placed in collagen gels, and they exhibited fourfold more insulin release than islets not in collagen. The insulin released by β-cells in islets encapsulated in collagen exhibited unobstructed diffusion within the collagen gels. Subsequent studies evaluated the ability to create a sandwich comprised of two layers of prevascularized collagen gels around a central collagen gel containing islets. In vitro characterization of the islets showed that islets are functional and responded to glucose stimulation. The PPEDs were implanted subcutaneously into severe combined immunodeficient mice. Islet survival was assessed after 7, 14, and 28 days. Immunohistochemical analysis was performed on the implants to detect insulin and the presence of intraislet endothelial cells. At all time points, insulin was localized in association with intact and partially dissociated islets. Moreover, cells that exhibited insulin staining were colocalized with intraislet endothelial cells. These data indicate that the PPED enhances islet survival by supporting islet viability and maintaining intraislet endothelial cell structures. © Copyright 2008, Mary Ann Liebert, Inc.

PMID: 12562941;PMCID: PMC2342612;Abstract:

Fetal pancreatic adaptations to relative hypoglycaemia, a characteristic of intra-uterine growth restriction, may limit pancreatic β-cell capacity to produce and/or secrete insulin. The objective of this study was to measure β-cell responsiveness in hypoglycaemic (H) fetal sheep and ascertain whether a 5 day euglycaemic recovery period would restore insulin secretion capacity. Glucose-stimulated insulin secretion (GSIS) was measured in euglycaemic (E) control fetuses, fetuses made hypoglycaemic for 14 days, and in a subset of 14-day hypoglycaemic fetuses returned to euglycaemia for 5 days (R fetuses). Hypoglycaemia significantly decreased plasma insulin concentrations in H (0.13 ± 0.01 ng ml^-1) and R fetuses (0.11 ± 0.01 ng ml^-1); insulin concentrations returned to euglycaemic control values (0.30 ± 0.01 ng ml^-1) in R fetuses (0.29 ± 0.04 ng ml^-1) during their euglycaemic recovery period. Mean steady-state plasma insulin concentration during the GSIS study was reduced in H fetuses (0.40 ± 0.07 vs. 0.92 ± 0.10 ng ml^-1 in E), but increased (P 0.05) in R fetuses (0.73 ± 0.10 ng ml^-1) to concentrations not different from those in the E group. Nonlinear modelling of GSIS showed that response time was greater (P 0.01) in both H (15.6 ± 2.8 min) and R (15.4 ± 1.5 min) than in E fetuses (6.3 ± 1.1 min). In addition, insulin secretion responsiveness to arginine was reduced by hypoglycaemia (0.98 ± 0.11 ng ml^-1 in H vs. 1.82 ± 0.17 ng ml^-1 in E, P 0.05) and did not recover (1.21 ± 0.15 ng ml^-1 in R, P 0.05 vs. E). Thus, a 5 day euglycaemic recovery period from chronic hypoglycaemia reestablished GSIS to normal levels, but there was a persistent reduction of β-cell responsiveness to glucose and arginine. We conclude that programming of pancreatic insulin secretion responsiveness can occur in response to fetal glucose deprivation, indicating a possible mechanism for establishing, in fetal life, a predisposition to type 2 diabetes.

PMID: 11356124;Abstract:

The placenta synthesizes a number of cytokines and growth factors that are involved in the establishment, maintenance or regulation of pregnancy. Included are interferons, placental lactogens, other members of the growth hormone/prolactin gene family, leptin, and an array of angiogenic growth factors. While their roles in pregnancy differ, in their absence pregnancy is either lost or compromised. Therefore an understanding of the cell-specific transcriptional regulation of these genes is imperative if we are ever to alter their expression to benefit pregnancy progression. Our understanding of transcriptional regulation in the placenta is still in its infancy, and there appears to be considerable divergence in the transcriptional regulation of these genes between species, as well as between the various cytokine genes being examined. For example, while there are some commonalities in the regulation of human, rodent and ruminant placental lactogens, there are differences that require the study of placental lactogen gene regulation across species. However, one common theme that is emerging with the angiogenic growth factors, such as vascular endothelial growth factor and the angiopoietins, is the transcriptional control of these genes by oxygen tension within the placenta. Examination of transcriptional regulation in normal and compromised pregnancies will provide additional insight in this area.

Radiation therapy for head and neck cancer results in severe secondary side-effects in salivary glands. We previously demonstrated that the administration of IGF1 preserves or restores salivary gland function following radiation. Based on these findings, we propose to study the effect of IGF1 on human head and neck carcinoma cells. Head and neck tumor cells treated with radiation have significant reductions in tumor cell survival, as measured by MTT and crystal violet assays, regardless of IGF1 pre-treatment. Head and neck squamous carcinoma cell xenografts treated with concurrent radiation+IGF1 also exhibit significant tumor growth delay; however, growth rates are elevated compared with those in irradiated xenografts. In contrast, administration of IGF1 after radiation treatment has no effect on tumor xenograft growth rates. Analysis of these data suggests that localized delivery may be required for concurrent therapy to prevent secondary side-effects of radiotherapy, while post-therapy administration of IGF1 could be considered for the restoration of salivary function.