Ryall, Claire Louise (2013) The role of SPARC in [beta] cells and diabetes. (PhD thesis), Kingston University, .
Abstract
Diabetes mellitus was responsible for 4.8 million deaths worldwide in 2012. Cardiovascular diseases arising from the condition are responsible for half of all diabetes related deaths. The loss of insulin due to pancreatic beta cell death can be restored by replacement with transplanted islets from a donor. However, beta cell replacement is limited by the number of donors and the limited capacity of the beta cell to proliferate. Attempts to stimulate beta cell proliferation and improve islet transplantation methods are successful in the short term, however preventing beta cell death after transplant and inducing growth with continued long-lasting insulin secretion is still the aim to prevent hypoglycaemia in patients with diabetes. Elucidating the mechanisms required for beta cell survival and proliferation would allow successful restoration of blood glucose regulation. Secreted Protein Acidic and Rich in Cysteine (SPARC) is secreted by stromal cells such as fibroblasts and endothelial cells and binds collagen. In adults it is expressed in tissues that have a high rate of proliferation and during tissue remodelling. Experimentally, SPARC has been found to prevent cell growth in vitro in certain cell types, as well as promoting cell rounding and detachment. The aims of this study were to determine whether SPARC had inhibitory effects on β cell growth and signalling as tested in the cell line INS-1, and whether this translated to islet cells tested ex vivo. SPARC was found to be sparsely located within islets to stromal cell types and peri-islet basement membranes. The expression of SPARC was higher in a 4 week pancreas compared to 12 week pancreas (p = 0.012) and was higher in a pre-diabetic model than in control pancreas (p = 0.008). This suggests the involvement of SPARC in early development of the pancreatic islets and indicates that SPARC may be important in the islet during the progression of diabetes. SPARC prevented IGF-1-induced INS-1 proliferation (p < 0.001) and islet survival (p = 0.045). Presence of a stellate cell line PS-1 in co-culture with islets was also found necessary for their survival (p = 0.010). The interference of SPARC with the growth-factor response was also demonstrated by the prevention of signalling protein Akt and ERK 1/2 activation in both INS-1 cells and islets. This study established that SPARC had a detrimental effect on beta cell lines and dispersed islet cells and was over-expressed in diabetic pancreas. SPARC as a regulator of beta cell growth may be promising as a target for diabetes therapy.
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