Physiological Studies of Native and Stem Cell-Derived Islets

Sammanfattning: In type 1 and type 2 diabetes, the β-cells of the islets of Langerhans are either destroyed by the immune system or stressed due to peripheral insulin resistance. To improve the life of patients with these diseases, new treatments are needed. This thesis examined the role of irisin and cocaine and amphetamine regulated transcript (CART) in islets of Langerhans and their potential pharmaceutical role in type 2 diabetes. Furthermore, β-cell replacement with stem cell-derived islets of Langerhans (SC-islets) for type 1 diabetes was evaluated for optimal implantation site.In paper I, the physiological role of CART in rat islets was examined. CART was shown to specifically lower islet blood flow, which could be a protective effect in type 2 diabetes. No effect from CART on glucose tolerance or insulin release was seen in rat islets, which highlights species differences.In paper II, the expression of irisin and its effect on hormone secretion and pancreatic blood flow was examined. Irisin was expressed in human islets and was secreted glucose dependently. It also lowered islet blood flow but did not affect glucose-stimulated insulin secretion in isolated human or rat islets. Thus, local secretion of irisin could serve as a protective function by lowering islet blood flow in a high glucose state.In paper III, the expression of irisin in SC-islets and its potential beneficial effects in transplantation was examined. SC-islets were found to express higher levels of irisin than human islets. Irisin treatment had no effects on viability and proliferation in SC-islets, in contrast to previous studies in other species. Thus, irisin signaling likely differs between SC-islets and murine and native human islets.In paper IV, SC-islets were transplanted to multiple sites in mice to find the optimal implantation site in terms of graft maturity, function and composition. The liver proved to be the most favorable site due to its higher expression of islet maturity genes and a higher β-cell function and fraction. This poses a dilemma, as the liver site is the most challenging to biopsy and monitor for safety.In summary, this thesis uncovered new physiological functions of irisin and CART, potentially offering insights relevant to the treatment of type 2 diabetes. Meanwhile, the role of irisin in transplantation of SC-islets seems limited.