Session: OR13-Systemic Regulation of Islet Development & Function
Room 304 (Moscone Center)
For restoration of β-cell function in diabetic patients, intraportal islet transplantation has evolved into a viable treatment option. However, several factors hamper a widespread application and long-term success: chronic hypoxia, exposure to an inappropriate microenvironment and suppression of regenerative and proliferative potential by the need of potent immunosuppressive agents.
The idea of the adrenal tissue as an alternative niche for pancreatic islets is derived from (1) the fact that both are endocrine tissues with similar microenvironment, (2) the unique feature of extensive vascularization of the adrenal, (3) anti-apoptotic and pro-proliferative effects of various signalling molecules within the adrenal, and (4) the advantage of a local anti-inflammatory and immunosuppressive microenvironment.
Method and Results
For analysis of in vitro islet viability and function a co-culture system of adrenal cells and pancreatic islets was established. Pancreatic islets and adrenal cells were isolated from Wistar rats and co-cultured using inserts for up to 7 days and sequentially assayed for viability, insulin secretion and reactive oxygen species (ROS). The co-culture setting did not significantly impact on islet viability, insulin content and secretion of pancreatic islets and even allowed for long-term culture.
For in vivo studies, Streptozotocin induced diabetic NOD-SCID mice were used as islet recipients (n=6). For islet transplantation, the adrenal was exteriorized via retroperitoneal incision and 300 islets were injected through the upper pole of the gland. Blood glucose levels were measured daily throughout the observation period of 30 days. Most animals showed a fast decrease in blood glucose and reached normoglycemia within 2 days. On day 5 an intraperitoneal glucose tolerance test was performed and four out of five animals reached target blood glucose levels. Upon removing of the islet graft by unilateral adrenalectomy, the animals showed an immediate recurrence of hyperglycemia. Immunostaining of insulin revealed intense cytosolic staining.
Our studies demonstrated that co-localization of adrenal cells and isolated islets allows for long-term culture of islets in vitro and intra-adrenal islet transplantation is a technically feasible and a functionally promising approach to restore normoglycemia in a diabetic mouse model. This novel concept might allow reducing the islet mass that is needed to reverse diabetes through ameliorated engraftment and minimized islet loss due to dense vascularisation and the endocrine microenvironment might be beneficial for long term survival and function of transplanted islets.
Nothing to Disclose: US, BL, HM, SRB
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