Abstract
Type 1 diabetes is an autoimmune disease caused by permanent destruction of insulin-producing pancreatic β cells and requires lifelong exogenous insulin therapy. Recently, islet transplantation has been developed, and although there have been significant advances, this approach is not widely used clinically due to the poor survival rate of the engrafted islets. We hypothesized that improving survival of engrafted islets through ex vivo genetic engineering could be a novel strategy for successful islet transplantation. We transduced islets with adenoviruses expressing betacellulin, an epidermal growth factor receptor ligand, which promotes β-cell growth and differentiation, and transplanted these islets under the renal capsule of streptozotocin-induced diabetic mice. Transplantation with betacellulin-transduced islets resulted in prolonged normoglycemia and improved glucose tolerance compared with those of control virus-transduced islets. In addition, increased microvascular density was evident in the implanted islets, concomitant with increased endothelial von Willebrand factor immunoreactivity. Finally, cultured islets transduced with betacellulin displayed increased proliferation, reduced apoptosis and enhanced glucose-stimulated insulin secretion in the presence of cytokines. These experiments suggest that transplantation with betacellulin-transduced islets extends islet survival and preserves functional islet mass, leading to a therapeutic benefit in type 1 diabetes.
Highlights
Transplantation of the pancreas or isolated islets is presently the only curative therapy for type 1 diabetes
Effects of betacellulin on cytokine-mediated cell death in isolated islets To investigate the effect of betacellulin on cytokine toxicity, we transduced mouse islets with adenovirus containing the betacellulin (Ad-BTC) or Ad-LacZ
This study was undertaken to evaluate the potential effect of betacellulin, an angiogenic, antiapoptotic and b-cell growth factor, on the extent of islet engraftment and glycemic control in diabetic mice
Summary
Transplantation of the pancreas or isolated islets is presently the only curative therapy for type 1 diabetes. Compared with whole pancreas transplantation, islet transplantation is a much less invasive procedure and is associated with lower morbidity.[1] international trials have demonstrated a constant decline of graft function and a relatively low rate of successful engraftment compared with pancreas transplantation.[2] This relatively high rate of transplant failure has been attributed to the mode of blood supply reestablishment. Similar to other solid organ transplantations, the transplanted pancreas is implanted as a vascularized tissue and can receive immediate blood supply via physical reconnection of blood vessels. The relatively harsh islet isolation procedure and immune-mediated injury of islets after transplantation limit successful islet transplantation.[4,5] strategies using genetic overexpression of proteins involved in promoting new blood vessel formation or inhibiting apoptosis may improve the transplantation outcome.[6]
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