Transplantation of betacellulin-transduced islets improves glucose intolerance in diabetic mice

Type 1 diabetes is an autoimmune disease caused by permanent destruction of insulin-producing pancreatic beta 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 beta-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.

Clinical islet transplantation for type 2 diabetes mellitus: 3 cases report / 中华器官移植杂志

Objective To evaluate the effect of islet transplantation for patients with type 2diabetes mellitus (DM). Methods Since December 2007, 4 cases of islet transplantations were performed on 3 patients with type 2 DM and end-stage renal disease (ESRD). Two patients received simultaneous islet-kidney transplant from single-donor (SIK), and one received 2 consecutive islet transplants 5 months following kidney transplantion (IAK). All recipients given insulin with a dose of percutaneous transhepatic portal catheterization. Anti-CD25 monoclonal antibody was used as induction. For SIK, low-doses of Tacrolimus and sirolimus were used as maintenance immunosuppression protocol. For IAK, the maintenance protocol included cyclosporine and MMF.Insulin dose, the level of blood glucose, C-peptide and the value of HbA1 were observed. Results The first patient of SIKhad normal glucose level 3 days after surgery and became insulin independent within the first month, but insulin was administered gradually and the dose reduced to 1/3. The second patient of SIK died of bleeding and secondary infection of liver puncture site 5 days following operation, the blood glucose level recovered to normal 24 h after operation. The insulin dose of the patient of IAK was reduced to 1/2 after the first transplant. The patient became insulin free after the second operation. The level of fasting and postprandial C-peptide of the surviving recipients increased by 600 pmol/L. The value of HbA1 of the SIK was 6.7 %～7.3 %, while that of the IAK was 5. 5 %～ 5. 9 %. Conclusion Islet transplantation is an effective treatment for patients with type 2 DM.

Recent progress in differentiation of mesenchymal stem cells into islet-like cells / 中华内分泌代谢杂志

Mesenchymal stem cells (MSCs) are multipotent stem cells existing in multi-organs and can differentiate into several kinds of somatic cells. Recently it has been found that MSCs, under defined conditions in vivo or in vitro, can be induced to trans-differentiate into islet-like cells, which can secrete a small amount of insulin and lower blood glucose levels in diabetic mice. Thus, two major obstacles of islet transplantation, the insufficience of donor islets and immunologic rejection, might be solved simultaneously with this technique. This finding provides a new insight into treatment for diabetes.

Pancreatic Islets Transplantation through Spleenic Pulp and Peritoneum Using Hollow Fiber in Streptozotocin-induced Diabetic Nude Mouse / 대한소아내분비학회지

PURPOSE: Recently islets transplantation has been become a hot issue in insulin dependant diabetes mellitus. This study is aimed to review the technical method of islet isolation, pruification, and microencapsulation in animal model and to study the actual ability of transplated islets on controlling hyperglycemia. Finally, we want to know whether hollow fiber model for immunoislation in islet transplantation is effective in diabetic nude mouse. Method: We use 5-6 weeks old Spregue-Dawley rats as donor. After midline incision, collagenase was infused to proximal common bile duct and pancreas was extracted. With HBSS treatment and discontinuous density gradient centrifugation, islets were isolated. From 500-1,000 numbers of islets were transplanted to 6 strepozotocin-induced nude mice via upper pole of spleen and serial blood glucose level of nude mice were checked from conjunctival veins. Also, we examined transplanted-islets in spleen histologically with light and electron microscopy. Finally, after impregnation of 500 to 1,000 numbers of islets to 2-4 hollow fibers(Amicon R, H1P30-43 type, M.W:30,000) for immunoisolation, we inserted hollow fiber into peritoneum of 3 streptozotocin-induced nude mice and checked blood glucose level serially. Results: 1) Isolation of islets from rats was done successfully and we could calculate the number of islets under microscopy. 2) In 3 diabetic nude mice without islet transplantation(control group), all of them revealed hyperglycemia above 200mg/dL after 5days from strptozotocin injection. After then, blood glucose level was ranged from 300 to 500mg/dL persistently and all of them were died after 120 days. 3) We could observe the transplabted-islets in spleen with microscopy. Blood glucose level began to be controlled after 5 days from transplantation in 3 diabetic nude mice and all of 6 diabetic nude mouses revealed normoglycemia after 25 days from transplantation. 4) Islets transplantation with holler fibers into peritoneum of diabetic nude mice was not satisfactory. Although no technical difficulty was occured, persistent hyperglycemia was observed and all of 3 diabetic nude mice were died. CONCLUSION: Though islet transplantation through spleen was sucessful in diabetic nude mouse, further study is needed to clear the cause of failure of hollow fiber model in islets transplantation.