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    • In terms of efficacy group IEQ

    2018-11-09

    In terms of efficacy, group 2 (10,000IEQ/kg×2 transplantation group) could maintain HbA1c<7.0% >600days with significant reduction of serious unaware hypoglycemia. Hence this study was able to show the clinical benefit by encapsulated porcine islet xenotransplantation without immunosuppression. On the other hand, HbA1c could be reduced by meticulous blood salubrinal control. To reduce the HbA1c by meticulous blood glucose control, the doses of insulin need to be increased. However, in our study, both HbA1c and daily insulin doses were decreased after transplantation. Increasing TEF after transplantation also reflects that the effect of reducing the HbA1c is theoretically due to implanted islets. In addition, we put 8weeks run-in period before transplantation and during the run-in period the TEF was approximately 0. Therefore meticulous blood glucose levels cannot explain the effect of both reducing HbA1c and daily insulin dose after transplantation. Oral glucose tolerance test in two recipients (2 and 5) at 15months after the first transplantation also suggested transplanted islets maintained their function. It has been demonstrated that measurements of C-peptide levels in peripheral blood is difficult when islets were transplanted into peritoneal cavity (Matsumoto et al., 2014; Tuch et al., 2009; Jacobs-Tulleneers-Thevissen et al., 2013). Therefore we applied TEF to assess the function of transplanted islets because the TEF does not require C-peptide levels. TEF was proved to be correlated with other islet function assessment methods including beta-score, C-peptide/glucose ratio, acute insulin response stimulated by Arginine, and SUITO index (Caumo et al., 2011). Among the assessment methods of islet function, SUITO index was well evaluated (Takita and Matsumoto, 2012). In cases of allogeneic islet transplantation, it was demonstrated that high SUITO index (>26), which usually needs multiple islet transplantations, was associated with achieving insulin independence, improving IVGTT profile, reducing hypoglycemic events, and improving quality of life (QOL) (Takita and Matsumoto, 2012). Middle SUITO index (10–25), which usually requires only one islet transplantation, was associated with improving IVGTT profile, reducing hypoglycemic events and improving QOL even without achieving insulin independence (Takita and Matsumoto, 2012). SUITO index 26 and 10 are equivalent to TEF 0.5 and 0.3 respectively (Caumo et al., 2011). Interestingly, in group 2, after the first transplantation TEF exceeded 0.3 and after the second transplantation the TEF exceeded 0.5 which were similar to the allogeneic islet transplantation. Previously we transplanted encapsulated porcine islets into type 1 diabetic patients with 4 different doses (5000IEQ/kg, 10,000IEQ/kg, 15,000IEQ/kg and 20,000IEQ/kg) (Matsumoto et al., 2014). TEF was the highest when transplanted 5000IEQ/kg but the average of the value was only 0.17 (Matsumoto et al., 2014). We speculated that too many islet transplantation into abdominal cavity at once caused oxygen insufficiency for each islet which led to cell death. To avoid this, we transplanted either 5000IEQ/kg or 10,000IEQ/kg first followed by a second transplantation after 3months in this study. Multiple small dose transplantation might contribute to improve the efficacy. This study demonstrated significant improvement of HbA1c, reduction of unaware hypoglycemic events with improved TEF; however, the reduction of insulin doses was marginal. In cases of allogeneic islet transplantation, it was demonstrated that single islet transplantation could improve glycemic control but marginally reduced insulin doses due to necessity of bolus insulin injection associated with meals (Sassa et al., 2006). In this study, transplanted encapsulated neonatal porcine islets might not sufficiently respond to the meal. Considering high TEF, which suggests sufficient insulin secretary ability of islets, this insufficiency might be due to intra-peritoneal transplant site for encapsulated islets. In addition, even HbA1c was significantly reduced after transplantation; HbA1c did not reach the normal levels. This might be also due to intra-peritoneal transplant site because there might be a lag time between sensing blood glucose levels and delivering insulin via ascites. Better transplant sites, for example vascularized areas under skin or omentum pouch might improve this issue.