Diabetes Research Center, Brussels Free University, Laarbeeklaan 103, 1090, Brussels, Belgium.
Diabetologia. 2013 Jul;56(7):1605-14. doi: 10.1007/s00125-013-2906-0. Epub 2013 Apr 26.
AIMS/HYPOTHESIS: Alginate-encapsulated human islet cell grafts have not been able to correct diabetes in humans, whereas free grafts have. This study examined in immunodeficient mice whether alginate-encapsulated graft function was inferior to that of free grafts of the same size and composition.
Cultured human islet cells were equally distributed over free and alginate-encapsulated grafts before implantation in, respectively, the kidney capsule and the peritoneal cavity of non-obese diabetic mice with severe combined immunodeficiency and alloxan-induced diabetes. Implants were followed for in vivo function and retrieved for analysis of cellular composition (all) and insulin secretory responsiveness (capsules).
Free implants with low beta cell purity (19 ± 1%) were non-functional and underwent 90% beta cell loss. At medium purity (50 ± 1%), they were functional at post-transplant week 1, evolving to normoglycaemia (4/8) or to C-peptide negativity (4/8) depending on the degree of beta cell-specific losses. Encapsulated implants immediately and sustainably corrected diabetes, irrespective of beta cell purity (16/16). Most capsules were retrievable as single units, enriched in endocrine cells that exhibited rapid secretory responses to glucose and glucagon. Single capsules with similar properties were also retrieved from a type 1 diabetic recipient at post-transplant month 3. However, the vast majority were clustered and contained debris, explaining the poor rise in plasma C-peptide.
CONCLUSIONS/INTERPRETATION: In immunodeficient mice, i.p. implanted alginate-encapsulated human islet cells exhibited a better outcome than free implants under the kidney capsule. They did not show primary non-function at low beta cell purity and avoided beta cell-specific losses by rapidly establishing normoglycaemia. Retrieved capsules presented secretory responses to glucose, which was also observed in a type 1 diabetic recipient.
目的/假设：藻酸盐包封的人胰岛细胞移植物未能纠正人类糖尿病，而游离移植物则可以。本研究在免疫缺陷小鼠中检查了藻酸盐包封的移植物功能是否不如相同大小和组成的游离移植物。
在植入非肥胖型糖尿病伴严重联合免疫缺陷和链脲佐菌素诱导糖尿病小鼠的肾囊和腹腔之前，将培养的人胰岛细胞均等分布在游离和藻酸盐包封的移植物上。对植入物进行体内功能检测，并对细胞组成（全部）和胰岛素分泌反应性（囊）进行分析。
β细胞纯度低（19±1%）的游离移植物无功能，并经历 90%的β细胞丢失。在中等纯度（50±1%）下，它们在移植后第 1 周具有功能，根据β细胞特异性丢失的程度，演变为正常血糖（4/8）或 C 肽阴性（4/8）。无论β细胞纯度如何（16/16），藻酸盐包封的移植物均可立即和持续地纠正糖尿病。大多数囊可作为单个单位回收，富含具有快速分泌反应性的内分泌细胞，对葡萄糖和胰高血糖素敏感。还从移植后第 3 个月的 1 型糖尿病受者中回收了具有类似特性的单个囊，但绝大多数是聚集的，含有碎片，这解释了血浆 C 肽水平升高不良的原因。
结论/解释：在免疫缺陷小鼠中，腹腔内植入的藻酸盐包封的人胰岛细胞在肾囊下表现出比游离移植物更好的结果。它们在低β细胞纯度下没有表现出原发性无功能，并且通过迅速建立正常血糖来避免β细胞特异性丢失。回收的囊对葡萄糖有分泌反应，在 1 型糖尿病受者中也观察到了这种反应。
