Udayasankar J, Kodama K, Hull R L, Zraika S, Aston-Mourney K, Subramanian S L, Tong J, Faulenbach M V, Vidal J, Kahn S E
VA Puget Sound Health Care System 151, Seattle, WA 98108, USA.
Diabetologia. 2009 Jan;52(1):145-53. doi: 10.1007/s00125-008-1185-7. Epub 2008 Nov 11.
AIMS/HYPOTHESIS: Islet transplantation is a potential cure for diabetes; however, rates of graft failure remain high. The aim of the present study was to determine whether amyloid deposition is associated with reduced beta cell volume in islet grafts and the recurrence of hyperglycaemia following islet transplantation.
We transplanted a streptozotocin-induced mouse model of diabetes with 100 islets from human IAPP (which encodes islet amyloid polypeptide) transgenic mice that have the propensity to form islet amyloid (n = 8-12) or from non-transgenic mice that do not develop amyloid (n = 6-10) in sets of studies that lasted 1 or 6 weeks.
Plasma glucose levels before and for 1 week after transplantation were similar in mice that received transgenic or non-transgenic islets, and at that time amyloid was detected in all transgenic grafts and, as expected, in none of the non-transgenic grafts. However, over the 6 weeks following transplantation, plasma glucose levels increased in transgenic but remained stable in non-transgenic islet graft recipients (p < 0.05). At 6 weeks, amyloid was present in 92% of the transgenic grafts and in none of the non-transgenic grafts. Beta cell volume was reduced by 30% (p < 0.05), beta cell apoptosis was twofold higher (p < 0.05), and beta cell replication was reduced by 50% (p < 0.001) in transgenic vs non-transgenic grafts. In summary, amyloid deposition in islet grafts occurs prior to the recurrence of hyperglycaemia and its accumulation over time is associated with beta cell loss.
CONCLUSIONS/INTERPRETATION: Islet amyloid formation may explain, in part, the non-immune loss of beta cells and recurrence of hyperglycaemia following clinical islet transplantation.
目的/假设：胰岛移植是治疗糖尿病的一种潜在方法；然而，移植失败率仍然很高。本研究的目的是确定胰岛移植后胰岛移植中淀粉样蛋白沉积是否与β细胞体积减少以及高血糖复发有关。
我们将链脲佐菌素诱导的糖尿病小鼠模型移植了100个胰岛，这些胰岛来自有形成胰岛淀粉样蛋白倾向的人IAPP（编码胰岛淀粉样多肽）转基因小鼠（n = 8 - 12）或来自不形成淀粉样蛋白的非转基因小鼠（n = 6 - 10），每组研究持续1周或6周。
接受转基因或非转基因胰岛的小鼠在移植前及移植后1周的血糖水平相似，此时在所有转基因移植物中均检测到淀粉样蛋白，而在所有非转基因移植物中均未检测到，这与预期一致。然而，在移植后的6周内，转基因胰岛移植受体的血糖水平升高，而非转基因胰岛移植受体的血糖水平保持稳定（p < 0.05）。在6周时，92%的转基因移植物中存在淀粉样蛋白，非转基因移植物中均未出现。与非转基因移植物相比，转基因移植物中的β细胞体积减少了30%（p < 0.05），β细胞凋亡增加了两倍（p < 0.05），β细胞复制减少了50%（p < 0.001）。总之，胰岛移植中的淀粉样蛋白沉积发生在高血糖复发之前，且其随时间的积累与β细胞丢失有关。
结论/解读：胰岛淀粉样蛋白的形成可能部分解释了临床胰岛移植后β细胞的非免疫性丢失和高血糖的复发。
