Since the seminal success of Edmonton protocol in 2000, pancreatic islet transplantation has been very actively pursued worldwide¹. This breakthrough has provided considerable encouragement to patients affected with type 1 diabetes, particularly those experiencing severe hypoglycemia and poor glycemic control, as well as healthcare professionals dedicated to their treatment. As of the latest report, over 1,300 patients have undergone pancreatic islet transplantation². Notably, several recent studies have presented long-term follow-up results extending beyond 10 or even 20 years².

Despite these advancements, the field faces a significant challenge stemming from the diverse criteria employed across studies for assessing graft survival and transplantation success. This challenge is exacerbated by disparate transplantation protocols and confinement of studies to specific countries or institutions, hindering a comprehensive assessment of transplantation responses and the identification of prognostic factors.

To integrate and compile data from islet transplantation, the Collaborative Islet Transplant Registry (CITR) was established in 2001, with participation from more than 39 centers across over 10 countries to date². Over the past two decades, this expansive registry has played a crucial role in aggregating islet transplantation data, significantly advancing our understanding of this therapeutic approach. This year, the CITR has reported three pivotal studies based on the accumulation and long-term analysis of this extensive dataset (Table 1)^2-4.

First, Bernhard Hering and colleagues⁴ provided important clinical insights into transplantation protocols and post-transplant management by proposing a common set of four favorable factors. This study involved an extensive and thorough exploration, encompassing various affecting factors such as recipient/donor characteristics, islet graft properties, and immunosuppression methods. Four factors were identified with the highest predictive power, including recipient age of 35years or older, total infused islets of 325,000 islet equivalents or more, induction of immunosuppression with T cell depletion and/or tumor necrosis factor-alpha (TNF-α) inhibition, and maintenance with both the mechanistic target of rapamycin (mTOR) and a calcineurin inhibitor with the highest predictive power. Importantly, with the exception of age, these factors are modifiable and amenable to intervention.

Secondly, David Baidal et al.³ observed a robust correlation between clinical outcomes and concurrent measurements of fasting and stimulated C-peptide levels, along with the C-peptide-to-glucose ratio. This finding implies that retention of C-peptide function should be regarded as another potential goal of islet transplantation.

Lastly, in The Lancet Diabetes & Endocrinology, Mikaël Chetboun et al.² reported the primary graft function (PGF; islet graft function after islet the last islet infusion) and 5 year outcome results. They utilized the BETA-2 score (derived from fasting C-peptide, fasting plasma glucose, HbA1c, and insulin dose expressed as continuous variables), based on 28 days after last islet transplantation, as an indicator to predict the 5 year success rate of islet transplantation². This is significant as it introduces an indicator for predicting the success rate of transplantation, which, until now, either did not exist or was challenging to apply in practice due to diverse standards in various studies. Notably, the correlation analysis between PGF and long-term outcome considered all possible confounding factors, enhancing the reliability and verification power of the study, given its multi-center nature involving more than 1,000 transplants. It is important to note that the PGF was evaluated at 28 days after the last islet infusion. As the authors have already mentioned², this timeframe is considered appropriate, taking into account graft engraftment and vascularization. Additionally, it could allow sufficient time for stabilizing glucose homeostasis after transplantation. Previous studies have measured the BETA-2 score at 3 months or continuously after islet transplantation to analyze its relationship with transplantation outcomes⁵. However, given the rapid decline in graft function during the first month after transplantation and a gradual decrement thereafter⁵, the 1-month time point suggested in this study appears to be appropriate for evaluating graft function to predict clinical outcomes. Lastly, they are unveiling a prediction model based on the results of this study (accessible on http://pgf.diabinnov.com/), providing crucial information for predicting the prognosis after islet transplantation, determining the need for additional islet transplantation, and offering valuable guidance to healthcare professionals and patients before and after islet transplantation.

It is imperative to emphasize that the BETA-2 score at 28 days after transplantation is derived from the composite outcomes of various donor and recipient factors, encompassing islet number and function, immune responses, metabolic factors, and even unknown or poorly measured elements. Therefore, considering a multivariate analysis incorporating PGF in the model, it is necessary to reevaluate their conclusion that the number of islet infusions and the transplanted islet mass had no significant impact on major clinical outcomes. While the BETA-2 score can serve as a useful indicator for assessing graft function and predicting long-term outcomes, successful islet transplantation still requires meticulous preparation and vigilant post-transplant management, addressing factors ranging from islet number, mass, and function to post-transplant immunosuppressants^{1, 3}.

Chetboun et al.² applied the Igls 2.0 criteria (revised from the original version), which distinguishes clinical outcomes based on glucose regulation from beta cell graft function using C-peptide and insulin requirement. Consequently, they excluded insulin dependence from the category of unsuccessful islet transplantation but considered fasting C-peptide as low as 0.2 ng/mL as a favorable outcome. This aspect warrants careful attention when interpreting their findings. As noted in another CITR report this year, the retention of C-peptide is closely tied to outcomes such as metabolic restoration, loss of severe hypoglycemic events (defined as hypoglycemia associated with loss of consciousness or requiring third-party assistance for recovery), and achieving insulin independence³. Despite the use of more lenient criteria for defining unsuccessful islet transplantation, the 5 year transplant success rate in this integrated registry remains below 30%. If more stringent parameters, such as insulin independence or a significant reduction in insulin requirement as suggested in the initial Igls criteria (a consensus definition for outcomes of beta cell replacement therapy in the treatment of diabetes from the international pancreas and islet transplantation association (IPITA)/European pancreas and islet transplantation (EPITA), consisting of four factors: HbA1c, severe hypoglycemia, insulin requirement, and C-peptide), and a higher C-peptide level (at least 0.3 ng/mL or more) are employed, the success rate could be anticipated to be even lower. This underscores that, despite significant progress in pancreatic islet transplantation, there is still considerable more room for improvement in achieving successful islet transplantation in the future.

Over the past two decades, remarkable advancements have transpired in islet transplantation. The outcomes delineated by the CITR, spanning this period and involving more than 30 centers, provide valuable insights that could significantly contribute to the broader adoption of islet transplantation. We are now able to systematically address common favorable factors associated with successful transplantation outcomes, and there is a growing recognition that maintaining C-peptide levels after transplantation may be another critical goal for successful outcomes. Furthermore, it is now pertinent to deliberate the utilization of the BETA-2 score, measured at 28 days after islet transplantation, as a pivotal tool for guiding re-transplantation decisions in patients. Prospective clinical trials are warranted to explore the BETA-2 score threshold at 28 days, guiding re-transplantation decisions, assessing the target goal of graft function, and validating these findings across diverse ethnic groups including Asian populations. In addition to benefiting from this extensive registry data, the development of modalities capable of assessing islet function before transplantation, such as islets-on-chip, along with the advancement of innovative immunomodulatory approaches, may pave the way for more successful islet transplantation in the future.

自 2000 年埃德蒙顿方案取得重大成功以来，胰岛移植在全世界范围内得到了非常积极的推广¹。这一突破为 1 型糖尿病患者，特别是那些患有严重低血糖和血糖控制不佳的患者，以及致力于治疗的医疗保健专业人员提供了相当大的鼓励。截至最新报告，已有超过1,300名患者接受了胰岛移植²。值得注意的是，最近的几项研究提出了超过 10 年甚至 20 年的长期随访结果²。

尽管取得了这些进步，该领域仍面临着重大挑战，因为评估移植物存活和移植成功的研究中采用了不同的标准。不同的移植方案和仅限于特定国家或机构的研究加剧了这一挑战，阻碍了对移植反应的全面评估和预后因素的识别。

为了整合和汇编胰岛移植数据，协作胰岛移植登记处 (CITR) 于 2001 年成立，迄今为止已有来自 10 多个国家的 39 个中心参与²。在过去的二十年中，这个广泛的登记在汇总胰岛移植数据方面发挥了至关重要的作用，显着增进了我们对这种治疗方法的理解。今年，CITR 报告了基于这一广泛数据集的积累和长期分析的三项关键研究（表 1）^2-4。

首先，Bernhard Hering 及其同事⁴提出了一组常见的四个有利因素，为移植方案和移植后管理提供了重要的临床见解。这项研究涉及广泛而彻底的探索，涵盖各种影响因素，例如受者/供者特征、胰岛移植物特性和免疫抑制方法。确定了具有最高预测能力的四个因素，包括受者年龄为 35 岁或以上、总输注胰岛数量为 325,000 胰岛当量或更多、T 细胞耗竭和/或肿瘤坏死因子-α (TNF-α) 抑制诱导免疫抑制、雷帕霉素 (mTOR) 机制靶点和具有最高预测能力的钙调磷酸酶抑制剂的维持治疗。重要的是，除了年龄之外，这些因素都是可以改变的并且易于干预。

其次，大卫·拜达尔等人。³观察到临床结果与空腹和刺激 C 肽水平的同时测量以及 C 肽与葡萄糖比率之间存在强大的相关性。这一发现意味着保留 C 肽功能应被视为胰岛移植的另一个潜在目标。

最后，在《柳叶刀糖尿病与内分泌学》中，Mikaël Chetboun等人。²报告了主要移植功能（PGF；最后一次胰岛输注后的胰岛移植功能）和 5 年结果结果。他们利用基于最后一次胰岛移植后 28 天的 BETA-2 评分（源自空腹 C 肽、空腹血糖、HbA1c 和以连续变量表示的胰岛素剂量）作为预测 5 年成功率的指标。胰岛移植²．这很重要，因为它引入了一个预测移植成功率的指标，而迄今为止，该指标要么不存在，要么由于各种研究的标准不同而在实践中应用具有挑战性。值得注意的是，PGF 与长期结果之间的相关性分析考虑了所有可能的混杂因素，鉴于其涉及超过 1,000 例移植的多中心性质，增强了该研究的可靠性和验证力。值得注意的是，PGF 在最后一次胰岛输注后 28 天进行评估。正如作者已经提到的²，考虑到移植物植入和血管化，这个时间范围被认为是合适的。此外，它可以在移植后留出足够的时间来稳定葡萄糖稳态。既往研究曾在胰岛移植后3个月或连续测量BETA-2评分，分析其与移植结果的关系⁵。然而，鉴于移植后第一个月内移植物功能迅速下降，并在此后逐渐下降⁵，本研究中建议的 1 个月时间点似乎适合评估移植物功能以预测临床结果。最后，他们根据这项研究的结果推出了一个预测模型（可在 http://pgf.diabinnov.com/ 上访问），为预测胰岛移植后的预后、确定是否需要额外的胰岛移植以及提供重要信息。为胰岛移植前后的医疗保健专业人员和患者提供宝贵的指导。

必须强调的是，移植后 28 天的 BETA-2 评分源自各种供体和受体因素的综合结果，包括胰岛数量和功能、免疫反应、代谢因素，甚至未知或测量不良的因素。因此，考虑到模型中纳入 PGF 的多变量分析，有必要重新评估他们的结论，即胰岛输注数量和移植胰岛质量对主要临床结果没有显着影响。虽然BETA-2评分可以作为评估移植物功能和预测长期结果的有用指标，但成功的胰岛移植仍然需要细致的准备和警惕的移植后管理，解决从胰岛数量、质量和功能到移植后的各种因素。 -移植免疫抑制剂^{1, 3}。

切特本等人。²应用了 Igls 2.0 标准（对原始版本进行了修订），该标准将基于葡萄糖调节的临床结果与使用 C 肽和胰岛素需求的 β 细胞移植功能区分开来。因此，他们将胰岛素依赖排除在不成功的胰岛移植类别之外，但认为空腹 C 肽低至 0.2 ng/mL 是一个有利的结果。在解释他们的发现时，这方面值得仔细注意。正如今年的另一份 CITR 报告所述，C 肽的保留与代谢恢复、严重低血糖事件消失（定义为与意识丧失或需要第三方协助恢复相关的低血糖）等结果密切相关，以及实现胰岛素独立³ .尽管使用更宽松的标准来定义不成功的胰岛移植，但该综合登记处的 5 年移植成功率仍然低于 30%。如果有更严格的参数，例如胰岛素独立性或胰岛素需求显着减少，如初始 Igls 标准（国际胰腺和胰岛移植协会 (IPITA) 对糖尿病治疗中 β 细胞替代疗法结果的共识定义）中所建议的/欧洲胰腺和胰岛移植（EPITA），由四个因素组成：HbA1c、严重低血糖、胰岛素需求和 C 肽），并采用较高的 C 肽水平（至少 0.3 ng/mL 或更高），预计成功率会更低。这强调，尽管胰岛移植取得了重大进展，但未来实现成功胰岛移植仍有相当大的改进空间。

在过去的二十年中，胰岛移植取得了显着的进步。 CITR 描述的跨越这一时期、涉及 30 多个中心的结果提供了宝贵的见解，可以极大地促进胰岛移植的更广泛采用。我们现在能够系统地解决与成功移植结果相关的常见有利因素，并且人们越来越认识到移植后维持 C 肽水平可能是成功结果的另一个关键目标。此外，现在有必要考虑利用胰岛移植后 28 天测量的 BETA-2 评分作为指导患者重新移植决策的关键工具。有必要进行前瞻性临床试验来探索 28 天时的 BETA-2 评分阈值，指导再移植决策，评估移植物功能的目标，并在包括亚洲人群在内的不同种族群体中验证这些发现。除了受益于这些广泛的注册数据外，能够在移植前评估胰岛功能的模式（例如胰岛芯片）的开发，以及创新免疫调节方法的进步，可能为在胰岛移植中更成功的胰岛移植铺平道路。未来。