细胞治疗糖尿病的临床突破与进展

doi:10.3877/cma.j.issn.2095-1221.2026.04.008

糖尿病患病率持续攀升，传统治疗难以逆转胰岛β细胞功能衰退。细胞治疗通过恢复或替代内源性胰岛素分泌，为实现糖尿病的功能性治愈提供新路径。本文系统梳理胰岛移植、干细胞衍生胰岛、间充质干细胞（MSCs）和免疫细胞治疗四大策略的临床进展。胰岛移植已应用于临床，但受限于供体短缺；干细胞衍生胰岛在解决细胞来源上取得突破；MSCs通过免疫调节改善血糖控制；免疫细胞治疗旨在重建免疫耐受。各类疗法仍面临免疫排斥、细胞存活和功能成熟等挑战，基因编辑、细胞封装和3D生物打印等新技术为解决这些瓶颈提供新方案。未来研究需聚焦通用型细胞产品开发、精准免疫干预及多机制协同治疗，推动糖尿病治疗从"血糖控制"迈向"功能重建"。

关键词: 细胞治疗, 糖尿病, 胰岛移植, 干细胞, 免疫调节, 临床转化

The prevalence of diabetes continues to rise, and traditional treatments struggle to reverse the decline in pancreatic islet β cell function. Cell therapy offers a new pathway for functional cure by restoring or replacing endogenous insulin secretion. This article systematically reviews the clinical progress of four major strategies: islet transplantation, stem cell-derived islets, mesenchymal stem cells (MSCs), and immune cell therapy. Islet transplantation has been clinically applied but is limited by the shortage of donors; stem cell-derived islets have made breakthroughs in providing a limitless cell source; MSCs improve glycemic control through immunomodulation; and immune cell therapy aims to restore immune tolerance. Each approach faces challenges such as immune rejection, cell survival, and functional maturation. Emerging technologies like gene editing, cell encapsulation, and 3D bioprinting offer novel solutions to these bottlenecks. Future research should focus on the development of universal cell products, precise immunological interventions, and multi-mechanism synergistic therapies to propel diabetes treatment from "glucose control" towards "functional reconstruction".

Key words: Cell therapy, Diabetes, Islet transplantation, Stem cell, Immunomodulation, Clinical translation

表1 细胞治疗糖尿病的分类及关键作用机制

细胞治疗类别	代表技术	关键作用机制	主要适应证
胰岛	自体胰岛移植^[12]	分离自体胰岛经门静脉回输肝脏，保护剩余胰岛功能，无需免疫抑制	慢性胰腺炎、胰腺良性或低度恶性肿瘤、严重的胰腺外伤
	同种异体胰岛移植^[13,14]	从捐赠胰腺分离纯化胰岛，移植至受体肝脏以分泌胰岛素，需长期免疫抑制	T1DM、T2DM、继发性糖尿病
干细胞衍生胰岛	iPSC/CiPSC衍生胰岛^[15]	通过化学或诱导重编程技术将体细胞转化为多能干细胞，再定向分化为功能性胰岛细胞，实现生理性胰岛素分泌	T1DM、胰岛素依赖型T2DM
	Zimislecel （VX-880） ^[11]	异体iPSC衍生胰岛的临床产品，机制同上
	自体E-islets ^[16]	自体血液细胞经重编程分化为内胚层干细胞来源的胰岛样细胞，分泌胰岛素且无需免疫抑制
间充质干细胞	hUC-MSCs ^[17,18]、hBM-MSCs^[9,19]	通过免疫调节、抗炎，促进胰岛β细胞功能恢复、改善胰岛素抵抗及旁分泌效应促进血管生成与组织修复	T1DM、T2DM、糖尿病肾病
免疫细胞	CD4⁺ CD25^high CD127- Tregs^[6]	抑制自身反应性T细胞，诱导免疫耐受	新发T1DM

表1 细胞治疗糖尿病的分类及关键作用机制

细胞治疗类别	代表技术	关键作用机制	主要适应证
胰岛	自体胰岛移植^[12]	分离自体胰岛经门静脉回输肝脏，保护剩余胰岛功能，无需免疫抑制	慢性胰腺炎、胰腺良性或低度恶性肿瘤、严重的胰腺外伤
	同种异体胰岛移植^[13,14]	从捐赠胰腺分离纯化胰岛，移植至受体肝脏以分泌胰岛素，需长期免疫抑制	T1DM、T2DM、继发性糖尿病
干细胞衍生胰岛	iPSC/CiPSC衍生胰岛^[15]	通过化学或诱导重编程技术将体细胞转化为多能干细胞，再定向分化为功能性胰岛细胞，实现生理性胰岛素分泌	T1DM、胰岛素依赖型T2DM
	Zimislecel （VX-880） ^[11]	异体iPSC衍生胰岛的临床产品，机制同上
	自体E-islets ^[16]	自体血液细胞经重编程分化为内胚层干细胞来源的胰岛样细胞，分泌胰岛素且无需免疫抑制
间充质干细胞	hUC-MSCs ^[17,18]、hBM-MSCs^[9,19]	通过免疫调节、抗炎，促进胰岛β细胞功能恢复、改善胰岛素抵抗及旁分泌效应促进血管生成与组织修复	T1DM、T2DM、糖尿病肾病
免疫细胞	CD4⁺ CD25^high CD127- Tregs^[6]	抑制自身反应性T细胞，诱导免疫耐受	新发T1DM

表2 异体胰岛移植进展与全球中心团队研究活动总结

主要领域	关键进展与结论	证据来源	全球中心团队研究活动
全球应用与登记概况	截至2023年底，全球累计完成1 477例异体胰岛移植	CITR第12版年度报告^[24]	北美（占46 %，共673例）	单独胰岛移植583例肾移植后胰岛移植86例胰岛肾脏同时移植1例胰岛移植后肾移植3例
			欧洲/亚洲/澳大利亚（占54 %，共804例）	单独胰岛移植551例肾移植后胰岛移植174例胰岛肾脏同时移植76例胰岛移植后肾移植3例
临床疗效的宏观验证	胰岛移植能有效控制脆性T1DM患者血糖，减少严重低血糖事件，整体安全性良好	CITR长期随访数据	各中心通过向CITR登记病例，共同构建支持该疗法有效性的最大规模真实世界证据体系。
临床疗效的方案探索	优化免疫抑制方案及探索联合用药以提升特定人群疗效	前瞻性临床试验	美国芝加哥大学（University of Chicago）：聚焦脆性糖尿病、新型免疫调节（抗CD40L）和肾移植后胰岛移植（NCT06305286，NCT01241864）
			美国希望之城国家医疗中心（City of Hope）：探索胃泌素对移植结局的改善作用（NCT03746769）
			美国西北大学（Northwestern University）：验证阿伦单抗在非尿毒症患者中的安全有效性（NCT01897688）
长期预后与功能维持	移植后早期C肽是预测长期成功的关键	前瞻性临床试验	荷兰莱顿大学（Leiden University）：正在开展ALADDIN研究，前瞻性验证精氨酸刺激的C肽作为早期功能预测指标（NCT05540197）
	探究达成长期疗效的有利因素	回顾性分析	研究明确了与长期移植物存活相关的有利因素（足量移植，优化免疫抑制方案等）^[13,25]
技术与方法创新	聚焦于移植部位优化与新型细胞处理技术，旨在提升移植效率与安全性	早期临床研究	意大利米兰圣拉斐尔科学研究院（RRCCS San Raffaele）：比较门静脉与大网膜移植部位的安全性与有效性（NCT02803905）加拿大阿尔伯塔大学（University of Alberta）：评估新型抗衰老糖肽（PKX-001）的细胞保护作用（NCT03073577）中国上海瑞金医院：探索扩增胰岛细胞的异体移植（NCT05990530）

表2 异体胰岛移植进展与全球中心团队研究活动总结

主要领域	关键进展与结论	证据来源	全球中心团队研究活动
全球应用与登记概况	截至2023年底，全球累计完成1 477例异体胰岛移植	CITR第12版年度报告^[24]	北美（占46 %，共673例）	单独胰岛移植583例肾移植后胰岛移植86例胰岛肾脏同时移植1例胰岛移植后肾移植3例
			欧洲/亚洲/澳大利亚（占54 %，共804例）	单独胰岛移植551例肾移植后胰岛移植174例胰岛肾脏同时移植76例胰岛移植后肾移植3例
临床疗效的宏观验证	胰岛移植能有效控制脆性T1DM患者血糖，减少严重低血糖事件，整体安全性良好	CITR长期随访数据	各中心通过向CITR登记病例，共同构建支持该疗法有效性的最大规模真实世界证据体系。
临床疗效的方案探索	优化免疫抑制方案及探索联合用药以提升特定人群疗效	前瞻性临床试验	美国芝加哥大学（University of Chicago）：聚焦脆性糖尿病、新型免疫调节（抗CD40L）和肾移植后胰岛移植（NCT06305286，NCT01241864）
			美国希望之城国家医疗中心（City of Hope）：探索胃泌素对移植结局的改善作用（NCT03746769）
			美国西北大学（Northwestern University）：验证阿伦单抗在非尿毒症患者中的安全有效性（NCT01897688）
长期预后与功能维持	移植后早期C肽是预测长期成功的关键	前瞻性临床试验	荷兰莱顿大学（Leiden University）：正在开展ALADDIN研究，前瞻性验证精氨酸刺激的C肽作为早期功能预测指标（NCT05540197）
	探究达成长期疗效的有利因素	回顾性分析	研究明确了与长期移植物存活相关的有利因素（足量移植，优化免疫抑制方案等）^[13,25]
技术与方法创新	聚焦于移植部位优化与新型细胞处理技术，旨在提升移植效率与安全性	早期临床研究	意大利米兰圣拉斐尔科学研究院（RRCCS San Raffaele）：比较门静脉与大网膜移植部位的安全性与有效性（NCT02803905）加拿大阿尔伯塔大学（University of Alberta）：评估新型抗衰老糖肽（PKX-001）的细胞保护作用（NCT03073577）中国上海瑞金医院：探索扩增胰岛细胞的异体移植（NCT05990530）

表3 细胞治疗糖尿病的关键临床试验概览

临床试验编号	发起人/主要研究者	适应症	研究阶段	研究干预措施	样本量	关键进展/状态
NCT01702051	San Raffaele Hospital	糖尿病	不适用	自体胰岛移植	150	招募中；观察性研究
NCT05990517	上海交通大学医学院	全胰切除术后糖尿病	Ⅱ期	自体胰岛移植	3	未知状态；单组试验
NCT02213003	Rodolfo Alejandro	T1DM	Ⅰ/Ⅱ期	同种异体胰岛移植	3	已完成，66.7 %受者实现HbA1c ≤ 6.5 %且无严重低血糖，报告手术并发症
NCT01897688	Northwestern University	T1DM	Ⅲ期	同种异体胰岛移植+阿伦单抗免疫抑制方案	40	活跃，不招募；验证特定免疫抑制方案在非尿毒症T1DM患者中的安全性与有效性
NCT02803905	Lorenzo Piedmonti	T1DM	Ⅱ期	同种异体胰岛移植（门静脉vs大网膜）	12	活跃，不招募；评估不同移植部位的安全性与有效性
NCT00160732	University of Chicago	脆性/复杂T1DM	Ⅰ/Ⅱ期	同种异体胰岛移植	50	活跃，不招募；单组分配/单臂试验
NCT00706420	City of Hope Medical Center	T1DM	Ⅰ期	同种异体胰岛移植联合不含糖皮质激素的免疫抑制方案	17	活跃，不招募
NCT01241864	University of Chicago	T1DM	Ⅱ期	同种异体胰岛移植	10	招募中；单组试验
NCT01630850	University of Chicago	脆性T1DM	不适用	同种异体胰岛移植	20	招募中；单组试验
NCT05990530	上海交通大学医学院	脆性T1DM	Ⅱ期	扩增胰岛细胞的异体移植	6	未知状态；探索细胞扩增技术的临床转化
NCT06239636	Per-Ola Carlsson	T1DM	Ⅰ期	UP421 （转基因同种异体胰岛）	2	招募中；早期探索性研究
NCT06575426	Otsuka Pharmaceutical Factory, Inc.	T1DM	Ⅰ/Ⅱ期	OPF-310 （异种移植的封装猪胰岛）	13	招募中；探索异种胰岛移植的可行性
NCT01909245	City of Hope Medical Center	T1DM	Ⅱ期	同种异体胰岛、免疫抑制剂、胃泌素17	10	活跃，不招募；单组试验
NCT04786262	Vertex Pharmaceuticals Incorporated	T1DM	Ⅲ期	Zimislecel （自体干细胞衍生胰岛）	52	招募中
NCT03973827	NextCell Pharma Ab	T1DM	Ⅰ/Ⅱ期	hUC-MSCs输注	15	已完成；结果待发布
NCT05308836	Vinmec Research Institute of Stem Cell and Gene Technology	T1DM	Ⅰ期	脂肪来源MSCs输注	10	活跃，不招募
NCT04061746	Medical University of South Carolina	T1DM	Ⅰ期	hUC-MSCs输注	60	招募中；评估hUC-MSCs对T1DM患者β细胞功能的保护作用与安全性
NCT06407297	上海长征医院	新发T1DM	不适用	hUC-MSCs输注	24	招募中；随机对照试验，评估疗效
NCT06727721	Lu jin ，MD	T2DM	Ⅱ期	OCN-19过表达hUC-MSCs	10	招募中；随机对照试验，评估疗效
NCT06751199	上海长征医院	糖尿病	不适用	hUC-MSCs联合同种异体胰岛	16	招募中；非随机的平行分配
NCT06688331	PolTREG S.A.	T1DM临床前期	Ⅱ期	CD4⁺CD25⁺CD127- Tregs和/或（利妥昔单抗）	150	招募中；旨在通过免疫调节治疗儿童T1DM （1期）的安全性与有效性
NCT06708780	南京大学医学院附属南京鼓楼医院	T1DM	Ⅰ期	自体Tregs输注	20	招募中；评估安全性及对免疫指标的调节作用

表3 细胞治疗糖尿病的关键临床试验概览

临床试验编号	发起人/主要研究者	适应症	研究阶段	研究干预措施	样本量	关键进展/状态
NCT01702051	San Raffaele Hospital	糖尿病	不适用	自体胰岛移植	150	招募中；观察性研究
NCT05990517	上海交通大学医学院	全胰切除术后糖尿病	Ⅱ期	自体胰岛移植	3	未知状态；单组试验
NCT02213003	Rodolfo Alejandro	T1DM	Ⅰ/Ⅱ期	同种异体胰岛移植	3	已完成，66.7 %受者实现HbA1c ≤ 6.5 %且无严重低血糖，报告手术并发症
NCT01897688	Northwestern University	T1DM	Ⅲ期	同种异体胰岛移植+阿伦单抗免疫抑制方案	40	活跃，不招募；验证特定免疫抑制方案在非尿毒症T1DM患者中的安全性与有效性
NCT02803905	Lorenzo Piedmonti	T1DM	Ⅱ期	同种异体胰岛移植（门静脉vs大网膜）	12	活跃，不招募；评估不同移植部位的安全性与有效性
NCT00160732	University of Chicago	脆性/复杂T1DM	Ⅰ/Ⅱ期	同种异体胰岛移植	50	活跃，不招募；单组分配/单臂试验
NCT00706420	City of Hope Medical Center	T1DM	Ⅰ期	同种异体胰岛移植联合不含糖皮质激素的免疫抑制方案	17	活跃，不招募
NCT01241864	University of Chicago	T1DM	Ⅱ期	同种异体胰岛移植	10	招募中；单组试验
NCT01630850	University of Chicago	脆性T1DM	不适用	同种异体胰岛移植	20	招募中；单组试验
NCT05990530	上海交通大学医学院	脆性T1DM	Ⅱ期	扩增胰岛细胞的异体移植	6	未知状态；探索细胞扩增技术的临床转化
NCT06239636	Per-Ola Carlsson	T1DM	Ⅰ期	UP421 （转基因同种异体胰岛）	2	招募中；早期探索性研究
NCT06575426	Otsuka Pharmaceutical Factory, Inc.	T1DM	Ⅰ/Ⅱ期	OPF-310 （异种移植的封装猪胰岛）	13	招募中；探索异种胰岛移植的可行性
NCT01909245	City of Hope Medical Center	T1DM	Ⅱ期	同种异体胰岛、免疫抑制剂、胃泌素17	10	活跃，不招募；单组试验
NCT04786262	Vertex Pharmaceuticals Incorporated	T1DM	Ⅲ期	Zimislecel （自体干细胞衍生胰岛）	52	招募中
NCT03973827	NextCell Pharma Ab	T1DM	Ⅰ/Ⅱ期	hUC-MSCs输注	15	已完成；结果待发布
NCT05308836	Vinmec Research Institute of Stem Cell and Gene Technology	T1DM	Ⅰ期	脂肪来源MSCs输注	10	活跃，不招募
NCT04061746	Medical University of South Carolina	T1DM	Ⅰ期	hUC-MSCs输注	60	招募中；评估hUC-MSCs对T1DM患者β细胞功能的保护作用与安全性
NCT06407297	上海长征医院	新发T1DM	不适用	hUC-MSCs输注	24	招募中；随机对照试验，评估疗效
NCT06727721	Lu jin ，MD	T2DM	Ⅱ期	OCN-19过表达hUC-MSCs	10	招募中；随机对照试验，评估疗效
NCT06751199	上海长征医院	糖尿病	不适用	hUC-MSCs联合同种异体胰岛	16	招募中；非随机的平行分配
NCT06688331	PolTREG S.A.	T1DM临床前期	Ⅱ期	CD4⁺CD25⁺CD127- Tregs和/或（利妥昔单抗）	150	招募中；旨在通过免疫调节治疗儿童T1DM （1期）的安全性与有效性
NCT06708780	南京大学医学院附属南京鼓楼医院	T1DM	Ⅰ期	自体Tregs输注	20	招募中；评估安全性及对免疫指标的调节作用

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Clinical breakthroughs and advances in cell therapy for diabetes

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Clinical breakthroughs and advances in cell therapy for diabetes