长病程1型糖尿病患者残余胰岛功能与自身免疫状态关系的研究  

The relation between residualβ-cell function and autoimmune status in long-term type 1 diabetes patients

作　　者：程靳[1] 钟婷 颜湘[1] 谢雨婷[1] 何斌斌[1] 李霞[1] 周智广[1] Cheng Jin;Zhong Ting;Yan Xiang;Xie Yuting;He Binbin;Li Xia;Zhou Zhiguang(National Clinical Research Center for Metabolic Diseases,Key Laboratory of Diabetes Immunology,Ministry of Education,and Department of Metabolism and Endocrinology,the Second Xiangya Hospital of Central South University,Changsha 410011,China)

机构地区：[1]中南大学湘雅二医院代谢内分泌科,国家代谢性疾病临床医学研究中心,糖尿病免疫学教育部重点实验室,长沙410011

出　　处：《中华医学杂志》2022年第16期1209-1215,共7页National Medical Journal of China

基　　金：湖南省科技创新计划(2020RC4044);国家自然科学基金(8207034059)。

摘　　要：目的:探讨长病程1型糖尿病(T1DM)患者残余胰岛功能与自身免疫状态的关系。方法:采用放射配体法测定的血清C肽对中南大学湘雅二医院T1DM综合管理门诊中长病程(病程≥10年)自身免疫T1DM患者的胰岛功能进行评价。将空腹或餐后2 h C肽高于仪器检测敏感度下限(16.7 pmol/L)定义为胰岛功能存留,否则为胰岛功能丧失。筛查并入组所有胰岛功能存留患者(19例),同时入组性别、年龄、病程、体质指数(BMI)匹配的胰岛功能丧失患者(19例)及健康对照(19例)。检测研究对象外周血CD4+T淋巴细胞亚群:Th1辅助细胞(Th1)、Th2辅助细胞(Th2)、Th17辅助细胞(Th17)、调节性T细胞(Treg)及B淋巴细胞亚群:边缘区B细胞(MZB)、滤泡状B细胞(FoB)、分泌白细胞介素10的调节性B细胞(B10)频率及CD4+T、CD8+T、CD19+B细胞表面程序性死亡受体1(PD-1)及其配体(PD-L1)的表达水平;测定研究对象空腹血清中炎症因子干扰素γ(IFN-γ)、肿瘤坏死因子α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-1受体抗体(IL-1RA)、白细胞介素-4(IL-4)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)、白细胞介素-12p40亚基(IL-12p40)、白细胞介素-12p70亚基(IL-12p70)、白细胞介素-23(IL-23)及干扰素诱生蛋白-10(IP-10)的水平。比较上述指标在胰岛功能存留组、胰岛功能丧失组患者与健康对照之间的差异。结果:19例胰岛功能存留组患者中男性占42.1%(8例),年龄[M(Q1,Q3)]为29.0(23.0,40.0)岁,病程[M(Q1,Q3)]为11.0(10.0,14.0)年;19例胰岛功能丧失组患者中男性占42.1%(8例),年龄[M(Q1,Q3)]为30.0(23.0,40.0)岁,病程[M(Q1,Q3)]为12.0(10.0,15.0)年;19例健康对照中男性占42.1%(8例),年龄[M(Q1,Q3)]为29.0(24.0,40.0)岁。健康对照、胰岛功能丧失组、胰岛功能存留组患者Th1细胞频率[M(Q1,Q3)]分别为9.93%(7.45%,15.20%)、14.90%(11.70%,18.00%)、10.20%(6.93%,15.80%)(P=0.015);Treg细胞频率[M(Q1,Q3)]分别为3.52%(2.92%,5.68%)、2.88%(1.64%Objective We aimed to investigate the autoimmune status of long-term type 1 diabetes mellitus(T1DM)patients with residualβ-cell function.Methods The residualβ-cell function of long-term(disease duration≥10 years)autoimmune T1DM patients from the T1DM Integrated Management Clinic of the Second Xiangya Hospital was assessed by serum C-peptide levels.Patients with fasting or 2-hour postprandial C-peptide levels over the lower sensitivity limit of detection(16.7 pmol/L)were grouped as C-peptide-positive,and others were grouped as C-peptide-negative.We screened and enrolled all the C-peptide-positive patients(n=19).C-peptide-negative patients with matched sex,age,duration,BMI(n=19)and healthy controls(n=19)were recruited at the same time.The frequencies of CD4+T cell(Th1/Th2/Th17/Treg)and B cell(MZB/FoB/B10)subsets,the expression of PD-1/PD-L1 on T and B lymphocytes,and the levels of T1DM related cytokines including IFN-γ,TNF-α,IL-1β,IL-1RA,IL-4,IL-6,IL-10,IL-12p40,IL-12p70,IL-23 and IP-10 were tested.We compared these parameters in patients with different levels ofβ-cell function.Results In healthy controls,C-peptide-negative and C-peptide-positive patients,the frequencies M(Q1,Q3)of Th1 cells were 9.93%(7.45%,15.20%),14.90%(11.70%,18.00%)and 10.20%(6.93%,15.80%)(P=0.015),and the frequencies M(Q1,Q3)of Treg cells were 3.52%(2.92%,5.68%),2.88%(1.64%,3.22%)and 3.12%(2.81%,4.81%)(P=0.005),and the frequencies M(Q1,Q3)of PD-1+B cells were 4.69%(2.64%,6.37%),2.11%(1.45%,3.63%)and 4.20%(2.53%,6.01%)(P=0.003),respectively.The levels of IL-6 M(Q1,Q3)were 26.43(18.06,33.35)ng/L,42.97(25.52,66.30)ng/L,and 22.07(14.85,34.45)ng/L(P=0.006),and the levels of IP-10 M(Q1,Q3)were 107.39(76.19,126.07)ng/L,188.82(131.27,348.18)ng/L and 128.26(114.31,136.50)ng/L(P<0.001)in healthy controls,C-peptide-negative and C-peptide-positive patients,respectively.Compared with C-peptide-positive patients,the frequency of Th1 cells and the levels of IL-6 and IP-10 cytokines were higher,while the frequencies of Treg cells and PD-1+B cells wer

关 键 词：糖尿病 1型 自身免疫 程序性死亡受体-1 白细胞介素-6 干扰素诱生蛋白-10 

分 类 号：R587.1[医药卫生—内分泌]