基于C肽的胰岛素抵抗指数可准确评估健康体检者的胰岛素抵抗与血尿酸水平的相关性.pdf

C肽来源于胰岛素原裂解过程中产生的生物活性肽，血清C肽比血清胰岛素更为精确地反映内源性胰岛素分泌 1。目前研究发现C肽具有生物活性 2。C肽对1型糖尿病动脉粥样硬化、周围神经病变有潜在治疗作用 3。Jeon等 4 研究发现，C肽可抑制谷氨酰胺转移酶2介导的微血管渗漏、炎症和细胞凋亡，减轻糖尿病患者高血糖诱导的肺纤维化。临床上C肽主要用于评价胰岛细胞功能、胰岛素抵抗。梁倩等 5 研究发现2型糖尿病患者空腹C肽与血尿酸水平存在关联，认为胰岛素抵抗与血尿酸水平升高密切相关。基于基于C C肽的胰岛肽的胰岛素抵抗指数可准确评估健康体检者的胰岛素抵素抵抗指数可准确评估健康体检者的胰岛素抵抗与血尿酸抗与血尿酸水平的相关性水平的相关性方福生1，王 宁2，刘星宇1，王 薇1，孙 菁2，李 红2，孙般若3，谷昭艳3，傅晓敏4，闫双通3解放军总医院第二医学中心1保健一科，2健康医学科，3内分泌科，4第一医学中心内分泌科，北京 100853Value of C-peptide-based insulin resistance index for evaluating correlation betweeninsulin resistance and serum uric acid level in individuals undergoing health examinationFANGFusheng1,WANGNing2,LIUXingyu1,WANGWei1,SUNJing2,LIHong2,SUNBanruo3,GUZhaoyan3,FUXiaomin4,YANShuangtong31Department of Health Care,2Department of Health Management,3Department of Endocrinology,Second Medical Center of Chinese PLAGeneral Hospital,Beijing 100853,China;4Department of Endocrinology,First Medical Center of Chinese PLA General Hospital,Beijing100853,China摘要：目的 探讨基于C肽的胰岛素抵抗指数在评估健康体检人群胰岛素抵抗与血尿酸（Ua）水平关联中的作用。方法 回顾性收集2017年1月2021年12月在解放军总医院第二医学中心进行健康体检的资料46 017例，根据Ua水平分为两组：Ua420 mol/L和Ua420 mol/L，比较两组胰岛素抵抗指数（HOMA2-IR）、基于C肽的胰岛素抵抗指数（HOMA2 IR-CP）水平的差异，采用Pearson相关分析、线性回归分析HOMA2-IR、HOMA2 IR-CP与Ua的相关性，分层交互分析不同亚组间HOMA2-IR、HOMA2IR-CP与Ua的关联是否存在差异，利用ROC曲线评价HOMA2-IR、HOMA2 IR-CP对Ua升高的预测能力。结果 Ua420 mol/L组HOMA2-IR、HOMA2 IR-CP水平均显著低于Ua420 mol/L（P0.001）。单因素Pearson相关分析显示HOMA2-IR与Ua（r=0.262，P0.001）弱相关，HOMA2 IR-CP与Ua（r=0.409，P0.001）中等强度相关。多因素线性回归分析提示在调整相关混淆因素后HOMA2-IR（R2=0.445，P0.001）或HOMA2 IR-CP（R2=0.461，P0.001）均是Ua水平的影响因素。分层交互分析发现不同性别、年龄、糖代谢亚组间胰岛素抵抗指数与Ua的关联均存在差异（P420 mol/Lgroup for comparison of HOMA insulin resistance index(HOMA2-IR)and HOMA insulin resistance-C peptide(HOMA2 IR-CP).The correlations of HOMA2-IR and HOMA2 IR-CP with Ua level were analyzed using Pearson correlation analysis andlinear regression analysis.Hierarchical interaction analysis was conducted to assess the differences in the association betweeninsulin resistance index and Ua level in different subgroups.The ROC curve was used to evaluate the predictive ability ofinsulin resistance index for an increased Ua level.Results The levels of HOMA2-IR and HOMA2 IR-CP were significantlylower in Ua420 mol/L group than in Ua420 mol/L group.Univariate Pearson correlation analysis showed a weakcorrelation of HOMA2-IR with Ua(r=0.262,P0.001)and moderate correlation of HOMA2 IR-CP with Ua(r=0.409,P0.001).Multivariate linear regression analysis,after adjustment for confounding factors,demonstrated that HOMA2-IR(R2=0.445,P0.001)and HOMA2 IR-CP(R2=0.461,P0.001)were both factors affecting Ua level.Hierarchical interaction analysis showedthat the association of insulin resistance index with Ua level varied significantly with gender,age,and glucose metabolism(P420mol/L 14。1.4 统计学分析采用SPSS 26软件进行统计学分析。正态分布的计量资料以均数标准差表示，组间比较采用独立样本t检验。非正态分布的计量资料以中位数（Q1，Q3）表示，组间比较采用非参数检验。计数资料以例数（%）表示，组间比较采用2检验。胰岛素抵抗指数与Ua的相关性分析采用单因素 Pearson 相关分析（r0.2，无相关；0.2r0.4，弱相关；0.4r420 mol/L）相关的HOMA2-IR、HOMA2 IR-CP值。以P420mol/L组女性比例、年龄、HDL-c、eGFR低于Ua420 mol/L组（P0.001），而体质量指数（BMI）、SBP、DBP、FPG、FINS、FCP、TC、TG、LDL-c、ALT、AST水平高于Ua420 mol/L组（P420 mol/L组HOMA2-IR、HOMA2 IR-CP水平均显著大于Ua420mol/L组（P0.001）。2.3 胰岛素抵抗指数与血尿酸的单因素Pearson相关分析分析HOMA2-IR、HOMA2 IR-CP与Ua的相关性，单因素Pearson相关分析显示HOMA2-IR（r=0.262，P0.001）与Ua弱相关，HOMA2 IR-CP（r=0.409，P0.001）与Ua中等强度相关，FPG与Ua不相关（r=0.093）。2.4 胰岛素抵抗指数与血尿酸的多因素线性回归分析以Ua为因变量，以HOMA2-IR或HOMA2 IR-CP为自变量，多因素线性回归分析显示（表2），在调整相关混淆因素（年龄、性别、BMI、SBP、TG、FPG、ALT、eGFR）后，HOMA2-IR（4.934，95%CI4.2305.637，P0.001，R2=0.445）或HOMA2 IR-CP（21.316，95%CI 20.19922.433，P0.001，R2=0.461）与Ua水平相关。J South Med Univ,2023,43(9):1509-1514http:/www.j-15102.5 分层交互分析不同亚组间胰岛素抵抗指数与血尿酸水平的关联对不同性别、年龄、糖代谢状态亚组分别进行分析（表 3），以 Ua 为因变量，以 HOMA2-IR（Q1Q4）或HOMA2 IR-CP（Q1Q4）、性别、年龄、糖代谢状态、BMI、SBP、TG、ALT、eGFR为自变量（分层变量除外），多因素Logistic回归分析显示，HOMA2-IR或HOMA2IR-CP均与Ua水平相关（P0.001）。交互检验作用发现不同性别、年龄、糖代谢亚组间关联均存在差异（Pinteraction420 mol/L）的ROC 曲线下面积为 0.662，切点为 1.45，敏感性为67.1%，特异性为56.9%，约登指数为0.240。应用ROC曲线分析HOMA2 IR-CP与Ua的相关程度，发现HOMA2 IR-CP预测Ua升高（420 mol/L）的 ROC 曲线下面积为 0.722，切点 1.78，敏感性为76.6%，特异性为56.7%，约登指数为0.333。CharacteristicsnGender(female)Age(year)BMI(kg/m2)SBP(mmHg)DBP(mmHg)HbA1c(%)FPG(mmol/L)FINS(U/mL)HOMA2-IRFCP(ng/mL)HOMA2 IR-CPTC(mmol/L)TG(mmol/L)LDL-c(mmol/L)HDL-c(mmol/L)ALT(U/L)AST(U/L)eGFR(mL/min/m2)Ua420 mol/L3724215637(42.0%)50.459.9824.623.38120.8518.8780.7411.855.790.795.581.328.65(5.99,12.46)1.32(0.91,1.91)2.22(1.75,2.83)1.67(1.29,2.16)4.710.941.651.453.150.881.310.3717.80(13.00,25.70)17.40(14.70,21.20)105.8914.89Ua420 mol/L8775290(3.3%)48.209.5826.943.24127.1317.4485.4511.575.790.675.741.1311.89(8.40,16.68)1.82(1.29,2.54)2.97(2.40,3.67)2.26(1.81,2.82)4.850.982.561.953.190.901.110.2925.20(18.20,36.80)20.00(16.70,25.10)103.3918.30t or 2-4693.419-19.17055.22726.93631.846-0.29510.68043.57740.88869.94065.38012.25149.2504.364-47.00537.66225.387-13.519P-0.0010.0010.0010.0010.0010.7680.0010.0010.0010.0010.0010.0010.0010.0010.0010.0010.0010.001表1 研究对象的一般资料Tab.1 GeneralinformationofstudysubjectsBMI:Body mass index;SBP:Systolic blood pressure;DBP:Diastolic blood pressure;HbA1c:Glycosylated hemoglobin;FPG:Fasting plasma glucose;FINS:Fasting insulin;HOMA2-IR:HOMA2 insulin resistance;FCP:Fasting C-peptide;HOMA2 IR-CP:C-peptide-based HOMA2 insulin resistance;TC:Total cholesterol;TG:Triglyceride;LDL-c:Lowdensity lipoprotein cholesterol;HDL-c:High density lipoprotein cholesterol;ALT:Alanine aminotransferase;AST:Aspartateaminotransferase;eGFR:Estimatedglomerularfiltrationrate.1mmHg=0.133kPa.ModelModel 0Model 1Model 2Model 3HOMA-IR20.9456.4306.3684.93495%CI20.239-21.6505.732-7.1275.648-7.0894.230-5.637P0.0010.0010.0010.001R20.0690.3750.4000.445HOMAIR-CP45.59722.88826.07421.31695%CI44.667-46.52721.863-23.91324.947-27.20020.199-22.433P0.0010.0010.0010.001R20.1670.3980.4250.461表2 胰岛素抵抗指数与血尿酸的多因素线性回归分析Tab.2 MultivariatelinearregressionanalysisofinsulinresistanceindexandserumuricacidlevelModel0:unadjusted;Model1:adjustedforage,genderandBMI;Model2:adjustedforage,sex,BMI,SBP,TGandFPG;Model3:adjustedforage,sex,BMI,SBP,TG,FPG,ALT,andeGFR.http:/www.j-J South Med Univ,2023,43(9):1509-151415113 讨论本研究发现，C肽胰岛素抵抗指数可更为准确地评估胰岛素抵抗与血尿酸水平关联，是个有用的评估方法。健康体检人群HOMA胰岛素抵抗指数与血尿酸水平相关，不同性别、年龄、糖代谢状态亚组间胰岛素抵抗指数与Ua的关联存在差异。与HOMA2-IR比较，C肽胰岛素抵抗指数与血尿酸的相关程度更高。HOMA2IR-CP 预测血尿酸升高的 ROC 曲线下面积也大于HOMA2-IR。因此，在评估胰岛素抵抗与血尿酸水平关联时，C肽胰岛素抵抗指数更具优势。目前应用最广泛的胰岛素抵抗评估指标是HOMA胰岛素抵抗指数 14,15。临床实践中通常使用血清胰岛素计算HOMA2-IR，C肽胰岛素抵抗指数应用相对较少 16。然而，C肽在体内半衰期显著长于胰岛素 17，血清C肽比血清胰岛素更稳定，可代替胰岛素计算HOMA胰岛素抵抗指数，特别是使用外源性胰岛素的糖尿病患者 18。Tekoh等 19 分析小样本非糖尿病人群HOMA2-IR与HOMA IR-CP 的相关性，发现两者之间没有关联。Ferrannini等 20 在欧洲心血管疾病和糖尿病调查中，计算 了 3 种 不 同 的 HOMA 指 数，发 现 HOMA-IR、HOMA2-IR和HOMA2 IR-CP诊断血糖异常的敏感性、特异性均较低。吴晓明等 21 发现C肽胰岛素抵抗指数与致动脉粥样硬化指数（AIP）相关，而HOMA-IR与AIP无关。本研究发现，HOMA2-IR、HOMA2 IR-CP均与血尿酸相关，但HOMA2 IR-CP相关程度更高，有一定临床应用价值。此外，HOMA指数诊断胰岛素抵抗的切点仍不清楚 22,23。Demir 等 24 研究发现应用HOMA2-IR评估胰岛素抵抗的最佳切点为1.40。本研究结果相似，HOMA2-IR区分血尿酸水平升高的切点为1.45，而C肽胰岛素抵抗指数的切点为1.78。胰岛素抵抗与血尿酸水平密切相关。有研究 25 发现非糖尿病人群胰岛素抵抗指数与血尿酸水平相关，而胰岛细胞功能与血尿酸水平无关。有研究 26 发现新诊图1 HOMA2-IR、HOMA2 IR-CP与血尿酸升高的ROC曲线Fig.1 ROC curves of HOMA2-IR,HOMA2 IR-CP andelevatedserumuricacid.0.00.20.40.60.81.01-SpecificitySensitivity1.00.80.60.40.20.0HOMA2-IRHOMA2-IR-CPReference表3 分层交互分析不同亚组间胰岛素抵抗指数与血尿酸的关联Tab.3 HierarchicalinteractionanalysisoftheassociationsbetweeninsulinresistanceindexandUaindifferentsubgroupsHOMA2-IR:HOMA2insulinresistance;FCP:FastingC-peptide;HOMA2IR-CP:HOMA2insulinresistance(C-peptide);T2DM:Type2diabetes.GroupHOMA2-IRHOMA2IR-CPQ1Q2Q3Q4P fortrendP forinteractionQ1Q2Q3Q4P fortrendP forinteractionTotal1.01.36(1.24-1.50)1.61(1.46-1.77)1.90(1.72-2.10)0.001-1.01.56(1.40-1.74)2.38(2.14-2.65)3.43(3.06-3.84)0.001-GenderMale1.01.37(1.25-1.52)1.60(1.45-1.76)1.85(1.67-2.05)0.0010.0011.01.57(1.40-1.76)2.32(2.08-2.59)3.30(2.94-3.72)0.0010.001Female1.01.02(0.61-1.70)2.07(1.30-3.29)3.48(2.18-5.57)0.0011.00.84(0.49-1.45)2.95(1.86-4.68)5.47(3.38-8.84)0.001Age60 years1.01.10(0.83-1.45)1.19(0.90-1.58)1.43(1.07-1.91)0.0010.0011.01.35(0.95-1.92)2.16(1.54-3.02)2.48(1.75-3.54)0.0010.00160 years1.01.39(1.26-1.54)1.66(1.50-1.83)1.95(1.76-2.18)0.0011.01.58(1.40-1.77)2.38(2.13-2.66)3.53(3.13-3.98)0.001Glucose metabolismT2DM1.01.38(1.01-1.87)1.47(1.10-1.95)1.78(1.34-2.35)0.0010.0011.01.43(0.90-2.29)2.15(1.39-3.33)2.89(1.88-4.44)0.0010.001Without T2DM1.01.32(1.19-1.46)1.56(1.41-1.72)1.84(1.65-2.05)0.0011.01.52(1.36-1.71)2.28(2.04-2.55)3.34(2.96-3.77)0.001J South Med Univ,2023,43(9):1509-1514http:/www.j-1512断2型糖尿病人群胰岛素抵抗指数与血尿酸水平升高有关。本研究发现，2型糖尿病患者胰岛素抵抗与血尿酸的关联不如非糖尿病成年人显著，与糖尿病患者比较注重膳食管理、不同个体间血尿酸水平差异较小可能有关。体内外研究发现高尿酸与心肌细胞、骨骼肌细胞胰岛素抵抗有关，二甲双胍可通过AMPK信号通路改善高尿酸诱导的胰岛素抵抗 27,28。高尿酸血症是痛风的发病基础，可导致痛风性关节炎、肾脏损害，与心血管风险增加有关。胰岛素抵抗导致血尿酸水平升高的机制尚不清楚。胰岛素抵抗可促进糖酵解的中间产物转化为磷酸核糖焦磷酸、5-磷酸核糖，有助于嘌呤的生物合成和转化，尿酸生成增多 8。胰岛素抵抗可引起高胰岛素血症，刺激近端小管尿酸盐阴离子转运蛋白，促进肾脏对尿酸的重吸收，导致尿酸水平升高 29。本研究的优点在于所有受试者均有血清胰岛素、血清C肽数据，分别应用胰岛素、C肽计算HOMA胰岛素抵抗指数，可以从多角度探讨胰岛素抵抗指数与血尿酸水平的关联。本研究也有一定的不足之处。首先，本研究为单中心回顾性横断面研究，无法根据本研究结果直接建立因果关系，有待多中心前瞻性研究加以证实。其次，2型糖尿病的诊断仅依据病史、空腹血糖及糖化血红蛋白，可能存在一定偏差。总之，本研究通过对健康体检数据进行回顾性分析，探讨不同胰岛素抵抗指数与健康体检人群血尿酸水平的关联，发现C肽胰岛素抵抗指数可以用于评估胰岛素抵抗与血尿酸的关联，且比基于血清胰岛素的胰岛素抵抗指数更有优势。基于C肽的胰岛素抵抗指数可能是一个很好的评价胰岛素抵抗的指标，值得在临床上探索应用。参考文献：1 PullicinAJ,Newsom SA,Robinson MM,et al.Use of c-peptide as ameasure of cephalic phase insulin release in humans J .PhysiolBehav,2022,255:113940.2 Landreh M,Jrnvall H.Biological activity versus physiologicalfunction of proinsulin C-peptide J .Cell Mol Life Sci,2021,78(3):1131-8.3 Washburn 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