-
非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是以脂肪在肝脏内过度沉积为主要病理特征的疾病,有研究[1]显示肝脏脂肪沉积对胰岛素抵抗的发生发展起关键核心作用。NAFLD常与2型糖尿病(type 2 diabetes mellitus,T2DM)并存,并且二者相互促进,NAFLD不仅使T2DM的发生风险增加,而且会使病人加快进展糖尿病各种并发症的风险以及发生心脑血管疾病死亡的风险,此外,T2DM亦能促进NAFLD进展非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)、肝硬化、肝细胞癌风险大大增加,因此,强调肝脏脂肪的早期检测和干预对评估和预防相关不良预后具有重要意义。
胱氨酸蛋白酶抑制剂C(Cystatin C, Cys C)是一种半胱氨酸蛋白酶抑制剂,既往学者们[2-3]认为血清Cys C用于评估糖尿病肾病生物标志物,本课题组前期研究[4]显示T2DM病人中Cys C与肝脏脂肪含量(liver fat content,LFC)二者具有明显关联性,二者都是胰岛素抵抗的重要影响因素,Cys C可能影响肝脏脂肪沉积从而参与胰岛素抵抗。
2021年《中国成人2型糖尿病合并非酒精性脂肪性肝病管理专家共识》[5]认为T2DM合并NAFLD药物治疗方面,考虑优先选择吡格列酮或胰高血糖素样肽-1受体激动剂,酌情选择二甲双胍、钠-葡萄糖协同转运蛋白2抑制剂(sodium-glucose transporter-2 inhibitor,SGLT-2i),其他降糖药物不作优选。由于吡格列酮具有心血管疾病等不良反应,胰高血糖素样肽-1受体激动剂需要注射的不便性以及潜在的不良反应等限制其应用。目前,对二甲双胍和达格列净等药物对脂肪肝的影响仍存在一定争议。此外,国内甚少文献报道二甲双胍、达格列净对T2DM病人LFC和Cys C的影响。所以,本研究采用氢质子磁共振波谱[6]检测LFC,探讨二甲双胍、达格列净对T2DM LFC和血清Cys C的影响,为未来T2DM合并NAFLD的防治研究提供血清学指标依据。
-
2组病人在年龄、性别构成比和患病时间之间的差异均无统计学意义(P>0.05)。与甲组相比,乙组病人LFC、血清Cys C水平、TC均明显降低(P<0.05~P<0.01),然而其TG和VLDL-C均升高(P<0.05)(见表 1)。
分组 n 年龄/岁 女 男 BMI/(kg/m2) 患病时间/年 SBP/mmHg DBP/mmHg 甲组 51 56.37±9.25 22 29 25.86±3.76 6.83±6.06 138.02±17.19 85.18±12.91 乙组 70 56.24±8.61 34 36 25.20±3.20 8.29±6.45 138.94±16.56 83.87±9.80 t — 0.08 0.35* 0.24 1.26 0.30 0.63 P — >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 分组 n FBG/(mmol/L) HbA1c/% 总胆红素/(μmol/L) AST/(U/L) ALT/(U/L) TG/(mmol/L) 甲组 51 7.24±1.89 7.30 (6.70, 8.90) 16.54±6.38 18.00 (16.00, 20.00) 22.00±14.45 1.52 (1.09, 1.95) 乙组 70 7.96±1.88 7.80 (7.20, 8.70) 15.89±6.06 19.00 (14.75, 21.25) 25.66±21.05 1.74 (1.34, 2.43) t — 0.31 1.35# 0.57 0.26# 1.07 2.19# P — >0.05 >0.05 >0.05 >0.05 >0.05 <0.05 分组 n TC/(mmol/L) HDL-C/(mmol/L) LDL-C/(mmol/L) VLDL-C/(mmol/L) Cr/(μmol/L) LFC/% Cys C/(mg/ L) 甲组 51 4.50±1.01 1.13±0.30 2.79±0.81 0.30 (0.22, 0.39) 65.31±14.24 19.71 (13.75, 31.30) 1.02±0.17 乙组 70 4.10±1.07 1.04±0.26 2.66±0.90 0.35 (0.27, 0.49) 60.80±15.03 3.10 (1.98, 18.97) 0.72±0.22 t — 2.05 1.87 0.83 2.16# 1.67 5.39# 8.18 P — <0.05 >0.05 >0.05 <0.05 >0.05 <0.01 <0.01 *示χ2值;#示Z值 表 1 不同药物治疗组间临床特征比较(x ±s)
-
结果发现甲组有46例(90.2%)患有NAFLD;而乙组仅有21例(30.0%),甲组NAFLD比例明显高于乙组(χ2=43.26,P < 0.01)。
-
相关性分析结果表明,LFC水平与BMI(r=-0.245)、FBG(r=-0.215)呈负相关关系(P < 0.01和P < 0.05),与Cys C呈正相关关系(r=0.247,P < 0.01)(见表 2)。
LFC LFC LFC 参数 r 参数 r 参数 r 年龄 0.067 HbA1c -0.082 HDL-C 0.106 BMI -0.245** TBIL -0.051 LDL-C -0.010 Duration 0.022 AST 0.025 VLDL-C -0.150 SBP -0.139 ALT -0.087 Cr -0.079 DBP -0.058 TG -0.152 Cys C 0.247** FBG -0.215* TC 0.089 *示P<0.05,**示P<0.01 表 2 LFC与一般人口学和临床特征的相关分析
-
以LFC为因变量(R=0.429, R2=0.184, Adjusted R2=0.149, F=5.199, Model P < 0.01),BMI、FBG、Cys C、病程(Duration)、传统危险因素(TC、TG)和药物治疗(Treatment)作为自变量进行多元线性回归分析,结果表明药物治疗是LFC的主要影响因素(P < 0.01),与甲组相比,乙组可降低0.440个单位的LFC(见表 3)。
自变量 B 95%CI P VIF Constant — — < 0.01 — BMI -0.027 -0.822~0.598 >0.05 1.078 FBG -0.124 -2.240~0.380 >0.05 1.080 TC 0.073 -1.426~3.433 >0.05 1.169 TG 0.055 -1.294~2.421 >0.05 1.160 Cys C -0.138 -6.218~4.403 >0.05 1.624 患病时间 0.075 -0.216~0.558 >0.05 1.030 药物治疗 -0.440 -2.167~6.332 < 0.01 1.758 表 3 多元线性回归分析LFC预测因素
-
以Cys C为因变量(R=0.651, R2=0.423, Adjusted R2=0.371, F=8.070, Model P < 0.01),BMI、FBG、LFC、病程、传统危险因素(TC、TG)和药物治疗为自变量进行多元线性回归分析,结果发现药物治疗是血清Cys C的主要影响因素,同甲组相比,乙组联合用药能够降低0.689个单位的血清Cys C(见表 4)。
自变量 B 95%CI P VIF Constant — — < 0.01 — BMI 0.059 -0.006~0.015 >0.05 1.095 FBG 0.093 -0.008~0.032 >0.05 1.158 LFC -0.111 -0.005~0.001 >0.05 1.231 TC 0.103 -0.012~0.059 >0.05 1.157 TG 0.087 -0.012~0.042 >0.05 1.151 患病时间 0.056 -0.004~0.008 >0.05 1.031 药物治疗 -0.689 -1.424~0.258 < 0.01 1.367 表 4 多元线性回归分析Cystatin C预测因素
达格列净对2型糖尿病病人肝脏脂肪含量及胱抑素C的影响
Effects of dapagliflozin on liver fat content and cystatin C in type 2 diabetes patients
-
摘要:
目的比较使用达格列净+二甲双胍联合用药与单纯使用二甲双胍治疗对2型糖尿病病人肝脏脂肪含量(LFC)和胱抑素C(Cys C)水平的影响。 方法选取住院病人121例,按照治疗方案不同分为二甲双胍治疗组(甲组, n=51)和二甲双胍联合达格列净治疗组(乙组,n=70),所有病人均连续稳定使用上述治疗方案达半年以上,利用氢质子磁共振波谱法检测LFC,血清Cys C水平使用免疫比浊法进行检测,收集病人的一般人口学资料及实验室检测指标数据。分析不同实验室指标与LFC的关联,探讨不同治疗方式及其他实验指标对LFC和Cys C的影响。 结果2组病人的年龄、性别构成比、患病时长和体质量指数(BMI)的差异均无统计学意义(P>0.05);与甲组相比,乙组病人的LFC、血清Cys C水平、总胆固醇(TC)均明显降低(P < 0.05~P < 0.01),但三酰甘油(TG)和极低密度脂蛋白(VLDL)均升高(P < 0.05);甲组的非酒精性脂肪肝(90.2%)比例高于乙组(30.0%)(P < 0.01);相关分析结果发现,BMI、空腹血糖(FBG)和Cys C均与LFC存在关联(P < 0.05~P < 0.01)。以LFC为因变量,BMI、FBG、Cys C、病程、TC、TG和药物治疗作为自变量进行多元线性回归分析,发现与甲组相比,乙组可降低0.440个单位的LFC(P < 0.01);同时以Cys C为因变量,BMI、FBG、LFC、病程、TC、TG和药物治疗作为自变量进行多元线性回归分析,与甲组相比,乙组联合用药能够降低0.689个单位的血清Cys C(P < 0.01)。 结论二甲双胍联合达格列净能有效降低2型糖尿病病人LFC、血清Cys C水平,是LFC、血清Cys C的重要影响因素。 Abstract:ObjectiveTo compare the impact of combined therapy with dapagliflozin and metformin versus metformin monotherapy on liver fat content (LFC) and cystatin C (Cys C) levels in patients with type 2 diabetes mellitus (T2DM). MethodsA total of 121 inpatients with T2DM were enrolled.Patients were divided into metformin monotherapy group (group A, n=51) and dapagliflozin combined with metformin therapy group (group B, n=70) based on their treatment regimen.All patients had been continuously and stably using their respective treatment regimens for more than six months, the levels of LFC were measured using 1H-magnetic resonance spectroscopy, and serum Cys C levels were assessed using the immunoturbidimetric method.The detailed information of basic demographic and laboratory indexes were collected.The correlations between different laboratory parameters and LFC were analyzed, and the effects of different treatment modalities and other laboratory indicators on LFC and Cys C were explored. ResultsThere were no statistically significant differences in age, gender composition, disease duration, and body mass index (BMI) between the two groups (P>0.05).Compared to the group A, patients in the group B showed a significant reduction in LFC, serum Cys C levels and total cholesterol (TC) (P < 0.05 to P < 0.01), but had the increases of triglycerides (TG) and very low-density lipoprotein (VLDL) (P < 0.05).The proportion of nonalcoholic fatty liver disease was higher in the group A (90.2%) than that in the group B (30.0%) (P < 0.01).Further correlation analysis revealed that BMI, fasting blood glucose (FBG), and Cys C were associated with LFC (P < 0.05 to P < 0.01).Using LFC as the dependent variable and BMI, FBG, Cys C, disease duration, TC, TG, and medication as independent variables in multiple linear regression analysis, it was found that compared to metformin monotherapy, combined dapagliflozin and metformin therapy reduced LFC by 0.440 units (P < 0.01).Similarly, when using Cys C as the dependent variable and BMI, FBG, LFC, disease duration, TC, TG, and medication as independent variables in multiple linear regression analysis, it was found that combined metformin and dapagliflozin therapy reduced serum Cys C by 0.689 units compared to metformin monotherapy (P < 0.01). ConclusionsThe combined therapy with metformin and dapagliflozin can effectively reduce the levels of LFC and serum Cys C in T2DM patients, suggesting that such treatment pattern is an important factor influencing LFC and serum Cys C. -
Key words:
- type 2 diabetes mellitus /
- dapagliflozin /
- cystatin C /
- liver fat content
-
表 1 不同药物治疗组间临床特征比较(x ±s)
分组 n 年龄/岁 女 男 BMI/(kg/m2) 患病时间/年 SBP/mmHg DBP/mmHg 甲组 51 56.37±9.25 22 29 25.86±3.76 6.83±6.06 138.02±17.19 85.18±12.91 乙组 70 56.24±8.61 34 36 25.20±3.20 8.29±6.45 138.94±16.56 83.87±9.80 t — 0.08 0.35* 0.24 1.26 0.30 0.63 P — >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 分组 n FBG/(mmol/L) HbA1c/% 总胆红素/(μmol/L) AST/(U/L) ALT/(U/L) TG/(mmol/L) 甲组 51 7.24±1.89 7.30 (6.70, 8.90) 16.54±6.38 18.00 (16.00, 20.00) 22.00±14.45 1.52 (1.09, 1.95) 乙组 70 7.96±1.88 7.80 (7.20, 8.70) 15.89±6.06 19.00 (14.75, 21.25) 25.66±21.05 1.74 (1.34, 2.43) t — 0.31 1.35# 0.57 0.26# 1.07 2.19# P — >0.05 >0.05 >0.05 >0.05 >0.05 <0.05 分组 n TC/(mmol/L) HDL-C/(mmol/L) LDL-C/(mmol/L) VLDL-C/(mmol/L) Cr/(μmol/L) LFC/% Cys C/(mg/ L) 甲组 51 4.50±1.01 1.13±0.30 2.79±0.81 0.30 (0.22, 0.39) 65.31±14.24 19.71 (13.75, 31.30) 1.02±0.17 乙组 70 4.10±1.07 1.04±0.26 2.66±0.90 0.35 (0.27, 0.49) 60.80±15.03 3.10 (1.98, 18.97) 0.72±0.22 t — 2.05 1.87 0.83 2.16# 1.67 5.39# 8.18 P — <0.05 >0.05 >0.05 <0.05 >0.05 <0.01 <0.01 *示χ2值;#示Z值 表 2 LFC与一般人口学和临床特征的相关分析
LFC LFC LFC 参数 r 参数 r 参数 r 年龄 0.067 HbA1c -0.082 HDL-C 0.106 BMI -0.245** TBIL -0.051 LDL-C -0.010 Duration 0.022 AST 0.025 VLDL-C -0.150 SBP -0.139 ALT -0.087 Cr -0.079 DBP -0.058 TG -0.152 Cys C 0.247** FBG -0.215* TC 0.089 *示P<0.05,**示P<0.01 表 3 多元线性回归分析LFC预测因素
自变量 B 95%CI P VIF Constant — — < 0.01 — BMI -0.027 -0.822~0.598 >0.05 1.078 FBG -0.124 -2.240~0.380 >0.05 1.080 TC 0.073 -1.426~3.433 >0.05 1.169 TG 0.055 -1.294~2.421 >0.05 1.160 Cys C -0.138 -6.218~4.403 >0.05 1.624 患病时间 0.075 -0.216~0.558 >0.05 1.030 药物治疗 -0.440 -2.167~6.332 < 0.01 1.758 表 4 多元线性回归分析Cystatin C预测因素
自变量 B 95%CI P VIF Constant — — < 0.01 — BMI 0.059 -0.006~0.015 >0.05 1.095 FBG 0.093 -0.008~0.032 >0.05 1.158 LFC -0.111 -0.005~0.001 >0.05 1.231 TC 0.103 -0.012~0.059 >0.05 1.157 TG 0.087 -0.012~0.042 >0.05 1.151 患病时间 0.056 -0.004~0.008 >0.05 1.031 药物治疗 -0.689 -1.424~0.258 < 0.01 1.367 -
[1] BRIL F, BARB D, PORTILLO-SANCHEZ P, et al. Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease[J]. Hepatology, 2017, 65(4): 1132. doi: 10.1002/hep.28985 [2] ELSAYED MS, EL BADAWY A, AHMED A, et al. Serum cystatin C as an indicator for early detection of diabetic nephropathy in type 2 diabetes mellitus[J]. Diabetes Metab Syndr, 2019, 13(1): 374. doi: 10.1016/j.dsx.2018.08.017 [3] QAMAR A, HAYAT A, AHMAD TM, et al. Serum cystatin C as an early diagnostic biomarker of diabetic kidney disease in type 2 diabetic patients[J]. J Coll Physicians Surg Pak, 2018, 28(4): 288. [4] 汪运生, 戴武, 张继, 等. 氢质子磁共振波谱法定量肝脏脂肪含量与不同糖耐量人群中胱抑素C的关系[J]. 安徽医科大学学报, 2020, 55(1): 128. [5] 中华医学会内分泌学分会, 中华医学会糖尿病学分会. 中国成人2型糖尿病合并非酒精性脂肪性肝病管理专家共识[J]. 中华内分泌代谢杂志, 2021, 37(7): 589. [6] LV S, JIANG S, LIU S, et al. Noninvasive quantitative detection methods of liver fat content in nonalcoholic fatty liver disease[J]. J Clin Transl Hepatol, 2018, 6(2): 217. doi: 10.14218/JCTH.2018.00021 [7] 中华医学会内分泌学分会. 非酒精性脂肪性肝病与相关代谢紊乱诊疗共识(第二版)[J]. 中华内分泌代谢杂志, 2018, 34(7): 549. [8] SZCZEPANIAK LS, NURENBERG P, LEONARD D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population[J]. Am J Physiol Endocrinol Metab, 2005, 288(2): E462. doi: 10.1152/ajpendo.00064.2004 [9] AL MUSAIMI O, ABU-NAWWAS AH, AL SHAER D, et al. Influence of age, gender, smoking, diabetes, thyroid and cardiac dysfunctions on cystatin C biomarker[J]. Semergen, 2019, 45(1): 44. doi: 10.1016/j.semerg.2018.07.005 [10] 王雅琴, 曹霞, 杨娉婷, 等. 体检人群代谢综合征与血清胱抑素C水平的相关性[J]. 中南大学学报(医学版), 2015, 40(7): 742. [11] JI X, YAO L, WANG M, et al. Cystatin C attenuates insulin signaling transduction by promoting endoplasmic reticulum stress in hepatocytes[J]. FEBS Lett, 2015, 589(24 Pt B): 3938. [12] DONGIOVANNI P, STENDER S, PIETRELLI A, et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver[J]. J Intern Med, 2018, 283(4): 356. doi: 10.1111/joim.12719 [13] MANTOVANI A, BYRNE CD, BONORA E, et al. Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis[J]. Diabetes Care, 2018, 41(2): 372. doi: 10.2337/dc17-1902 [14] WATT MJ, MIOTTO PM, DE NARDO W, et al. The liver as an endocrine organ-linking NAFLD and insulin resistance[J]. Endocr Rev, 2019, 40(5): 1367. doi: 10.1210/er.2019-00034 [15] TAHARA A, KUROSAKI E, YOKONO M, et al. Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice[J]. Eur J Pharmacol, 2013, 715(1/3): 246. [16] TAHARA A, TAKASU T. Therapeutic effects of SGLT2 inhibitor ipragliflozin and metformin on NASH in type 2 diabetic mice[J]. Endocr Res, 2020, 45(2): 147. doi: 10.1080/07435800.2020.1713802 [17] KUCHAY MS, KRISHAN S, MISHRA SK, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial(E-LIFT Trial)[J]. Diabetes Care, 2018, 41(8): 1801. doi: 10.2337/dc18-0165 [18] KAHL S, GANCHEVA S, STRASSBURGER K, et al. Empagliflozin effectively lowers liver fat content in well-controlled type 2 diabetes: a randomized, double-blind, Phase 4, placebo-controlled trial[J]. Diabetes Care, 2020, 43(2): 298. doi: 10.2337/dc19-0641 [19] PHRUEKSOTSAI S, PINYOPORNPANISH K, EUATHRONGCHIT J, et al. The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non-alcoholic fatty liver disease[J]. J Gastroenterol Hepatol, 2021, 36(10): 2952. doi: 10.1111/jgh.15580 [20] ARASE Y, SHIRAISHI K, ANZAI K, et al. Effect of sodium glucose co-transporter 2 inhibitors on liver fat mass and body composition in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus[J]. Clin Drug Investig, 2019, 39(7): 631. doi: 10.1007/s40261-019-00785-6