非诺贝特联合热量限制饮食治疗非酒精性脂肪性肝病合并2型糖尿病患者疗效研究

doi:10.3969/j.issn.1672-5069.2021.01.014

摘要/Abstract

摘要： 目的探讨应用非诺贝特联合热量限制饮食治疗非酒精性脂肪性肝病(NAFLD)合并2型糖尿病(T2DM)患者的疗效及患者血清人类软骨糖蛋白-39(HCGP39)、脂联素(APN)和非对称二甲基精氨酸(ADMA)水平的变化。方法将128例NAFLD合并T2DM患者随机分为对照组64例和观察组64例,分别采用热量限制饮食或在此基础上给予非诺贝特口服治疗、观察12周。采用免疫层析法检测血清糖化血红蛋白(HbA1c)水平,采用葡萄糖氧化酶法检测血清空腹血糖(FPG)和餐后2h血糖(2 h PPG)水平,采用磁微粒化学发光法检测血清空腹胰岛素(FINS)水平,并计算胰岛素抵抗(IR)指数。采用ELISA法检测血清HCGP39、APN和ADMA水平。结果在治疗结束时,观察组血清谷丙转氨酶(ALT)水平为(39.4±5.3)U/L,显著低于对照组【(46.8±7.9)U/L ,P<0.05】,血清谷草转氨酶(AST)水平为(46.3±4.4)U/L,显著低于对照组【(54.7±7.5)U/L,P<0.05】,血清谷氨酰转移酶(GGT)水平为(33.9±8.6)U/L,显著低于对照组【(43.7±14.6)U/L,P<0.05】;血清FBG水平为(5.9±1.9)mmol/L,显著低于对照组【(6.8±2.0)mmol/L,P<0.05】,血清2 h PPG水平为(7.4±2.2)mmol/L,显著低于对照组【(8.5±2.4)mmol/L,P<0.05】,IR水平为(4.1±0.4),显著低于对照组【(4.7±0.5),P<0.05】;血清总胆固醇(TC)水平为(1.5±0.2)mmol/L,显著低于对照组【(2.1±0.2)mmol/L,P<0.05】,血清三酰甘油(TG)水平为(4.0±0.7)mmol/L,显著低于对照组【(5.5±0.8)mmol/L,P<0.05】,血清低密度脂蛋白(LDL)水平为(2.1±0.5)mmol/L,显著低于对照组【(2.5±0.6)mmol/L,P<0.05】,而血清高密度脂蛋白(HDL)水平为(1.6±0.5)mmol/L,显著高于对照组【(1.4±0.3)mmol/L,P<0.05】;血清HCGP39水平为(61.4±7.5)ng/mL,显著低于对照组【(73.3±9.2)ng/mL,P<0.05】,血清ADMA水平为(1.8±0.3)μmol/mL,显著低于对照组【(2.2±0.5)μmol/mL,P<0.05】,而血清APN水平为(14.6±6.2)ng/mL,显著高于对照组【(11.3±4.9)ng/mL,P<0.05】。结论应用非诺贝特联合热量限制饮食可降低NAFLD合并T2DM患者血清HCGP39和ADMA水平,而提高血清APN水平,可能与改善了IR,进而改善了肝功能和糖脂代谢有关。

关键词: 非酒精性脂肪性肝病, 2型糖尿病, 非诺贝特, 热量限制饮食, 脂联素, 人类软骨糖蛋白-39, 非对称二甲基精氨酸

Abstract: Objective The aim of this study was to investigate the efficacy of fenofibrate at base of calorie restriction diet in treatment of patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) and serum human cartilage glycoprotein-39 (HCGP39), adiponectin (APN) and asymmetric dimethylarginine (ADMA) level changes. Methods 128 patients with NAFLD complicated by T2DM were randomly divided into control (n=64) and observation group (n=64), receiving calorie-restricted diet or oral fenofibrate at the basis of calorie-restricted diet, respectively for 12 weeks. Serum glycated hemoglobin (HbA1c) levels were detected by immunochromatography, serum fasting blood glucose (FPG) and postprandial 2 hour blood glucose (2 h PPG) level were detected by glucose oxidase method, serum fasting insulin (FINS) level was detected by microparticle chemiluminescence method, by which the insulin resistance (IR) index was calculated, and serum HCGP39, APN and ADMA levels were detected by ELISA. Results At the end of 12 week observation, serum alanine aminotransferase level in the observation group was (39.4±5.3) U/L, significantly lower than , serum aspartate aminotransferase level was (46.3±4.4) U/L, significantly lower than , and serum glutamyl transferase level was (40.7±14.6) U/L, significantly lower than in the control; serum FBG level was (5.9±1.9) mmol/L, significantly lower than , serum 2 h PPG level was (7.4±2.2) mmol/L, significantly lower than , and IR level was (4.1±0.4), significantly lower than that【(4.7±0.5), P<0.05】 in the control; serum total cholesterol level was (1.5±0.2) mmol/L, significantly lower than , serum triacylglycerol level was (4.0±0.7 ) mmol/L, significantly lower than , serum low-density lipoprotein level was (2.1±0.5) mmol/L, significantly lower than , while serum high density lipoprotein level was (1.6±0.5) mmol/L, significantly higher than in the control; serum HCGP39 level was (61.4±7.5) ng/mL, significantly lower than , serum ADMA level was (1.8±0.3) μmol/mL, significantly lower than [(2.2±0.5) μmol/mL, P<0.05】, while serum APN level was (14.6±6.2) ng/mL, significantly higher than in the control.Conclusion The administration of fenofibrate at base of calorie restriction diet in treating patients with NAFLD and T2DM could reduce serum HCGP39 and ADMA levels and elevate serum APN levels, which might reduce liver injury, improve insulin resistance, and thus improve liver function, and glucose and lipid metabolism.

Key words: Nonalcoholic fatty liver disease, Type 2 diabetes mellitus, Fenofibrate, Calorie restricted diet, Adiponectin, Human cartilage glycoprotein-39, Asymmetric dimethylarginine

梁小丽, 邝继孙, 刘秋莉, 符弟. 非诺贝特联合热量限制饮食治疗非酒精性脂肪性肝病合并2型糖尿病患者疗效研究[J]. 实用肝脏病杂志, 2021, 24(1): 51-54.

Liang Xiaoli,Kuang Jisun,Liu Qiuli,et al. Therapeutic efficacy of fenofibrate at base of calorie restriction diet in the treatment of patients with non-alcoholic fatty liver disease and type 2 diabetes[J]. Journal of Practical Hepatology, 2021, 24(1): 51-54.

参考文献

[1] Chen Y, Feng R, Yang X, et al. Yogurt improves insulin resistance and liver fat in obese women with nonalcoholic fatty liver disease and metabolic syndrome: a randomized controlled trial. Am J Clin Nutr, 2019, 109(6):1611-1619.
[2] Zhang QQ, Li Q, Dong L, et al. Genotoxicity and embryotoxicity study of bicyclol methyl ether, main impurity in bicyclol. Chin J Integr Med, 2019, 25(10):743-749.
[3] Qiu FF, Meng T, Chen Q, et al. Fenofibrate-loaded biodegradable nanoparticles for the treatment of experimental diabetic retinopathy and neovascular age-related macular degeneration. Mol Pharm, 2019, 16(5): 1958-1970.
[4] Yuan J, Tan JTM, Rajamani K, et al. Fenofibrate rescues diabetes-related impairment of ischemia-mediated angiogenesis by PPARα-independent modulation of thioredoxin-interacting protein. Diabetes, 2019, 68(5):1040-1053.
[5] 中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2017年版). 中华糖尿病杂志, 2018, 10(1):4-67.
[6] 中华医学会肝病学分会脂肪肝和酒精性肝病学组, 中国医师协会脂肪性肝病专家委员会. 非酒精性脂肪性肝病防治指南(2018年更新版). 实用肝脏病杂志, 2018, 21(2):177-186.
[7] Chen Y, Feng R, Yang X, et al. Yogurt improves insulin resistance and liver fat in obese women with nonalcoholic fatty liver disease and metabolic syndrome: a randomized controlled trial. Am J Clin Nutr, 2019, 109(6):1611-1619.
[8] 邵幼林, 范建高. 非酒精性脂肪性肝病的流行现状与危害. 中华肝脏病杂志, 2019, 27(1):10-13.
[9] Koh YX, Tan HJ, Liew YX, et al. Liver resection for nonalcoholic fatty liver disease-associated hepatocellular carcinoma. J Am Coll Surg, 2019, 229(5):467-478.
[10] 彭馨仪, 罗新华, 杨勤, 等. 异烟肼致药物性肝损伤大鼠肝脏葡萄糖调节蛋白78和生长停滞DNA损伤基因的表达及双环醇的干预作用. 中华肝脏病杂志, 2019, 27(2):133-139.
[11] Eddowes PJ, Sasso M, Allison M, et al. Accuracy of fibroscan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology, 2019, 156(6):1717-1730.
[12] Yang S, Hu JP, Li Y, et al. Evaluation of pharmacokinetic interactions between bicyclol and co-administered drugs in rat and human liver microsomes in vitro and in rats in vivo. Xenobiotica, 2019, 49(8):987-994.
[13] Wang H, Zhang H, Huang B, et al. Mesenchymal stem cells reverse highfat dietinduced nonalcoholic fatty liver disease through suppression of CD4⁺ T lymphocytes in mice. Mol Med Rep, 2018, 17(3):3769-3774.
[14] Gumede NM, Lembede BW, Nkomozepi P, et al. β-Sitosterol mitigates the development of high-fructose diet-induced nonalcoholic fatty liver disease in growing male Sprague-Dawley rats. Can J Physiol Pharmacol, 2020, 98(1):44-50.
[15] Yavarow ZA, Kang HR, Waskowicz LR, et al. Fenofibrate rapidly decreases hepatic lipid and glycogen storage in neonatal mice with glycogen storage disease type Ia. Hum Mol Genet, 2020, 29(2):286-294.
[16] Oscarsson J, nnerhag K, Risérus U, et al. Effects of free omega-3 carboxylic acids and fenofibrate on liver fat content in patients with hypertriglyceridemia and non-alcoholic fatty liver disease: a double-blind, randomized, placebo-controlled study. J Clin Lipidol, 2018, 12(6):1390-1403.
[17] Huang K, Du M, Tan X, et al. PARP1-mediated PPARα poly(ADP-ribosyl)ation suppresses fatty acid oxidation in non-alcoholic fatty liver disease. J Hepatol, 2017, 66(5):962-977.