Clinical Study of Gegen Qinlian Decoction in Type 2 Diabetes with Non-alcoholic Fatty Liver Disease

doi:10.12114/j.issn.1007-9572.2021.02.058

Abstract

Abstract: Background　Recent years have seen considerable growth in the prevalence of type 2 diabetes mellitus （T2DM） combined with non-alcoholic fatty liver disease （NAFLD），but there is still a lack of effective targeted interventions. Traditional Chinese medicine（TCM） may have some merits in treating T2DM with NAFLD，but few studies have investigated the effects and mechanism of actions of TCM in treating the disease. Objective　To investigate the clinical efficacy of adding Gegen Qinlian Decoction（GD） to care as usual to treat T2DM with NAFLD. Methods　One hundred patients with T2DM with NAFLD who were treated in the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine，Nanjing University of Chinese Medicine from January 2020 to March 2021 were selected. They were randomly allocated to either the control group（n=51） or the observation group （n=49）. The control group received usual care. The observation groupreceived usual care plus GD. The therapeutic course for all was 8 weeks. Data about the pre- and post-treatment TCM symptom score，glycemic indices〔fasting plasma glucose （FPG），two-hour postprandial glucose（2 hPG）〕，glycated hemoglobin（HbA1c），blood lipid indices〔triglyceride （TG），total cholesterol （TC），low-density lipoprotein cholesterol（LDL-C）〕，homeostatic model assessment for insulin resistance （HOMA-IR），liver function indices（ALT，AST，GGT），lymphocyte subsets，and NAFLD fibrosis score measured by color Doppler ultrasonography of two groups were obtained. Results　All patients were included for final analysis except for 10 dropouts（four cases and six controls）. After treatment，the TCM symptom score decreased more significantly in the observation group（P<0.05）. But HbA1c and TC were still similar in both groups after treatment（P>0.05）. The FPG，2 hPG，TG，LDL-C and HOMA-IR decreased more significantly in the observation group after treatment（P<0.05）. Similarly，ALT，AST and GGT were lowered more significantly in the observation group after treatment（P<0.05）. In terms of post-treatment levels of lymphocyte subsets，CD4+ T cell，CD4+/CD8+ ratio and NK cell were elevated while CD8+ T cell was lowered more significantly in the observation group（P<0.05）. The post-treatment NAFLD fibrosis score was also much lower in the observation group（P<0.05）. Conclusion　Patients with T2DM and NAFLD could be treated with GD to improve glycolipid metabolism，insulin resistance，and immune function more effectively.

Key words: Diabetes mellitus, type 2, Non-alcoholic fatty liver disease, Gegen Qinlian Decoction, Immune function, Glycolipid metabolism, Treatment outcome

摘要： 背景　近年来，2型糖尿病（T2DM）合并非酒精性脂肪性肝病（NAFLD）的患病率大幅升高，但目前针对T2DM合并NAFLD尚缺乏有效干预措施。中医药治疗本病具有一定优势，但相关研究及作用机制尚缺乏。目的　探讨葛根芩连汤治疗T2DM合并NAFLD患者的临床疗效。方法　选取2020年1月至2021年3月就诊于南京中医药大学附属中西医结合医院的T2DM合并NAFLD患者100例，采用随机数字表法将其分为观察组（n=49）和对照组（n=51）。对照组给予常规治疗，观察组在对照组治疗基础上加用葛根芩连汤，两组疗程均为8周。分别比较两组治疗前后中医证候积分、血糖〔空腹血糖（FPG）、餐后2 h血糖（2 hPG）〕、糖化血红蛋白（HbA1c）、血脂〔三酰甘油（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）〕、稳态模型评估胰岛素抵抗指数（HOMA-IR）、肝功能〔丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、谷氨酰转肽酶（GGT）〕、淋巴细胞亚群变化及肝脏彩色超声评分。结果　观察组脱落4例，共纳入45例；对照组脱落6例，共纳入45例。治疗后，观察组中医证候积分低于对照组（P<0.05）。治疗后，两组患者HbA1c、TC水平比较，差异均无统计学意义（P>0.05）。治疗后，观察组FPG、2 hPG、TG、LDL-C、HOMA-IR低于对照组（P<0.05）。治疗后，观察组ALT、AST、GGT水平低于对照组（P<0.05）。治疗后，观察组CD4+ T淋巴细胞、CD4+/CD8+、自然杀伤细胞（NK细胞）水平高于对照组，CD8+ T淋巴细胞水平低于对照组（P<0.05）。治疗后，观察组肝脏超声评分低于对照组（P<0.05）。结论　葛根芩连汤可以有效改善T2DM合并NAFLD患者的糖脂代谢，减轻胰岛素抵抗，改善机体免疫功能。

关键词: 糖尿病，2型, 非酒精性脂肪性肝病, 葛根芩连汤, 免疫功能, 糖脂代谢, 治疗结果

FAN Yaofu，CAO Lin，SUN Hongping，XU Juan，BAO Weiping，CHU Xiaoqiu. Clinical Study of Gegen Qinlian Decoction in Type 2 Diabetes with Non-alcoholic Fatty Liver Disease　[J]. Chinese General Practice, 2021, 24(36): 4587-4592.

范尧夫,曹琳,孙洪平等. 葛根芩连汤治疗2型糖尿病合并非酒精性脂肪性肝病效果的临床研究[J]. 中国全科医学, 2021, 24(36): 4587-4592. DOI: 10.12114/j.issn.1007-9572.2021.02.058.

Figures/Tables 6

References 28

[1]	LI J, ZOU B, YEO Y H，et al. Prevalence，incidence，and outcome of non-alcoholic fatty liver disease in Asia，1999—2019：a systematic review and meta-analysis[J]. Lancet Gastroenterol Hepatol，2019，4(5):389-398.DOI：10.1016/s2468-1253(19)30039-1.
[2]	RINELLA M E.Nonalcoholic fatty liver disease：a systematic review[J]. JAMA，2015，313(22):2263-2273.DOI：10.1001/jama.2015.5370.
[3]	KIM H, LEE D S, AN T H，et al. Metabolic spectrum of liver failure in type 2 diabetes and obesity：from NAFLD to NASH to HCC[J]. Int J Mol Sci，2021，22(9):4495.DOI：10.3390/ijms22094495.
[4]	HAZLEHURST J M, WOODS C, MARJOT T，et al. Non-alcoholic fatty liver disease and diabetes[J]. Metabolism，2016，65(8):1096-1108.DOI：10.1016/j.metabol.2016.01.001.
[5]	LIM S, KIM J W, TARGHER G.Links between metabolic syndrome and metabolic dysfunction-associated fatty liver disease[J]. Trends Endocrinol Metab，2021，32(7):500-514.DOI：10.1016/j.tem.2021.04.008.
[6]	BRIL F, CUSI K.Management of nonalcoholic fatty liver disease in patients with type 2 diabetes：a call to action[J]. Diabetes Care，2017，40(3):419-430.DOI：10.2337/dc16-1787.
[7]	LEE C H, LUI D T W, LAM K S L.Adipocyte fatty acid-binding protein，cardiovascular diseases and mortality[J]. Front Immunol，2021，12:589206.DOI：10.3389/fimmu.2021.589206.
[8]	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）[J]. 中国实用内科杂志，2018，38(4):292-344.DOI：10.19538/j.nk2018040108.
[9]	隋淼，蒋小飞，范尧夫，等. 葛根芩连汤含药血清通过miR-146b/SIRT1信号通路改善HepG2细胞胰岛素抵抗的研究[J]. 中药材，2019，42(3):630-635.DOI：10.13863/j.issn1001-4454.2019.03.034.
[10]	SUI M, CHEN G F, MAO X D，et al. Gegen Qinlian decoction ameliorates hepatic insulin resistance by silent information Regulator1 （SIRT1）-dependent deacetylation of forkhead box O1 （FOXO1）[J]. Med Sci Monit，2019，25:8544-8553.DOI：10.12659/MSM.919498.
[11]	DAVIS T M E.Diabetes and metabolic dysfunction-associated fatty liver disease[J]. Metabolism，2021，123:154868.DOI：10.1016/j.metabol.2021.154868.
[12]	KHNEIZER G, RIZVI S, GAWRIEH S.Non-alcoholic fatty liver disease and diabetes mellitus[J]. Adv Exp Med Biol，2021，1307:417-440.DOI：10.1007/5584_2020_532
[13]	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）[J]. 临床肝胆病杂志，2018，34(5):947-957.
[14]	李先进，王瑾茜，刘侃.体针配合葛根芩连汤治疗肥胖型糖尿病湿热困脾证的临床观察[J]. 辽宁中医杂志，2016，43(7):1475-1478.DOI：10.13192/j.issn.1000-1719.2016.07.044.
[15]	International Diabetes Federation.IDF Diabetes Atlas，8th ed[EB/OL]. [2021-03-20]. .
[16]	王雨涵，高影.非酒精性脂肪性肝病并发2型糖尿病诊断和治疗的研究进展[J]. 吉林大学学报：医学版，2020，46(6):1324-1331.DOI：10.13481/j.1671-587x.20200634.
[17]	YAMAZAKI H, TSUBOYA T, TSUJI K，et al. Independent association between improvement of nonalcoholic fatty liver disease and reduced incidence of type 2 diabetes[J]. Diabetes Care，2015，38(9):1673-1679.DOI：10.2337/dc15-0140.
[18]	吴勇，吴应林，李瑞麟.褪黑素对2型糖尿病患者细胞免疫功能和感染的影响[J]. 安徽医学，2019，40(11):1212-1215.
[19]	MA C, KESARWALA A H, EGGERT T，et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis[J]. Nature，2016，531(7593):253-257.DOI：10.1038/nature16969.
[20]	FERNÁNDEZ-DELGADO I, CALZADA-FRAILE D, SÁNCHEZ-MADRID F.Immune regulation by dendritic cell extracellular vesicles in cancer immunotherapy and vaccines[J]. Cancers，2020，12(12):3558.DOI：10.3390/cancers12123558.
[21]	AKHTAR M, NIZAM N N, BASHER S R，et al. dmLT adjuvant enhances cytokine responses to T cell stimuli，whole cell vaccine antigens and lipopolysaccharide in both adults and infants[J]. Front Immunol，2021，12:654872.DOI：10.3389/fimmu.2021.654872.
[22]	TANG T, SUI Y, LIAN M，et al. Pro-inflammatory activated Kupffer cells by lipids induce hepatic NKT cells deficiency through activation-induced cell death[J]. PLoS One，2013，8(12):e81949.DOI：10.1371/journal.pone.0081949.
[23]	李勤，倪青，石白，等. 2型糖尿病合并非酒精性脂肪性肝病中医药研究进展[J]. 中国中医药信息杂志，2019，26(8):141-144.
[24]	韩智慧，王亚玲，王淑美，等. 基于1H NMR代谢组学方法研究葛根芩连汤对IR大鼠模型血浆代谢组的影响[J]. 广东药学院学报，2015，31(6):786-790.
[25]	LI Y C, WANG B Y, SHEN J D，et al. Berberine attenuates fructose-induced insulin resistance by stimulating the hepatic LKB1/AMPK/PGC1α pathway in mice[J]. Pharm Biol，2020，58(1):385-392.DOI：10.1080/13880209.2020.1756349.
[26]	SONG M Y, WANG J H, EOM T，et al. Schisandra chinensis fruit modulates the gut microbiota composition in association with metabolic markers in obese women：a randomized，double-blind placebo-controlled study[J]. Nutr Res，2015，35(8):655-663.DOI：10.1016/j.nutres.2015.05.001.
[27]	LAN X F, OLALEYE O E, LU J L，et al. Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots （Gancao） after dosing Lianhua Qingwen capsule[J]. Acta Pharmacol Sin，2021.DOI：10.1038/s41401-021-00651-2.
[28]	YANG Y M, SEO S Y, KIM T H，et al. Decrease of microRNA-122 causes hepatic insulin resistance by inducing protein tyrosine phosphatase 1B，which is reversed by licorice flavonoid[J]. Hepatology，2012，56(6):2209-2220.DOI：10.1002/hep.25912.

组别	例数	性别（男/女）	年龄（岁）	病程（年）	体质量（kg/m²）	高血压〔n（%）〕
对照组	45	30/15	38.0±7.8	3.54±1.36	27.9±3.6	8（17.8）
观察组	45	28/17	37.4±8.1	3.37±1.40	28.2±3.7	6（13.3）
t（χ²）值		0.194^a	0.380	0.584	-0.348	0.338^a
P值		0.660	0.705	0.561	0.728	0.561

组别	例数	性别（男/女）	年龄（岁）	病程（年）	体质量（kg/m²）	高血压〔n（%）〕
对照组	45	30/15	38.0±7.8	3.54±1.36	27.9±3.6	8（17.8）
观察组	45	28/17	37.4±8.1	3.37±1.40	28.2±3.7	6（13.3）
t（χ²）值		0.194^a	0.380	0.584	-0.348	0.338^a
P值		0.660	0.705	0.561	0.728	0.561

组别	例数	治疗前	治疗后	t_配对值	P值
对照组	45	6.47±2.12	4.33±1.32	5.748	<0.001
观察组	45	6.69±2.25	3.07±1.09	9.713	<0.001
t值		0.477	4.937
P值		0.634	<0.001

组别	例数	治疗前	治疗后	t_配对值	P值
对照组	45	6.47±2.12	4.33±1.32	5.748	<0.001
观察组	45	6.69±2.25	3.07±1.09	9.713	<0.001
t值		0.477	4.937
P值		0.634	<0.001

组别	例数	FPG（mmol/L）				2 hPG（mmol/L）
组别	例数	治疗前	治疗后	t_配对值	P值	治疗前	治疗后	t_配对值	P值
对照组	45	7.3±1.3	5.9±1.3	5.294	<0.001	14.0±2.3	9.9±2.0	9.076	<0.001
观察组	45	7.4±1.3	5.3±1.2	8.191	<0.001	13.9±2.4	7.5±1.8	14.228	<0.001
t值		0.450	2.203			0.287	5.813
P值		0.654	0.030			0.775	<0.001