慢性肝病合并2型糖尿病的rs2943650位点变异及胰岛素抵抗之间的关系
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摘要
目的探讨肝病合并糖尿病患者中胰岛素抵抗的特点,并寻找导致胰岛素抵抗的可能途径。方法选取2017年9月-2018年3月北京佑安医院收治的肝病合并2型糖尿病患者67例,分析在慢性肝炎及肝硬化阶段胰岛B细胞分泌功能和胰岛素抵抗情况,并检测rs2943650位点是否变异,分析该位点变异与不同程度肝损伤的胰岛素抵抗的关系。计量资料组间比较采用t检验或Kruskal Wallis H秩和检验,计数资料组间比较采用χ~2检验。结果慢性肝炎合并2型糖尿病患者胰岛B细胞的分泌功能与肝硬化合并2型糖尿病患者比较差异无统计学意义(52. 72±34. 56 vs 52. 35±36. 59,t=0. 24,P=0. 99),胰岛素抵抗指数在二者间差异具有统计学意义(1. 33±0. 62 vs 2. 08±1. 79,t=2. 27,P=0. 02)。rs2943650位点变异组胰岛素抵抗与未变异组比较差异有统计学意义(t=2. 11,P=0. 04); rs2943650变异和未变异在肝脏疾病的不同阶段存在明显差异(χ~2=6. 73,P=0. 01),rs2943650位点变异在肝硬化患者中更多见。结论慢性肝病合并糖尿病患者中,随着肝损伤的加重,胰岛B细胞功能下降不明显,而胰岛素抵抗明显增加,rs2943650位点变异与胰岛素抵抗明显相关,其变异加重导致胰岛素抵抗,并且随着肝损伤加重而明显增加,可能是肝病合并糖尿病导致胰岛素抵抗的重要途径。
Objective To investigate the features of insulin resistance in patients with liver disease and diabetes and possible pathways leading to insulin resistance. Methods A total of 67 patients with liver disease and type 2 diabetes who were admitted to Beijing You'an Hospital from September 2017 to March 2018 were enrolled. The insulin secretory function of pancreas islet B cells and insulin resistance in the stages of chronic hepatitis and liver cirrhosis were analyzed. The presence or absence rs2943650 mutation was detected,and the association between rs2943650 mutation and insulin resistance in different degrees of liver injury was analyzed. The t-test or the rank sum test was used for comparison of continuous data between groups,and the chi-square test was used for comparison of categorical data between groups. Results There was no significant difference in the secretory function of pancreas islet B cells between the patients with chronic hepatitis and type 2 diabetes and those with liver cirrhosis and type 2 diabetes( 52. 72 ± 34. 56 vs 52. 35 ± 36. 59,t = 0. 24,P = 0. 99),while there was a significant difference in insulin resistance index( 1. 33 ± 0. 62 vs 2. 08 ± 1. 79,t = 2. 27,P = 0. 02). There was a significant difference in insulin resistance between the patients with rs2943650 mutation and those without such mutation( t = 2. 11,P = 0. 04). There was a significant difference in the presence or absence of rs2943650 mutation between different stages of liver disease( χ~2= 6. 73,P = 0. 01),and rs2943650 mutation was more common in patients with liver cirrhosis. Conclusion In patients with chronic liver disease and diabetes,there is no significant reduction in the function of pancreas islet B cells with the increase in the degree of liver injury,while there is a significant increase in insulin resistance. The rs2943650 mutation is significantly associated with insulin resistance and increases significantly with the aggravation of liver injury,and therefore,it may be an important pathway for insulin resistance induced by liver disease and diabetes.
Objective To investigate the features of insulin resistance in patients with liver disease and diabetes and possible pathways leading to insulin resistance. Methods A total of 67 patients with liver disease and type 2 diabetes who were admitted to Beijing You'an Hospital from September 2017 to March 2018 were enrolled. The insulin secretory function of pancreas islet B cells and insulin resistance in the stages of chronic hepatitis and liver cirrhosis were analyzed. The presence or absence rs2943650 mutation was detected,and the association between rs2943650 mutation and insulin resistance in different degrees of liver injury was analyzed. The t-test or the rank sum test was used for comparison of continuous data between groups,and the chi-square test was used for comparison of categorical data between groups. Results There was no significant difference in the secretory function of pancreas islet B cells between the patients with chronic hepatitis and type 2 diabetes and those with liver cirrhosis and type 2 diabetes( 52. 72 ± 34. 56 vs 52. 35 ± 36. 59,t = 0. 24,P = 0. 99),while there was a significant difference in insulin resistance index( 1. 33 ± 0. 62 vs 2. 08 ± 1. 79,t = 2. 27,P = 0. 02). There was a significant difference in insulin resistance between the patients with rs2943650 mutation and those without such mutation( t = 2. 11,P = 0. 04). There was a significant difference in the presence or absence of rs2943650 mutation between different stages of liver disease( χ~2= 6. 73,P = 0. 01),and rs2943650 mutation was more common in patients with liver cirrhosis. Conclusion In patients with chronic liver disease and diabetes,there is no significant reduction in the function of pancreas islet B cells with the increase in the degree of liver injury,while there is a significant increase in insulin resistance. The rs2943650 mutation is significantly associated with insulin resistance and increases significantly with the aggravation of liver injury,and therefore,it may be an important pathway for insulin resistance induced by liver disease and diabetes.
引文
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[2] SHANIK MH,XU Y,SKRHA J,et al. Insulin resistance and hyperinsulinemia:Is hyperinsulinemia the cart or the horse?[J]. Diabetes Care,2008,31(Suppl 2):s262-s268.
[3] KILPELINEN TO,ZILLIKENS MC,STANCKOVA,et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile[J]. Nat Genet,2011,43(8):753-760.
[4] Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B:A 2015 update[J]. J Clin Hepatol,2015,33(12):1941-1960.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
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[6] Drug-induced Liver Disease Study Group,Chinese Society of Hepatology,Chinese Medical Association. Guidelines for the management of drug-induced liver injury[J]. J Clin Hepatol,2015,31(11):1752-1769.(in Chinese)中华医学会肝病学分会药物性肝病学组.药物性肝损伤诊治指南[J].临床肝胆病杂志,2015,31(11):1752-1769.
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[8] ZHANG JQ. HOMA2-IR is a good basal insulin resistance index[J]. Chin J Endocrinol Metal,2005,21(4):304-305.(in Chinese)张家庆. HOMA2-IR是个较好的胰岛素抵抗指数[J].中华内分泌代谢杂志,2005,21(4):304-305.
[9] DOU AH,ZHENG JF,LIU H,et al. The study on incidence of primary hepatic carcinoma of liver cirrhosis patients with type 2 diabetes mellitus[J]. Beijing Med J,2013,35(6):412-415.(in Chinese)窦爱华,郑俊福,刘辉,等.肝硬化合并2型糖尿病发生原发性肝癌的风险研究[J].北京医学,2013,35(6):412-415.
[10] YOU YL,DENG MH,GONG JP. The association between type 2diabetes mellitus and hepatocellular carcinoma[J]. J Clin Hepatol,34(8):1793-1796.(in Chinese)游宇来,邓明华,龚建平. 2型糖尿病与肝细胞癌的关系[J].临床肝胆病杂志,2018,34(8):1793-1796.
[11] HICKMAN IJ,MACDONALD GA. Impact of diabetes on the severity of liver disease[J]. Am J Med,2007,120(10):829-834.
[12] YANG S,JIANG XD. Clinical effect of linagliptin combined with insulin aspart 50 in treatment of hepatogenous diabetes[J]. J Clin Hepatol,33(5):928-931.(in Chinese)杨硕,姜晓迪.利格列汀联合门冬胰岛素50治疗肝源性糖尿病的效果观察[J].临床肝胆病杂志,2017,33(5):928-931.
[13] MATTHEWSDR,HOSKERJP,RUDENSKIAS,et al. Homeostasis model assessment:Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man[J]. Diabetologia,1985,28(7):412-419.
[14] LOOS RJ,LINDGREN CM,LI S,et al. Common variants near MC4R are associated with fat mass,weight and risk of obesity[J]. Nat Genet,2008,40(6):768-775.
[15] RUNG J,CAUCHI S,ALBRECHTSEN A,et al. Genetic variant near IRS1 is associated with type 2 diabetes,insulin resistance and hyperinsulinemia[J]. Nat Genet,2009,41(10):1110-1115.
[16] SAMANI NJ,ERDMANN J,HALL AS,et al. Genomewide association analysis of coronary artery disease[J]. N Engl J Med,2007,357(5):443-453.
[17] YANG L,PENG ZS,CAO YA,et al. Effect of glucose control on oxidative stress in patients with refractory diabetes[J]. Clin J Med Offic,2018,46(1):100-101.(in Chinese)杨璐,彭朝胜,曹悦鞍,等.血糖控制对难治性糖尿病患者氧化应激影响研究[J].临床军医杂志,2018,46(1):100-101.
[18] ROHDE K,KLS M,HOPP L,et al. IRS1 DNA promoter methylation and expression in human adipose tissue are related to fat distribution and metabolic traits[J]. Sci Rep,2017,7(1):12369.
[19] LINDGREN CM,HEID IM,RANDALL JC,et al. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution[J]. PLo S Genet, 2009, 5(6):e1000508.
[20] van VLIET-OSTAPTCHOUK JV,SNIEDER H,LAGOU V.Gene-lifestyle interactions in obesity[J]. Curr Nutr Rep,2012,1:184-196.
[2] SHANIK MH,XU Y,SKRHA J,et al. Insulin resistance and hyperinsulinemia:Is hyperinsulinemia the cart or the horse?[J]. Diabetes Care,2008,31(Suppl 2):s262-s268.
[3] KILPELINEN TO,ZILLIKENS MC,STANCKOVA,et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile[J]. Nat Genet,2011,43(8):753-760.
[4] Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B:A 2015 update[J]. J Clin Hepatol,2015,33(12):1941-1960.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
[5] Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association. The guideline of prevention and treatment for hepatitis C:A 2015 update[J]. J Clin Hepatol,2015,31(12):1961-1979.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.丙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1961-1979.
[6] Drug-induced Liver Disease Study Group,Chinese Society of Hepatology,Chinese Medical Association. Guidelines for the management of drug-induced liver injury[J]. J Clin Hepatol,2015,31(11):1752-1769.(in Chinese)中华医学会肝病学分会药物性肝病学组.药物性肝损伤诊治指南[J].临床肝胆病杂志,2015,31(11):1752-1769.
[7] Chinese Diabetes Society,Chinese Medical Association. Guidelines for the prevention and control of type 2 diabetes in China(2017 Edition)[J]. Chin J Pract Intern Med,2018,38(4):292-344.(in Chinese)中华医学会糖尿病学分会.中国2型糖尿病防治指南[J].中国实用内科杂志,2018,38(4):292-344.
[8] ZHANG JQ. HOMA2-IR is a good basal insulin resistance index[J]. Chin J Endocrinol Metal,2005,21(4):304-305.(in Chinese)张家庆. HOMA2-IR是个较好的胰岛素抵抗指数[J].中华内分泌代谢杂志,2005,21(4):304-305.
[9] DOU AH,ZHENG JF,LIU H,et al. The study on incidence of primary hepatic carcinoma of liver cirrhosis patients with type 2 diabetes mellitus[J]. Beijing Med J,2013,35(6):412-415.(in Chinese)窦爱华,郑俊福,刘辉,等.肝硬化合并2型糖尿病发生原发性肝癌的风险研究[J].北京医学,2013,35(6):412-415.
[10] YOU YL,DENG MH,GONG JP. The association between type 2diabetes mellitus and hepatocellular carcinoma[J]. J Clin Hepatol,34(8):1793-1796.(in Chinese)游宇来,邓明华,龚建平. 2型糖尿病与肝细胞癌的关系[J].临床肝胆病杂志,2018,34(8):1793-1796.
[11] HICKMAN IJ,MACDONALD GA. Impact of diabetes on the severity of liver disease[J]. Am J Med,2007,120(10):829-834.
[12] YANG S,JIANG XD. Clinical effect of linagliptin combined with insulin aspart 50 in treatment of hepatogenous diabetes[J]. J Clin Hepatol,33(5):928-931.(in Chinese)杨硕,姜晓迪.利格列汀联合门冬胰岛素50治疗肝源性糖尿病的效果观察[J].临床肝胆病杂志,2017,33(5):928-931.
[13] MATTHEWSDR,HOSKERJP,RUDENSKIAS,et al. Homeostasis model assessment:Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man[J]. Diabetologia,1985,28(7):412-419.
[14] LOOS RJ,LINDGREN CM,LI S,et al. Common variants near MC4R are associated with fat mass,weight and risk of obesity[J]. Nat Genet,2008,40(6):768-775.
[15] RUNG J,CAUCHI S,ALBRECHTSEN A,et al. Genetic variant near IRS1 is associated with type 2 diabetes,insulin resistance and hyperinsulinemia[J]. Nat Genet,2009,41(10):1110-1115.
[16] SAMANI NJ,ERDMANN J,HALL AS,et al. Genomewide association analysis of coronary artery disease[J]. N Engl J Med,2007,357(5):443-453.
[17] YANG L,PENG ZS,CAO YA,et al. Effect of glucose control on oxidative stress in patients with refractory diabetes[J]. Clin J Med Offic,2018,46(1):100-101.(in Chinese)杨璐,彭朝胜,曹悦鞍,等.血糖控制对难治性糖尿病患者氧化应激影响研究[J].临床军医杂志,2018,46(1):100-101.
[18] ROHDE K,KLS M,HOPP L,et al. IRS1 DNA promoter methylation and expression in human adipose tissue are related to fat distribution and metabolic traits[J]. Sci Rep,2017,7(1):12369.
[19] LINDGREN CM,HEID IM,RANDALL JC,et al. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution[J]. PLo S Genet, 2009, 5(6):e1000508.
[20] van VLIET-OSTAPTCHOUK JV,SNIEDER H,LAGOU V.Gene-lifestyle interactions in obesity[J]. Curr Nutr Rep,2012,1:184-196.