DOI院10.16658/ki.1672-4062.2022.10.010新诊断2型糖尿病肥胖患者早期联合不同剂型GLP-1RA对胰岛茁细胞功能的影响赵晨袁陈婧袁韩敏娜袁谭畅袁周影哈尔滨市第一医院内分泌科袁黑龙江哈尔滨150010[摘要]目的观察新诊断2型糖尿病肥胖患者早期联合不同剂型胰高血糖素样肽-1受体激动剂渊GLP-1RA冤对血糖及胰岛茁细胞功能的影响遥方法选取2020年10月要2021年8月于该院住院治疗的60例新诊断2型糖尿病肥胖患者袁按照随机数表法随机分为利拉鲁肽组和洛塞那肽组袁各30例遥利拉鲁肽组应用胰岛素泵尧二甲双胍尧利拉鲁肽降糖治疗袁洛塞那肽组将利拉鲁肽替换为聚乙二醇洛塞那肽治疗遥12周后对比治疗前后空腹血糖渊FPG冤尧餐后2h血糖渊2hPG冤尧糖化血红蛋白渊HbA1c冤尧体质指数渊BMI冤尧胰岛素抵抗指数(HOMA-IR)尧胰岛素茁细胞功能指数渊HOMA-茁冤及两组临床疗效尧不良反应遥结果两组治疗后BMI尧FPG尧2hPG尧HbA1c尧HOMA-IR均较治疗前降低袁HOMA-茁升高袁差异有统计学意义(P约0.05)曰治疗后袁洛塞那肽组FPG尧较利拉鲁肽组降低袁BMI尧HOMA-茁较利拉鲁肽组升高袁差异有统计学意义(P约0.05)曰两组HbA1c尧2hPG尧HOMA-IR比较袁差异无统计学意义渊P跃0.05冤遥两组血糖达标率对比袁差异无统计学意义(字2=0.127袁P=0.730)遥两组治疗后均未出现严重的低血糖遥结论对于新诊断的2型糖尿病肥胖患者袁利拉鲁肽尧聚乙二醇洛塞那肽联合胰岛素短期强化治疗后袁均具有降糖尧减重尧改善胰岛茁细胞功能的作用曰聚乙二醇洛塞那肽在降低FPG尧改善胰岛茁细胞功能方面较利拉鲁肽更有优势袁但利拉鲁肽减重效果更强遥[关键词]利拉鲁肽曰聚乙二醇洛塞那肽曰胰岛茁功能曰GLP-1RA[中图分类号]R587.1[文献标识码]A[文章编号]1672-4062渊圆园22冤05渊b冤原园010-05 Effects of Early Combined with Different Dosage forms of GLP-1RA on Pancreatic茁-cell Function in Obese Patients with Newly Diagnosed Type2Diabetes MellitusZHAO Chen,CHEN Jing,HAN Minna,TAN Chang,ZHOU YingDepartment of Endocrinology,Harbin First Hospital,Harbin,Heilongjiang Province,150010China[Abstract]Objective To observe the effect of early combination of different dosage forms of glucagon-like peptide-1receptor agonist(GLP-1RA)on blood glucose and islet茁-cell function in obese patients with newly diagnosed type2diabetes.Methods60obese patients with newly diagnosed type2diabetes mellitus who were hospitalized in the hospital from October2020to August2021were randomly divided into liraglutide group and losentatide group according to the random number table,with30cases in each group.In the liraglutide group,insulin pump, metformin and liraglutide were used for hypoglycemic treatment,while in the losentapeptide group,liraglutide was replaced with polyethylene glycol losentapeptide,for treatment.After12weeks,fasting blood glucose(FPG),2h postprandial blood glucose(2hPG),glycosylated hemoglobin(HbA1c),body mass index(BMI),insulin resistance index(HOMA-IR)and insulin茁cell function index(HOMA-茁冤were compared before and after treatment,the clinical efficacy and adverse reactions of the two groups were compared.Results After treatment,BMI,FPG,2hPG, HbA1c and HOMA-IR of the two groups were lower than those before treatment,the difference was statistically significant(P约0.05);after treatment,the FPG of losetatide group were lower than those of liraglutide group,BMI尧[作者简介]赵晨渊1989-冤袁女袁硕士袁主治医师袁研究方向为糖尿病遥糖尿病是一组以慢性血糖升高为主要临床特征的代谢性疾病袁其发病率逐年增高遥目前中国成人糖尿病患病率已超过11.2豫袁约占全球总数的1/4[1]遥其中袁2型糖尿病是我国糖尿病患者最常见的分型遥目前研究显示袁2型糖尿病的发病机制不仅与胰岛素分泌缺陷相关袁同时还伴随着显著的胰岛素抵抗[2]遥胰岛素抵抗是2型糖尿病发生的始动因素袁而肥胖则是其发病的重要环境因素遥相比于正常人群袁葡萄糖及脂代谢异常的肥胖人群患2型糖尿病的风险更高遥对于伴有严重高血糖且初发糖尿病的人群袁宜采用胰岛素强化降糖治疗袁以利于缓解高糖毒性袁从而促进胰岛茁细胞的再分化[3]遥若上述人群同时伴有肥胖渊BMI逸24kg辕m2冤袁在应用大量外源胰岛素治疗的情况下袁极有可能会使胰岛素抵抗加重袁引起体质量增加等不良反应遥而胰高糖素样肽-1受体激动剂渊GLP-1RA冤在有效降糖的同时还具有减轻体质量尧改善胰岛素抵抗尧降压尧心血管等作用[4-5]遥该研究选取2020年10月要2021年8月于该院住院治疗的60例新诊断2型糖尿病肥胖患者袁在短期胰岛素强化治疗基础上加用了不同剂型的GLP-1RA袁用以观察早期联合不同剂型GLP-1RA对血糖及胰岛茁细胞功能的影响遥现报道如下遥1资料与方法1.1一般资料选取该院住院治疗的新诊断2型糖尿病肥胖患者60例袁根据随机数表法随机分为利拉鲁肽组和洛塞那肽组袁各30例袁均符合2型糖尿病诊断标准遥利拉鲁肽组中男18例尧女12例曰年龄25耀63岁袁平均渊52.62依8.26冤岁遥洛塞那肽组男14例尧女16例曰年龄30耀65岁袁平均渊54.27依7.83冤岁遥两组一般资料对比袁差异无统计学意义渊P跃0.05冤遥具有可比性遥纳入标准院BMI逸25kg/m2袁FPG逸11.1mmol/L和辕或HbA1c逸9.0豫曰未应用过药物降糖曰胰岛素自身抗体阴性遥排除标准院2型糖尿病合并急性并发症尧感染尧应激尧严重肝肾功能异常及心功能不全者曰既往有胰腺炎尧肿瘤病史者曰多发性内分泌肿瘤综合征2型者曰胃轻瘫或严重胃食管反流病者曰三酰甘油逸4.5mmol/L者遥该研究经医院伦理委员会审核批准袁患者均签署知情同意书遥1.2方法为所有受试者予以饮食指导袁每日活动量相对稳定袁接受糖尿病健康教育遥利拉鲁肽组佩带胰岛素泵渊门冬胰岛素袁国药准字J20150072袁规格院300IU/3 mL冤袁联合二甲双胍500mg三餐后口服袁并加用利拉鲁肽注射液渊国药准字J20160037袁规格院18mg/3 mL冤袁首周0.6mg袁1次/d皮下注射袁第二周无不良反应改为1.2mg袁1次/d皮下注射曰洛塞那肽组将利拉鲁肽替换为聚乙二醇洛塞那肽注射液渊国药准字H20190025袁规格院0.2mg/0.5mL冤0.2mg袁1次/周皮下注射遥胰岛素治疗2周后停用袁不另加胰岛素降糖袁其他治疗方案不变遥应用胰岛素期间依据血糖情况调整基础量及追加量袁圆耀源哉辕次曰空腹血糖目标值4.4mmol/L臆FPG臆6mmol/L袁餐后2h血糖目标值6mmol/L臆2hPG臆8mmol/L遥当血糖臆3.9mmol/L袁伴或不伴有心慌尧大汗尧手抖等症状时判定为轻度低血糖袁需及时调整胰岛素剂量曰若出现意识障碍袁判断为严重低血糖遥1.3观察指标入组人员需空腹8~10h袁于第2天晨起空腹采集前臂肘正中静脉血袁检测空腹血糖渊fasting plasma glucose袁FPG冤尧糖化血红蛋白渊hemoglobin A1c袁HbA1c冤尧空腹胰岛素渊fasting insulin袁FINS冤袁测定体质量指数渊body mass index袁BMI冤袁行馒头餐后检测餐后2h 血糖渊2h postprandial blood glucose袁2hPG冤袁由FINS计算出胰岛素抵抗指数渊homeostasis model as鄄sessment-insulin resistance袁HOMA‐IR冤和胰岛茁细HOMA-茁was higher than that in liraglutide group,the difference was statistically significant(P约0.05);there was no significant difference in HbA1c,2hPG and HOMA-IR between the two groups(P跃0.05).There was no significant difference between the two groups in the blood glucose compliance rate(字2=0.127,P=0.730).No severe hypoglycemia occurred in both groups after treatment.Conclusion For newly diagnosed obese patients with type2 diabetes,liraglutide,polyethylene glycol loxenatide combined with short-term intensive insulin therapy can reduce blood glucose,reduce weight and improve islet茁-cell function.Diolloxenatide has more advantages than liraglutide in reducing FPG and improving islet茁-cell function,but liraglutide has a stronger weight loss effect.[Key words]Liraglutide;Polyethylene glycol loxenatide;Islet beta function;GLP-1RA胞功能指数渊homeostasis model assessment -茁袁HOMA-茁冤渊计算公式为HOMA-茁越20伊FINS/渊FPG-3.5冤尧HOMA-IR越FPG伊FINS/22.5冤袁治疗12周后复测上述指标遥根据HbA1c 水平计算血糖达标率袁采用中华医学会糖尿病学分会(CDS)对糖尿病血糖控制目标袁将HbA1c<7.0%作为血糖达标的标准遥1.4统计方法采用SPSS 24.0统计学软件处理数据袁符合正态分布的计量资料用渊x依s 冤表示袁采用t 检验曰计数资料频数和百分比渊%冤表示袁采用字2检验袁P约0.05为差异有统计学意义遥2结果2.1两组患者治疗前实验室指标比较两组治疗前实验室指标对比袁差异无统计学意义渊P跃0.05冤遥见表1遥2.2两组患者治疗后实验室指标比较两组治疗后BMI尧FPG尧2hPG尧HbA1c尧HOMA-IR 均较治疗前明显下降袁HOMA-茁明显升高袁差异有统计学意义渊P约0.05冤曰治疗后袁洛塞那肽组FPG 较利拉鲁肽组降低袁BMI尧HOMA-茁较利拉鲁肽组升高袁差异有统计学意义渊P约0.05冤袁HbA1c尧2hPG尧HOMA-IR 与利拉鲁肽组相比有所升高袁但差异无统计学意义渊P跃0.05冤遥见表2遥2.3两组患者血糖达标率及低血糖发生情况比较利拉鲁肽组治疗后血糖达标率为13.33%渊4例达标冤袁洛塞那肽组治疗后血糖达标率为6.67%渊2例达标冤袁两组血糖达标率对比袁差异无统计学意义(字2=0.127袁P=0.730)遥治疗后利拉鲁肽组中2例患者因饮食和运动不规律出现轻度低血糖袁给予指导后未再发生低血糖袁两组均未出现严重低血糖遥3讨论肥胖是2型糖尿病发生尧发展中的重要因素袁二者往往相伴相随遥不单是糖尿病袁肥胖还与多种代谢障碍性疾病袁如心血管疾病尧代谢综合征等息息相关[6]遥截至2021年全球有20亿人肥胖或超重袁我国成人超重肥胖率已超50%遥肥胖人数的增加将导致慢性非传染性疾病的患病率升高袁给人类健康带来极大危害[7]遥当人体处于肥胖状态时袁可诱发脂肪细胞释放炎症因子参与胰岛素抵抗[8]遥而胰岛素抵抗是肥胖与各种疾病联系的枢纽遥脂肪合成受阻尧葡萄糖向细胞内转移利用受限袁均由胰岛素抵抗所致袁最终可引起循环中三酰甘油尧脂肪酸和葡萄糖堆积袁导致高血脂尧高血糖[9]遥长期持续的高血糖状态可导致人体胰岛茁细胞非生理性的损伤袁针对这类新诊断的2型糖尿病患者指南建议行短期胰岛素强化治疗袁而胰岛素强化治疗中以胰岛素泵降糖效果最佳袁降糖同时可有效逆转胰岛茁细胞的功能尧减轻氧化应激及炎症状态等作用[10-11]遥但初发2型糖尿病肥胖患者自身胰岛素抵抗严重袁应用外源胰岛素治疗后可能会加重原有胰岛素抵抗袁并伴有体质量增加的风险遥因此袁对于这类患者需要权衡利弊尧综合考虑制订降糖方案袁有效控糖的同时还需关注体质量的变化遥利拉鲁肽属于GLP-1RA 日制剂袁需每日一次皮下注射遥研究显示袁利拉鲁肽在降低2型糖尿病患者血糖的同时袁还可延缓胃排空尧减少进食量袁具有减重的作用[12]遥对于单纯肥胖人群的减重效果亦显著袁且不引起低血糖遥聚乙二醇洛塞那肽是我国第一个利拉鲁肽组渊n=30冤洛塞那肽组渊n=30冤t 值P 值组别渊25.32依1.13冤*渊26.08依1.58冤*-2.1150.039BMI渊kg/m 2冤渊6.86依1.10冤*渊6.18依1.67冤*2.2920.026FPG(mmol/L)渊12.91依2.18冤*渊13.67依2.05冤*-1.3610.1792hPG(mmol/L)渊8.09依0.99冤*渊8.58依0.94冤*-1.8970.063HbA1c 渊%)渊2.33依0.36冤*渊2.18依0.29冤*1.5920.120渊54.87依6.75冤*渊59.19依7.83冤*-2.2500.029HOMA-IR HOMA-茁注院与治疗前比较袁*P约0.05表2两组患者治疗后实验室指标比较渊x依s 冤利拉鲁肽组渊n=30冤洛塞那肽组渊n=30冤t 值P 值组别28.04依1.3727.85依1.340.5460.587BMI渊kg/m 2冤12.72依0.8612.28依0.891.9060.062FPG(mmol/L)20.69依2.7319.81依2.031.3840.1722hPG(mmol/L)11.16依1.1010.89依1.080.9430.350HbA1c 渊%)4.37依0.434.58依0.40-1.9400.06714.62依3.1315.28依2.83-0.8370.406HOMA-IR HOMA-茁表1两组患者治疗前实验室指标比较渊x依s 冤原研创新的GLP-1RA超长效制剂袁只需每周一次皮下注射遥该药物由聚乙二醇渊PEG冤修饰得到袁目的是增加抵抗二肽基肽酶-4渊DPP-4冤的降解能力尧提高生物利用度袁从而延长给药间隔袁减少给药次数[13]遥该研究发现利拉鲁肽和聚乙二醇洛塞那肽在降糖尧减重的同时袁一定程度上促进了胰岛茁细胞功能的恢复遥这与针对利拉鲁肽进行的LEAD研究结论吻合遥该研究还发现聚乙二醇洛塞那肽在降低FPG尧改善胰岛茁细胞功能方面较利拉鲁肽更有优势遥同样有报道指出袁周制剂主要通过促进空腹胰岛素分泌尧抑制胰高血糖素分泌袁降低空腹血糖曰而日制剂的上述作用较周制剂弱袁主要依赖延迟胃排空降低餐后血糖[14]遥中国人群数据显示袁当HbA1c跃8.0%时袁基础血糖对HbA1c的相对贡献可接近80%[15]袁可见控制好FPG是HbA1c达标的关键因素遥而FPG和FINS 与HOMA-IR尧HOMA-茁相关袁也进一步决定了胰岛茁细胞的功能遥该研究还发现袁利拉鲁肽减重效果更好袁这可能与日制剂抑制胃排空的作用更强相关遥但该研究未对利拉鲁肽1.8mg这一剂量进行分组研究袁对于聚乙二醇洛塞那肽与利拉鲁肽1.8mg/d之间差异有待进一步考证遥综上所述袁对于新确诊2型糖尿病患者袁胰岛素治疗一般需持续2~3个月遥但该研究中患者还合并肥胖袁考虑到肥胖患者自身的胰岛素抵抗情况袁只进行了短期强化即停用了胰岛素袁在治疗早期联合了不同剂型的GLP-1RA袁二者降糖效果均显著袁且不良反应少遥但GLP-1RA能否代替撤泵后的胰岛素治疗及其远期疗效探索袁仍需进行大样本的研究遥[1]Li YZ,Teng D,Shi XG,et al.Prevalence of diabetes recorded in mainland China using2018diagnostic crite鄄ria from the American Diabetes Association:national cross sectional study[J].BMJ,2020,369:m997. [2]Gurtsova K,Da Rocha Fernandes J D,Huang Y,et al. IDF Diabetes Atlas:global estimates for the prevalence of diabetes for2015and2040[J].Diabetes research and clinical practice,2017,128:40-50.[3]Liu HT,Gao Y.Efficacy of shortterm intensive treatment with insulin pump to improve islet茁cell function in newly diagnosed type2diabetes via inhibition of oxida鄄tive stress[J].Experimental and Therapeutic Medicine,2019, 18(3):2293-2298.[4]Sandoval DA,D'Alessio DA.Physiology of proglucagon peptides:role of glucagon and GLP-1in health and dis鄄ease[J].Physiological reviews,2015,95(2):513-548. [5]Bunck MC,Corn佴r A,Eliasson B,et al.Effects of exe鄄natide on measures of茁-cell function after3years in metformin-treated patients with type2diabetes[J].Dia鄄betes Care,2011,34(9):2041-2047.[6]Asghari G,Hasheminia M,Heidari A,et al.Adolescent metabolic syndrome and its components associations with incidence of type2diabetes in early adulthood:Tehran lipid and glucose study[J].Diabetology&Metabolic Syn鄄drome,2021,13(1):1-9.[7]刘月姣.叶中国居民营养与慢性病状况报告(2020年)曳发布[J].中国食物与营养,2020,26(12):封2. [8]Katsiki N,Mikhailidis DP,Banach M.Leptin,cardiovas鄄cular diseases and type2diabetes mellitus[J].Acta Phar鄄macologica Sinica,2018,39(7):1176-1188. [9]Petersen M C,Shulman G I.Mechanisms of insulin ac鄄tion and insulin resistance[J].Physiological reviews, 2018,98(4):2133-2223.[10]Chon S,Rhee S Y,Ahn K J,et al.Long‐term effects on glycaemic control and茁‐cell preservation of early intensive treatment in patients with newly diagnosed type2diabetes:A multicentre randomized trial[J].Dia鄄betes,Obesity and Metabolism,2018,20(5):1121-1130.[11]Retnakaran R,Emery A,Ye C,et al.Short‐term in鄄tensive insulin as induction and maintenance therapy for the preservation of beta‐cell function in early type 2diabetes(RESET‐IT Main):A2‐year randomized controlled trial[J].Diabetes,Obesity and Metabolism, 2021,23(8):1926-1935.[12]Paternoster S,Falasca M.Dissecting the physiology and pathophysiology of glucagon-like peptide-1[J].Frontiers in endocrinology,2018:584.[13]Chen XP,Lv XF,Yang GY,et al.Polyethylene glycol[参考文献]者血糖及血脂的影响分析[J].河北医科大学学报,2019, 40(1):95-98.[9]刘争艳.低聚果糖联合个体化营养治疗对妊娠期糖尿病患者临床疗效的影响[J].数理医药学杂志,2021,34(6): 941-942.[10]王尊,何书励,李振水,等.综合营养干预对改善2型糖尿病患者血脂尧血糖效果评价[J].中国食物与营养, 2017,23(8):81-83.[11]杨春苓.营养评估联合专病一体化饮食指导对糖尿病患者血糖控制效果的影响[J].当代护士,2021,28(7上旬刊):60-62.[12]徐言.数字化营养膳食模式对老年2型糖尿病住院患者营养状况尧饮食自我效能的影响[J].中国数字医学, 2020,15(9):150-153.[13]许飞,陈林军,聂志妍,等.膳食营养素在2型糖尿病中降血糖作用及其机制的研究进展[J].生物学杂志,2020, 37(3):96-101.[14]曾婷,林楚慧,叶小芳,邓宇虹.30豫低碳水化合物饮食治疗2型糖尿病的效果研究[J].中国全科医学,2020, 23(16):2030-2033.[15]段云卉,贾凯.复合型营养制剂在糖尿病中的干预效果及对患者血糖的影响[J].广东医学,2020,41(6):618-621.渊收稿日期院2022-02-15冤loxenatide injections added to metformin effectively im鄄prove glycemic control and exhibit favorable safety in type2diabetic patients[J].Journal of Diabetes,2017,9(2): 158-167.[14]Aroda Vanita R,Bain StePhen C,Cariou B,et al.Effi鄄cacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas)in insulin-naive patients with type2diabetes(SUSTAIN4):a randomized,open-lable,parallel-group,multicentre,multinational,phase 3a trial[J].The Lancet Diabetes&Endocrinology,2017,5 (5):355-366.[15]Kang X,Wang C,Chen DW,et al.Contributions of basal glucose and postprandial glucose concentrations to hemoglobin A1c in the newly diagnosed patients with type 2diabetes-the preliminary study[J].Diabetes Technolo鄄gy&Therapeutics,2015,17(7):445-448.渊收稿日期院2022-02-16冤渊上接第9页冤。
