益生菌干预糖耐量异常向2型糖尿病转化的随机、双盲、安慰剂对照临床研究

Probiotics for the prevention of type 2 diabetes mellitus in patients with impaired glucose tolerance:a double-blind randomized controlled trial

目的探讨益生菌干预对预防糖耐量异常(IGT)患者向2型糖尿病(T2DM)转化的有效性和安全性。方法选择2014年9月—2016年9月在同济大学附属东方医院门诊筛查IGT的患者106例,经口服75 g葡萄糖耐量试验(OGTT)明确为IGT的患者77例,其中男33例、女44例;采用随机数字表法将IGT患者分入益生菌组(44例)和安慰剂组(33例),两组分别给予益生菌或安慰剂口服。随访2年。行OGTT评估患者的糖代谢状况。主要终点为随访结束时两组间T2DM累积发生率的差异;次要终点为两组间正常葡萄糖耐量(NGT)患者比例、空腹和葡萄糖负荷后血糖水平、胰岛素水平、血脂水平和BMI的变化,以及益生菌的安全性,可能的菌群所占比例的变化。结果两组间患者基线资料的差异均无统计学意义(P值均>0.05)。益生菌组、安慰剂组分别有41、31例患者完成随访,纳入分析集。两组间随访2年内累积T2DM发生率的差异无统计学意义(48.9%比41.9%,P=0.861)。随访结束时,仅益生菌组BMI显著大于安慰剂组[(25.9±3.6)kg/m^(2)比(23.6±4.3)kg/m^(2),P=0.018]。与干预前比较,两组患者干预后FBG显著降低[(5.7±0.7)mmol/L比(5.4±0.7)mmol/L,P=0.001],服糖后30 min胰岛素(30mINS)水平显著增高[53.2(37.3,63.3)mU/L比59.2(46.1,75.9)mU/L,P=0.020],服糖后2h胰岛素(2hINS)水平降低[98.7(74.9,116.2)mU/L比70.5(61.2,87.5)mU/L,P=0.05]。干预前,两组间仅瘤胃球菌属(Ruminococcus gauvreauii)占比的差异有统计学意义(P<0.013);干预后,两组间卡氏伯克霍尔德菌-副伯克霍尔德菌属(Burkholderia-Caballeronia-Paraburkholderia)、产丁酸菌属(Alistipes)占比的差异均有统计学意义(P值均<0.013)。益生菌组干预后较同组干预前乳杆菌属(Lactobaciuus)、挑剔真杆菌属(Eubacterium eligens)占比显著增高(P值均<0.013)。Cox回归模型分析结果显示,益生菌干预(HR=0.98,95%CI为0.39~2.46)、年龄(HR=1.00,95%CI为0.97~1.04)、BMI(HR=0.91,95%CI为0.74~1.13)、腰围(HR=1.01,95%CI为0.95~1.08)、收缩压(HR=1.02,95%CI为1.00~1.05)、舒张压(HR=0.95,95%CI为0.90~1.01)、ALT(HR=1.01,95%CI为0.99~1.03)、γ-谷氨酰转肽酶(HR=1.00,95%CI为0.99~1.01)、TG(HR=1.67,95%CI为0.63~4.46)、TC(HR=0.23,95%CI为0.01~4.13)、HDL-C(HR=3.42,95%CI为0.25~47.60)、LDL-C(HR=4.42,95%CI为0.24~80.20)、胰岛素抵抗指数(HR=1.09,95%CI为0.96~1.23)均不是IGT向T2DM转化的影响因素(P值均>0.05)。两组间不良反应发生率的差异无统计学意义(P=0.075)。结论补充益生菌治疗可能无法降低IGT向T2DM转化的风险。

Objective To investigate the efficacy and safety of probiotics intervention in preventing type 2 diabetes mellitus(T2DM)in Chinese patients with impaired glucose tolerance(IGT).Methods A randomized,double-blind,placebo-controlled study was conducted.A total of 106 outpatients screened for IGT in Shanghai East Hospital between September 2014 and September 2016 were chosen.IGT was found in 77(33 males and 44 females)of them by oral glucose tolerance test.They were randomly divided into probiotics group(n=44)and placebo group(n=33)and followed up for 2 years.The primary endpoint was the conversion rate of T2DM between the two groups,and the secondary endpoints were the proportion of patients with normal glucose tolerance(NGT),the changes in blood glucose levels,insulin sensitivity,serum lipid levels and body mass index(BMI),and safety of probiotics,and potential changes in gut microbes.Results There was no significant difference in the baseline data between the two groups(P>0.05).Finally,41 and 31 patients completed follow-up in the probiotics group and placebo group,respectively.The BMI of patients in probiotics group was significantly higher than that in placebo group([(25.9±3.6)kg/m^(2) vs.(23.6±4.3)kg/m^(2)],P=0.018).There was no significant difference in the risk of diabetes within 2 years between the two groups(P=0.861).The level of fasting blood glucose(FBG)was significantly decreased([5.7±0.7]mmol/L vs.[5.4±0.7]mmol/L,P=0.001)during follow\|up,insulin at 30 min after taking sugar was significantly increased(53.2[37.3,63.3]mU/L vs.59.2[46.1,75.9]mU/L,P=0.020),and insulin at 2 h after taking sugar was significantly decreased(98.7[74.9,116.2]mU/L vs.70.5[61.2,87.5]mU/L,P=0.05).There was significant difference in the Ruminococcus gauvreauii between the two groups before intervention(P<0.013).There were significant differences in the Burkholderia-Caballeronia-Paraburkholderia and Alistipes between the two groups after intervention(P<0.013).The levels of Lactobaciuus and Eubacterium eligens were significantly increased in the probiotics group after intervention(P<0.013).Cox regression analysis showed that probiotics intervention(HR=0.98,95%CI:0.39-2.46),age(HR=1.00,95%CI:0.97-1.04),BMI(HR=0.91,95%CI:0.74-1.13),waistline(HR=1.01,95%CI:0.95-1.08),systolic blood pressure(HR=1.02,95%CI:1.00-1.05),diastolic blood pressure(HR=0.95,95%CI:0.90-1.01),alanine transaminase(HR=1.01,95%CI:0.99-1.03),γ-glutamyl transpeptidase(HR=1.00,95%CI:0.99-1.01),TG(HR=1.67,95%CI:0.63-4.46),TC(HR=0.23,95%CI:0.01-4.13),HDL-C(HR=3.42,95%CI:0.25-47.60),LDL-C(HR=4.42,95%CI:0.24-80.20),and HOMA-IR(HR=1.09,95%CI:0.96-1.23)were not influencing factors of T2DM in IGT patients(P>0.05).There was no significant difference in the incidence of adverse events between the two groups(P=0.075).Conclusion Probiotics supplementation may not reduce the risk of T2DM in IGT patients.