AIMS/HYPOTHESIS IL-6 is a cytokine with various effects on metabolism. In mice, IL-6 improved beta cell function and glucose homeostasis via upregulation of glucagon-like peptide 1 (GLP-1), and IL-6 release from muscle during exercise potentiated this beneficial increase in GLP-1. This study aimed to identify whether exercise-induced IL-6 has a similar effect in humans. METHODS In a multicentre, double-blind clinical trial, we randomly assigned patients with type 2 diabetes or obesity to intravenous tocilizumab (an IL-6 receptor antagonist) 8 mg/kg every 4 weeks, oral sitagliptin (a dipeptidyl peptidase-4 inhibitor) 100 mg daily or double placebos (a placebo saline infusion every 4 weeks and a placebo pill once daily) during a 12 week training intervention. The primary endpoints were the difference in change of active GLP-1 response to an acute exercise bout and change in the AUC for the concentration-time curve of active GLP-1 during mixed meal tolerance tests at baseline and after the training intervention. RESULTS Nineteen patients were allocated to tocilizumab, 17 to sitagliptin and 16 to placebos. During the acute exercise bout active GLP-1 levels were 26% lower with tocilizumab (multiplicative effect: 0.74 [95% CI 0.56, 0.98], p = 0.034) and 53% higher with sitagliptin (1.53 [1.15, 2.03], p = 0.004) compared with placebo. After the 12 week training intervention, the active GLP-1 AUC with sitagliptin was about twofold that with placebo (2.03 [1.56, 2.62]; p < 0.001), while GLP-1 AUC values showed a small non-significant decrease of 13% at 4 weeks after the last tocilizumab infusion (0.87 [0.67, 1.12]; p = 0.261). CONCLUSIONS/INTERPRETATION IL-6 is implicated in the regulation of GLP-1 in humans. IL-6 receptor blockade lowered active GLP-1 levels in response to a meal and an acute exercise bout in a reversible manner, without lasting effects beyond IL-6 receptor blockade. TRIAL REGISTRATION Clinicaltrials.gov NCT01073826. FUNDING Danish National Research Foundation. Danish Council for Independent Research. Novo Nordisk Foundation. Danish Centre for Strategic Research in Type 2 Diabetes. European Foundation for the Study of Diabetes. Swiss National Research Foundation.

中文翻译：

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GLP-1分泌受IL-6信号调节：一项随机，安慰剂对照的研究。

目的/假设IL-6是一种对代谢具有多种作用的细胞因子。在小鼠中，IL-6通过上调胰高血糖素样肽1（GLP-1）改善了β细胞功能和葡萄糖稳态，并且在运动过程中IL-6从肌肉释放可增强GLP-1的这种有益增加。这项研究旨在确定运动诱导的IL-6在人类中是否具有相似的作用。方法在一项多中心，双盲的临床试验中，我们随机将2型糖尿病或肥胖症患者随机分配为每4周静脉给予tocilizumab（一种IL-6受体拮抗剂）8 mg / kg，口服西他列汀（一种二肽基肽酶-4抑制剂）。在12周的训练干预期间，每天100毫克或双重安慰剂（每4周一次安慰剂盐水输注和每天一次安慰剂药丸）。主要终点是在基线和训练干预后的混合餐耐受性测试期间，针对急性运动发作的主动GLP-1反应变化与主动GLP-1浓度-时间曲线的AUC变化之间的差异。结果19例患者被分配使用托珠单抗，17例患者接受西他列汀治疗，16例患者接受安慰剂治疗。在急性运动期间，托珠单抗的活性GLP-1水平降低26％（乘法作用：0.74 [95％CI 0.56，0.98]，p = 0.034），西他列汀升高53％（1.53 [1.15，2.03]，p = 0.004）与安慰剂相比。经过12周的培训干预后，西格列汀的有效GLP-1 AUC约为安慰剂的两倍（2.03 [1.56，2.62]； p <0.001），而GLP-1 AUC值显示了13％的小幅不显着下降在最后一次tocilizumab输注后4周（0.87 [0。67，1.12]; p = 0.261）。结论/解释IL-6与人类GLP-1的调节有关。IL-6受体阻滞剂以可逆的方式响应进餐和急性运动而降低了活性GLP-1水平，没有超过IL-6受体阻滞剂的持久作用。试验注册Clinicaltrials.gov NCT01073826。资助丹麦国家研究基金会。丹麦独立研究理事会。诺和诺德基金会。丹麦2型糖尿病战略研究中心。欧洲糖尿病研究基金会。瑞士国家研究基金会。没有IL-6受体阻滞剂以外的持久作用。试验注册Clinicaltrials.gov NCT01073826。资助丹麦国家研究基金会。丹麦独立研究理事会。诺和诺德基金会。丹麦2型糖尿病战略研究中心。欧洲糖尿病研究基金会。瑞士国家研究基金会。没有IL-6受体阻滞剂以外的持久作用。试验注册Clinicaltrials.gov NCT01073826。资助丹麦国家研究基金会。丹麦独立研究理事会。诺和诺德基金会。丹麦2型糖尿病战略研究中心。欧洲糖尿病研究基金会。瑞士国家研究基金会。