Fernández-Real J M, Broch M, Ricart W, Casamitjana R, Gutierrez C, Vendrell J, Richart C
Department of Endocrinology, University Hospital of Girona Dr. Josep Trueta, Spain.
Diabetes. 1998 Nov;47(11):1757-62. doi: 10.2337/diabetes.47.11.1757.
Recent studies have shown that the tumor necrosis factor (TNF) system is implicated in the insulin resistance of human obesity. Plasma concentrations of the soluble fraction of the TNF receptors 1 and 2 (sTNFR1 and sTNFR2) are thought to reflect the degree of activation of the TNF system. The purpose of this study was to explore whether this activation, as measured by the levels of circulating sTNFR1 and sTNFR2, is associated with insulin resistance. A total of 19 men (mean age 36.2 +/- 1.9; BMI 28.8 +/- 1.2, range 22.2-35.7) and 17 premenopausal women (age 34.9 +/- 1.4; BMI 28.1 +/- 0.8, range 19-37.9) were studied. Men showed higher levels of plasma sTNFR1 and sTNFR2 than women. However, obese men showed increased levels of sTNFR2 but similar levels of sTNFR1 in comparison with obese women. In fact, sTNFR2 levels correlated with BMI (r = 0.50, P = 0.002), fat-free mass (FFM) (r = 0.61, P < 0.0001), and waist-to-hip ratio (WHR) (r = 0.39, P = 0.02), but not with fat mass or percent fat mass. sTNFR2 levels correlated with basal glucose levels (r = 0.45, P = 0.007), area under the curve (AUC) for glucose during an oral glucose tolerance test (r = 0.42, P = 0.013), and with the quotient AUC glucose/log AUC insulin (r = 0.41, P = 0.015). sTNFR2 also correlated negatively with insulin sensitivity (S(I)), evaluated using the frequently sampled intravenous glucose tolerance test with minimal model analysis (r = -0.38, P = 0.02). Plasma sTNFR1 levels were not associated with any of these variables. Because WHR influenced both S(I) and sTNFR2 levels, we constructed a multiple linear regression to predict S(I), with WHR and sTNFR2 as independent variables. In this model, both WHR (P = 0.0078) and sTNFR2 levels (P = 0.025) contributed to 47% of the variance in S(I). In parallel with higher FFM, lean and obese men showed a lower S(I) (2.9 +/- 0.9 vs. 5.2 +/- 1.3 min(-1) x mU x l(-1), P = 0.001; and 1.15 +/- 1.1 vs. 1.8 +/- 0.8 min(-1) x mU x l(-1), P = 0.035, respectively) and higher sTNFR2 levels in comparison with lean and obese women, respectively. After controlling for FFM, the correlation between S(I) and sTNFR2 levels disappeared, indicating that FFM was significantly influencing these associations. In summary, plasma sTNFR2 levels, but not sTNFR1, were proportional to BMI, WHR, FFM (a well-known confounder in the evaluation of insulin sensitivity), basal and postload glucose levels, and insulin resistance. These findings support TNF-alpha as a system regulating insulin action in human obesity.
近期研究表明，肿瘤坏死因子（TNF）系统与人类肥胖中的胰岛素抵抗有关。TNF受体1和2的可溶性部分（sTNFR1和sTNFR2）的血浆浓度被认为反映了TNF系统的激活程度。本研究的目的是探讨通过循环sTNFR1和sTNFR2水平测量的这种激活是否与胰岛素抵抗相关。共研究了19名男性（平均年龄36.2±1.9岁；BMI 28.8±1.2，范围22.2 - 35.7）和17名绝经前女性（年龄34.9±1.4岁；BMI 28.1±0.8，范围19 - 37.9）。男性的血浆sTNFR1和sTNFR2水平高于女性。然而，与肥胖女性相比，肥胖男性的sTNFR2水平升高，但sTNFR1水平相似。实际上，sTNFR2水平与BMI（r = 0.50，P = 0.002）、去脂体重（FFM）（r = 0.61，P < 0.0001）和腰臀比（WHR）（r = 0.39，P = 0.02）相关，但与脂肪量或脂肪质量百分比无关。sTNFR2水平与基础血糖水平（r = 0.45，P = 0.007）、口服葡萄糖耐量试验期间葡萄糖的曲线下面积（AUC）（r = 0.42，P = 0.013）以及AUC葡萄糖/log AUC胰岛素的商（r = 0.41，P = 0.015）相关。sTNFR2也与使用频繁采样静脉葡萄糖耐量试验和最小模型分析评估的胰岛素敏感性（S(I)）呈负相关（r = -0.38，P = 0.02）。血浆sTNFR1水平与这些变量均无关联。由于WHR影响S(I)和sTNFR2水平，我们构建了一个多元线性回归模型，以WHR和sTNFR2作为自变量来预测S(I)。在该模型中，WHR（P = 0.0078）和sTNFR2水平（P = 0.025）共同解释了S(I)中47%的变异。与较高的FFM情况相似，瘦男性和肥胖男性的S(I)较低（分别为2.9±0.9与5.2±1.3 min⁻¹×mU×l⁻¹，P = 0.001；以及1.15±1.1与1.8±0.8 min⁻¹×mU×l⁻¹，P = 0.035），且与瘦女性和肥胖女性相比，sTNFR2水平较高。在控制FFM后，S(I)与sTNFR2水平之间的相关性消失，表明FFM对这些关联有显著影响。总之，血浆sTNFR2水平而非sTNFR1水平与BMI、WHR、FFM（胰岛素敏感性评估中一个众所周知的混杂因素）、基础和负荷后血糖水平以及胰岛素抵抗成正比。这些发现支持TNF-α作为人类肥胖中调节胰岛素作用的一个系统。
