背景:体外和体内研究表明,某些细胞因子和激素可能在2型糖尿病(T2D)的发生和发展中起作用。然而,关于它们在人类T2D中的作用的研究很少。我们评估了撒哈拉以南非洲人中11种循环细胞因子和激素与T2D之间的关联,并使用孟德尔随机化(MR)分析测试了因果关系。
方法:我们使用逻辑回归分析调整了年龄,性别,身体质量指数,和招募国家回归11种细胞因子和激素的水平(脂肪素,瘦素,visfatin,PAI-1,GIP,GLP-1,ghrelin,抵抗素,IL-6,IL-10,IL-1RA)在加纳人中的T2D,尼日利亚人,来自非洲美国糖尿病研究的肯尼亚人包括2276名T2D患者和2790名非T2D患者。类似的线性回归模型拟合了胰岛素敏感性(HOMA-S)和β细胞功能(HOMA-B)的稳态建模评估,作为非T2D个体(n=2790)的因变量。我们在非T2D个体中使用了与这11种细胞因子和激素中的至少一种相关的35种遗传变异作为单变量和多变量MR分析中的辅助变量。统计显著性设定为0.0045(0.05/11细胞因子和激素)。
结果:循环GIP和IL-1RA水平与T2D相关。11种细胞因子和激素中有9种(GLP-1和IL-6除外)与HOMA-S相关,HOMA-B,或者在非T2D个体中两者兼有。两阶段最小二乘MR分析在多变量分析中提供了GIP和IL-RA对HOMA-S和HOMA-B的因果影响的证据(GIP〜HOMA-Sβ=-0.67,P值=1.88×10-6和HOMA-Bβ=0.59,P值=1.88×10-5;IL-1RA〜HOMA-Sβ=-0.51,P-71-10=0.49IL-RA部分通过BMI介导(30-34%),但GIP不是。逆方差加权MR分析为脂肪素对T2D的因果效应提供了证据(多变量OR=1.83,P值=9.79×10-6),尽管这些关联在所有敏感性分析中并不一致.
结论:这项全面的MR分析结果表明,循环GIP和IL-1RA水平是降低胰岛素敏感性和增加β细胞功能的原因。GIP的作用与BMI无关,这表明GIP的循环水平可能是T2D风险的早期生物标志物。我们的MR分析未提供其他循环细胞因子在撒哈拉以南非洲人T2D中的因果作用的确凿证据。
In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses.
We used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones).
Circulating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S β = - 0.67, P-value = 1.88 × 10-6 and HOMA-B β = 0.59, P-value = 1.88 × 10-5; IL-1RA ~ HOMA-S β = - 0.51, P-value = 8.49 × 10-5 and HOMA-B β = 0.48, P-value = 5.71 × 10-4). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P-value = 9.79 × 10-6), though these associations were not consistent in all sensitivity analyses.
The findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP\'s effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.