Simeoni E, Hoffmann M M, Winkelmann B R, Ruiz J, Fleury S, Boehm B O, März W, Vassalli G
Department of Cardiology, University Hospital, CHUV-BH10, 1011, Lausanne, Switzerland.
Diabetologia. 2004 Sep;47(9):1574-80. doi: 10.1007/s00125-004-1494-4. Epub 2004 Sep 2.
AIMS/HYPOTHESIS: The molecular mechanisms of obesity-related insulin resistance are incompletely understood. Macrophages accumulate in adipose tissue of obese individuals. In obesity, monocyte chemoattractant protein-1 (MCP-1), a key chemokine in the process of macrophage accumulation, is overexpressed in adipose tissue. MCP-1 is an insulin-responsive gene that continues to respond to exogenous insulin in insulin-resistant adipocytes and mice. MCP-1 decreases insulin-stimulated glucose uptake into adipocytes. The A-2518G polymorphism in the distal regulatory region of MCP-1 may regulate gene expression. The aim of this study was to investigate the impact of this gene polymorphism on insulin resistance.
We genotyped the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort ( n=3307). Insulin resistance, estimated by homeostasis model assessment, and Type 2 diabetes were diagnosed in 803 and 635 patients respectively.
Univariate analysis revealed that plasma MCP-1 levels were significantly and positively correlated with WHR ( p=0.011), insulin resistance ( p=0.0097) and diabetes ( p<0.0001). Presence of the MCP-1 G-2518 allele was associated with decreased plasma MCP-1 ( p=0.017), a decreased prevalence of insulin resistance (odds ratio [OR]=0.82, 95% CI: 0.70-0.97, p=0.021) and a decreased prevalence of diabetes (OR=0.80, 95% CI: 0.67-0.96, p=0.014). In multivariate analysis, the G allele retained statistical significance as a negative predictor of insulin resistance (OR=0.78, 95% CI: 0.65-0.93, p=0.0060) and diabetes (OR=0.80, 95% CI: 0.66-0.96, p=0.018).
CONCLUSIONS/INTERPRETATION: In a large cohort of Caucasians, the MCP-1 G-2518 gene variant was significantly and negatively correlated with plasma MCP-1 levels and the prevalence of insulin resistance and Type 2 diabetes. These results add to recent evidence supporting a role for MCP-1 in pathologies associated with hyperinsulinaemia.
目的/假设：肥胖相关胰岛素抵抗的分子机制尚未完全明确。巨噬细胞在肥胖个体的脂肪组织中积聚。在肥胖状态下，单核细胞趋化蛋白-1（MCP-1）作为巨噬细胞积聚过程中的关键趋化因子，在脂肪组织中过度表达。MCP-1是一种胰岛素反应性基因，在胰岛素抵抗的脂肪细胞和小鼠中仍对外源性胰岛素产生反应。MCP-1可降低胰岛素刺激的脂肪细胞对葡萄糖的摄取。MCP-1远端调控区域的A-2518G多态性可能调节基因表达。本研究旨在探讨该基因多态性对胰岛素抵抗的影响。
我们对路德维希港风险与心血管健康（LURIC）队列（n = 3307）进行基因分型。分别在803例和635例患者中通过稳态模型评估法估算胰岛素抵抗情况，并诊断2型糖尿病。
单因素分析显示，血浆MCP-1水平与腰臀比（WHR）（p = 0.011）、胰岛素抵抗（p = 0.0097）和糖尿病（p < 0.0001）显著正相关。MCP-1 G-2518等位基因的存在与血浆MCP-1水平降低相关（p = 0.017），胰岛素抵抗患病率降低（比值比[OR] = 0.82，95%置信区间：0.70 - 0.97，p = 0.021），糖尿病患病率降低（OR = 0.80，95%置信区间：0.67 - 0.96，p = 0.014）。多因素分析中，G等位基因作为胰岛素抵抗（OR = 0.78，95%置信区间：0.65 - 0.93，p = 0.0060）和糖尿病（OR = 0.80，95%置信区间：0.66 - 0.96，p = 0.018）的负性预测因子仍具有统计学意义。
结论/解读：在一大群白种人中，MCP-1 G-2518基因变异与血浆MCP-1水平、胰岛素抵抗患病率和2型糖尿病显著负相关。这些结果为支持MCP-1在与高胰岛素血症相关的病理过程中发挥作用的最新证据增添了内容。
