Is the influence of variation in the ACE gene on the prospective risk of Type 2 diabetes in middle-aged men modified by obesity?
Is the influence of variation in the ACE gene on the prospective risk of Type 2 diabetes in middle-aged men modified by obesity?
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DOI：
10.1042/cs20070158
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发表时间：
2007-12-01
期刊：
影响因子：
6
通讯作者：
Humphries, Steve E.
中科院分区：
文献类型：
--
作者：
Muthumala, Arnal;Gable, David R.;Humphries, Steve E.
有强有力的证据表明，糖尿病组织中存在功能强大的肾素-血管紧张素系统，血管紧张素转换酶(ACE)抑制剂可能会改善T2 DM(2型糖尿病)高危人群的葡萄糖代谢。在这项研究中，我们测试了这样一种假设，即在2642名健康的中年高加索男性(平均年龄56岁)中，血浆和组织ACE活性遗传较低的受试者，由于他们的ACE[I/D(插入/缺失)]基因型，患T2 DM的风险较低，并进行了15年的随访。肥胖是T2 DM的最强预测因子，HR(95%CI)[危险比(95%可信区间)]为3.74(2.66-5.26)(P<；0.0001)。总体而言，ACE基因(II纯合子，n=623；D等位基因携带者，n=2019)与T2 DM的风险没有关联，尽管在瘦削男性中，D等位基因携带者与II纯合子相比在风险方面没有基因差异[调整后的HR=0.75(95%CI，0.46-1.22)]，但在肥胖(体重指数和GT；30 kg/m(2))男性中，T2 DM的风险更高[调整后的HR=4.26(95%CI，1.30-13.93)]，基因-肥胖交互作用P=0.01。以前发表的一项病例对照研究的重新分析也发现了类似的风险模式，在非肥胖时，D等位基因携带者患T2 DM的风险是II纯合子的1.3倍(0.97-1.74)，但在肥胖时D等位基因携带者患T2 DM的风险是II纯合子的1.79(1.17-2.72)(P=0.007)。需要进一步的前瞻性研究来证实这些发现。ACE D等位基因可能会恶化糖代谢，这可能会增加肥胖男性患T2 DM的风险，但在瘦男性中不会。在肥胖患者中，脂肪组织经历了炎性渗透，随后更高水平的促炎血管紧张素II可能解释了这种联系。
There is strong evidence for the presence of a functional renin-angiotensin system in diabetogenic tissues, and ACE (angiotensin-converting enzyme) inhibitors may improve glucose metabolism in those individuals at high risk of developing T2DM (Type 2 diabetes). In the present study, we tested the hypothesis that subjects with genetically lower plasma and tissue ACE activity, because of their ACE [I/D (insertion/deletion)] genotype, would have a lower risk of T2DM in 2642 healthy middle-aged Caucasian men (mean age, 56 years) followed-up for 15 years. Obesity was the strongest predictor of T2DM, with an HR (95% CI) [hazard ratio (95% confidence interval)] of 3.74 (2.66-5.26) (P < 0.0001). Overall there was no association between ACE genotype (II homozygotes, n = 623; and D allele carriers, n = 2019) and risk of T2DM, and although in lean men there was no genotype difference in risk in D allele carriers compared with II homozygotes [adjusted HR = 0.75 (95% CI, 0.46-1.22)], in obese (body mass index > 30 kg/m(2)) men the risk of T2DM was higher [adjusted HR = 4.26 (95% CI, 1.30-13.93)] with a genotype-obesity interaction of P = 0.01. A similar pattern of risk was seen by re-analysis of a previously published case-control study, where D allele carriers had a non-significant 1.30 (0.97-1.74)-fold higher risk of developing T2DM than II homozygotes when non-obese, but a 1.79 (1.17-2.72) (P = 0.007)-fold higher risk when obese. Further prospective studies are needed to confirm these findings. The ACE D allele may worsen glucose metabolism, which could raise the prospective T2DM risk in obese men, but not in lean men. In obesity, adipose tissue undergoes inflammatory infiltration and the subsequent higher levels of pro-inflammatory angiotensin II may explain this association.