Proinflammatory endothelial activation detected by molecular imaging in obese nonhuman primates coincides with onset of insulin resistance and progressively increases with duration of insulin resistance.
Proinflammatory endothelial activation detected by molecular imaging in obese nonhuman primates coincides with onset of insulin resistance and progressively increases with duration of insulin resistance.
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DOI：
10.1161/circulationaha.113.003645
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发表时间：
2014-01-28
期刊：
影响因子：
37.8
通讯作者：
Lindner JR
中科院分区：
文献类型：
--
作者：
Chadderdon SM;Belcik JT;Bader L;Kirigiti MA;Peters DM;Kievit P;Grove KL;Lindner JR
炎症和胰岛素抵抗（IR）是肥胖患者心血管疾病风险增加的相关过程。IR和炎症之间的时间关系尚未完全确定。我们假设，在灵长类动物中，大动脉内皮细胞粘附分子（ECAM）的表达是与饮食诱导的肥胖和IR相一致的早期事件。在基线和每4-6个月对10只成年雄性恒河猴进行高脂肪饮食（HFD）研究，为期2年。通过对比增强超声分子成像评估躯干脂肪、颈动脉内膜-中膜厚度（IMT）、血浆炎症生物标志物以及颈动脉p -选择素和VCAM-1的表达。在基线、4个月和18个月进行静脉葡萄糖耐量试验（IVGTT）。HFD使体重、躯干脂肪、胰岛素曲线下面积和葡萄糖消失率（IVGTT）显示的IR程度迅速增加（p<0.01）；所有这些都在此后轻微恶化。分子成像检测到随着时间的推移，ECAM表达逐渐增加（2年时比对照剂信号高5-7倍，p<0.01）。直到2年后才检测到IMT的变化，虽然血浆炎症标志物（MCP-1， CRP）有增加的趋势，但随着时间的推移，增加的模式变化很大。在饮食性肥胖的灵长类动物中，内皮炎症激活是与IR发展一致的早期事件，早在任何可测量的颈动脉IMT变化之前就发生了。内皮细胞激活与IR的持续时间相关，而不是严重程度，并且不反映血浆生物标志物的变化。
Inflammation and insulin resistance (IR) are associated processes that potentiate risk for cardiovascular disease in obesity. The temporal relation between IR and inflammation is not completely characterized. We hypothesized that endothelial cell adhesion molecule (ECAM) expression in large arteries is an early event that coincides with diet-induced obesity and IR in primates. Ten adult male rhesus macaques were studied at baseline and every 4-6 months on high-fat diet (HFD) for 2 years. Truncal fat, carotid intima-media thickness (IMT), plasma inflammatory biomarkers, and carotid P-selectin and VCAM-1 expression by contrast-enhanced ultrasound molecular imaging were assessed. Intravenous glucose tolerance test (IVGTT) was performed at baseline, 4 and 18 months. HFD produced a rapid increase (p<0.01) in weight, truncal fat, and degree of IR indicated by the insulin area-under-the-curve and glucose disappearance rate on IVGTT; all of which worsened minimally thereafter. Molecular imaging detected a progressive increase in ECAM expression over time (5-7-fold greater than control agent signal at 2 yrs, p<0.01). Changes in IMT were not detected until 2 years and, while there was a trend toward an increase in plasma markers of inflammation (MCP-1, CRP), the pattern of increase varied considerably over time. In primates with diet-induced obesity, endothelial inflammatory activation is an early event that occurs coincident with the development of IR and long before any measurable change carotid IMT. Endothelial activation is more related to the duration rather than severity of IR and is not mirrored by changes in plasma biomarkers.