Dissociation between metabolic and vascular insulin resistance in aging.
Dissociation between metabolic and vascular insulin resistance in aging.
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DOI：
10.1152/ajpheart.00138.2007
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发表时间：
2007-07
期刊：
影响因子：
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通讯作者：
I. Schulman;Ming-Sheng Zhou;E. Jaimes;L. Raij
中科院分区：
文献类型：
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作者：
I. Schulman;Ming-Sheng Zhou;E. Jaimes;L. Raij
胰岛素通过激活内皮细胞中的磷脂酰肌醇3-激酶/Akt通路发挥生理作用，调节血流动力学和代谢动态平衡。胰岛素抵抗、内皮功能障碍和高血压的患病率随着年龄的增长而增加。我们研究了24个月龄和3个月龄SD大鼠胰岛素的代谢和内皮功能。使用高胰岛素正血糖钳夹后，24个月和3个月大鼠维持等值血糖所需的葡萄糖输注速度(5.5mmol.L)与空腹血糖(5.2mmol.33vs.4.4+/-0.37mmol.L；均值+/-SE)和胰岛素(0.862+/-0.193 vs.1.307+/-0.230 mg/L)相似。24个月组大鼠的收缩压较高(133+/-5vs.110+/-4 mm Hg；P=0.005)。24个月与3个月大鼠的主动脉内皮细胞一氧化氮(NO)依赖的胰岛素松弛功能受损(最大反应8.9%+/-4.3vs.34.9+/-3.9%；P=0.002)，N(G)-硝基-L-精氨酸甲酯可阻断3mo大鼠的胰岛素介导的松弛。3个月和24个月大鼠的内皮NO依赖性(乙酰胆碱)和非依赖性(硝普钠)松弛以及NADPH氧化酶活性相似。胰岛素使3个月大鼠主动脉Akt丝氨酸磷酸化较24个月大鼠增加120%(P<；0.05)，内皮型一氧化氮合酶(ENOS)丝氨酸磷酸化增加380%(P<；0.05)。3个月和24个月大鼠的主动脉中磷酸化c-jun氨基末端激酶-1和丝氨酸磷酸化胰岛素受体底物-1的表达相似，它们是已知的代谢性胰岛素抵抗的中介。ENOS活性和胰岛素信号转导调节因子小窝蛋白-1的表达在24个月的大鼠比3个月的大鼠低55%(P=0.002)。综上所述，老年患者对胰岛素的血管松弛功能受损与代谢胰岛素敏感性无关，与胰岛素介导的Akt/eNOS通路激活受损有关，但与乙酰胆碱介导的Ca(2+)-钙调蛋白/eNOS通路的完整激活有关。老龄化中的血管胰岛素抵抗可能会增加这一人群对传统心血管危险因素导致的血管损伤的易感性。
Physiological actions of insulin via activation of the phosphatidylinositol 3-kinase/Akt pathway in the endothelium serve to couple regulation of hemodynamic and metabolic homeostasis. Insulin resistance, endothelial dysfunction, and hypertension increase in prevalence with aging. We investigated the metabolic and endothelial actions of insulin in 24- vs. 3-mo Sprague-Dawley rats. With the use of the hyperinsulinemic euglycemic clamp, the rate of glucose infusion necessary to maintain equivalent plasma glucose (5.5 mmol/l) was similar in 24- vs. 3-mo rats, as was fasting glucose (5.2 +/- 0.33 vs. 4.4 +/- 0.37 mmol/l; mean +/- SE) and insulin (0.862 +/- 0.193 vs. 1.307 +/- 0.230 mg/l). Systolic blood pressure was higher in 24-mo rats (133 +/- 5 vs. 110 +/- 4 mmHg; P = 0.005). Endothelial nitric oxide (NO)-dependent relaxation to insulin was impaired in aortas of 24- vs. 3-mo rats (maximal response 8.9 +/- 4.3 vs. 34.9 +/- 3.9%; P = 0.002); N(G)-nitro-l-arginine methyl ester abolished insulin-mediated relaxation in 3- but not 24-mo rats. Endothelium NO-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxation, as well as NADPH oxidase activity, were similar in 3- and 24-mo rats. Insulin increased aortic serine phosphorylation of Akt in 3-mo rats by 120% over 24-mo rats (P < 0.05) and serine phosphorylation of endothelial NO synthase (eNOS) in 3-mo rats by 380% over 24-mo rats (P < 0.05). Aortic expression of phosphorylated c-Jun NH(2)-terminal kinase-1 and serine phosphorylated insulin receptor substrate-1, known mediators of metabolic insulin resistance, was similar in 3- and 24-mo rats. Expression of caveolin-1, a regulator of eNOS activity and insulin signaling, was 55% lower in 24- than 3-mo rats (P = 0.002). In summary, impaired vasorelaxation to insulin in aging was independent of metabolic insulin sensitivity and associated with impaired insulin-mediated activation of the Akt/eNOS pathway, but intact activation of the acetylcholine-mediated Ca(2+)-calmodulin/eNOS pathway. Vascular insulin resistance in aging may add to the increased susceptibility of this population to vascular injury induced by traditional cardiovascular risk factors.