Insulin resistance with enhanced insulin signaling in high-salt diet-fed rats
Insulin resistance with enhanced insulin signaling in high-salt diet-fed rats
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DOI：
10.2337/diabetes.50.3.573
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发表时间：
2001-03-01
期刊：
影响因子：
7.7
通讯作者：
Fujita, T
中科院分区：
文献类型：
--
作者：
Ogihara, T;Asano, T;Fujita, T
先前的临床研究表明高血压与胰岛素抵抗之间存在明显的相关性，并且已知糖尿病患者对盐负荷的血压反应性增加。为了研究高盐摄入对胰岛素敏感性和胰岛素信号通路的影响，我们给7周龄SD大鼠喂食高盐饮食（8% NaCl）或正常饮食2周。高盐喂养大鼠的收缩压略高于对照组（133 +/- 2 vs 117 +/- 2 mmHg, P < 0.001），食物摄入量和体重没有变化。与对照组相比，高盐喂养大鼠在空腹状态下轻度高血糖（108.5 +/- 2.8 vs. 97.8 +/- 2.5 mg/dl, P = 0.01）和轻度高胰岛素（0.86 +/- 0.07 vs. 0.61 +/- 0.06 ng/ml, P = 0.026）。高胰岛素-正糖钳夹研究显示，与对照组相比，高盐喂养大鼠的葡萄糖输注率降低了52.7%，肝脏葡萄糖产量增加了196%，离体骨骼肌对2-脱氧葡萄糖的摄取减少了66.4%，胰岛素诱导的肝脏糖原合成酶激活减少了44.5%。有趣的是，尽管存在胰岛素抵抗，高盐喂养的大鼠表现出胰岛素诱导的胰岛素受体底物(IRS)-1、IRS-2（肝脏和肌肉）和IRS-3（仅肝脏）的酪氨酸磷酸化增强。磷脂酰肌醇（PI） 3-激酶活性与IRS和磷酸酪氨酸在胰岛素刺激条件下：增加2.1- 4.1倍，与对照组相比。在高盐喂养的大鼠肝脏中，胰岛素诱导的Akt的Ser-473和糖原合成酶激酶3的Ser-21磷酸化也分别增加了2.9倍和1倍。因此，在高盐喂养大鼠的肝脏和肌肉中，导致PI 3激酶激活的细胞内胰岛素信号增强，胰岛素作用减弱。高胰岛素-正血糖钳夹研究表明，高盐饮食诱导的胰岛素敏感性降低不能通过吡格列酮逆转。由此可以得出以下结论：1)高盐饮食可能是促进胰岛素抵抗的一个因素，2)高盐摄入导致的胰岛素信号通路受损可能位于PI 3-激酶或Akt激活的下游，3)这种独特的胰岛素抵抗机制可能与高血压患者糖尿病的发生有关。
Previous clinical studies showed an apparent correlation between hypertension and insulin resistance, and patients with diabetes are known to have increased blood pressure responsiveness to salt loading. To investigate the effect of high salt intake on insulin sensitivity and the insulin signaling pathway, a high-salt diet (8% NaCl) or a normal diet was given to 7-week-old SD rats for 2 weeks. High salt-fed rats developed slightly but significantly higher systolic blood pressure than controls (133 +/- 2 vs. 117 +/- 2 mmHg, P < 0.001)], with no change in food intake or body weight. High salt-fed rats were slightly hyperglycemic (108.5 +/- 2.8 vs. 97.8 +/- 2.5 mg/dl, P = 0.01) and slightly hyperinsulinemic (0.86 +/- 0.07 vs. 0.61 +/- 0.06 ng/ml, P = 0.026) in the fasting condition, as compared with controls. Hyperinsulinemic-euglycemic clamp study revealed a 52.7% decrease in the glucose infusion rate and a 196% increase in hepatic glucose production in high salt-fed rats, which also showed a 66.4% decrease in 2-deoxyglucose uptake into isolated skeletal muscle and a 44.5% decrease in insulin-induced glycogen synthase activation in liver, as compared with controls. Interestingly, despite the presence of insulin resistance, high salt-fed rats showed enhanced insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1, IRS-2 (liver and muscle), and IRS-3 (liver only). Phosphatidylinositol (PI) 3-kinase activities associated with IRS and phosphotyrosine in the insulin-stimulated condition :increased 2.1- to 4.1-fold, as compared with controls. Insulin-induced phosphorylation of Ser-473 of Akt and Ser-21 of glycogen synthase kinase-3 also increased 2.9- and a-fold, respectively, in the liver of the high salt-fed rats. Therefore, in both the liver and muscle off high salt-fed rats, intracellular insulin signaling leading to PI 3-kinase activation is enhanced and insulin action is attenuated. The hyperinsulinemic-euglycemic clamp study showed that decreased insulin sensitivity induced with a high-salt diet was not reversed by administration of pioglitazone. The following can be concluded: 1) a high-salt diet may be a factor promoting insulin resistance, 2) the insulin-signaling step impaired by high salt intake is likely to be downstream from PI 3-kinase or Akt activation, and 3) this unique insulin resistance mechanism may contribute to the development of diabetes in patients with hypertension.