Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat
Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat
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DOI：
10.1152/ajpendo.1997.273.5.e1014
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发表时间：
1997-11-01
影响因子：
5.1
通讯作者：
Ernsberger, P
中科院分区：
文献类型：
--
作者：
Friedman, JE;Ishizuka, T;Ernsberger, P
胰岛素抵抗与肥胖和高血压有关。然而，肥胖高血压遗传模型中胰岛素抵抗的细胞机制尚未确定。本研究的目的是研究遗传性高血压背景下遗传性肥胖对骨骼肌和肝脏中胰岛素信号转导途径和葡萄糖转运的初始成分的影响。SHROB口服葡萄糖耐量试验表明，与瘦型自发性高血压大鼠（SHR）同窝仔相比，在180和240 min时血糖持续升高，提示葡萄糖耐受不良。空腹血浆胰岛素水平升高18倍SHROB。胰岛素刺激的3-O-甲基葡萄糖转运率降低68%，从SHROB与SHR相比，在离体上滑车肌。胰岛素刺激的酪氨酸磷酸化的胰岛素受体β亚基和胰岛素受体底物-1（IRS-1）在完整的骨骼肌SHROB分别减少了36和23%，与SHR相比，主要是由于32和60%的胰岛素受体和IRS-1蛋白表达，分别减少。与SHR相比，SHROB肌肉中磷脂酰肌醇-3-激酶和GLUT-4蛋白的p85 α调节亚基的量减少了28%和25%。在SHROB的肝脏中，胰岛素对IRS-1酪氨酸磷酸化的影响没有改变，但与SHR相比，胰岛素受体磷酸化降低了41%，这是由于胰岛素受体水平降低了30%。我们的观察表明，高血压背景下的瘦素受体突变f α（k）导致极端高胰岛素血症、葡萄糖耐受不良和骨骼肌中受体后胰岛素信号蛋白表达减少。尽管有这些变化，但与SHR相比，SHROB中的高血压并没有加重，这表明这些代谢异常可能不会导致X综合征模型中的高血压。
Insulin resistance is associated with both obesity and hypertension. However, the cellular mechanisms of insulin resistance in genetic models of obese-hypertension have not been identified. The objective of the present study was to investigate the effects of genetic obesity on a background of inherited hypertension on initial components of the insulin signal transduction pathway and glucose transport in skeletal muscle and liver. Oral glucose tolerance testing in SHROB demonstrated a sustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR) littermates, which is suggestive of glucose intolerance. Fasting plasma insulin levels were elevated 18-fold in SHROB. The rate of insulin-stimulated 3-O-methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the SHROB compared with SHR. Insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%, respectively, compared with SHR, due primarily to 32 and 60% decreases in insulin receptor and IRS-1 protein expression, respectively. The amounts of p85 alpha regulatory subunit of phosphatidylinositol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared with SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin receptor phosphorylation was decreased by 41%, compared with SHR, due to a 30% reduction in insulin receptor levels. Our observations suggest that the leptin receptor mutation f alpha(k) imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, and decreased expression of postreceptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbated in SHROB compared with SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X.