Morisco C, Condorelli G, Orzi F, Vigliotta G, Di Grezia R, Beguinot F, Trimarco B, Lembo G
Department of Neurocardiology, IRCCS INM Neuromed, Pozzilli (IS), Italy.
J Hypertens. 2000 Apr;18(4):465-73. doi: 10.1097/00004872-200018040-00017.
Although the heart is one of the target organs of insulin, it is still unknown whether the effect of insulin on cardiac muscle is preserved in essential hypertension, where insulin resistance has been observed in skeletal muscle.
We evaluated cardiac glucose uptake and the early steps of insulin signalling in spontaneously hypertensive (SHR, 10-12 weeks old) and in age-matched normotensive Wistar-Kyoto (WKY) rats. Cardiac glucose uptake (micromol/100 g per min) was assessed by 2-[14C]deoxyglucose method. After an overnight fast, 16 WKY rats and 17 SHR underwent a hyperinsulinemic euglycemic clamp. In particular, 2-h intravenous (i.v.) infusion of insulin (10 mU/kg per min) or saline (NaCl 0.9%) was administered, followed by an i.v. bolus injection of 2-[14C]deoxyglucose (100 microCi/kg) to measure cardiac glucose uptake.
During saline infusion, cardiac glucose uptake was significantly higher in SHR compared to WKY rats (85 +/- 18 versus 8 +/- 3 mg/kg per min, P < 0.01). Furthermore, insulin was able to markedly increase cardiac glucose uptake in WKY rats whereas this insulin action was entirely abolished in SHR; thus, the cardiac glucose uptake became similar in the two rat strains (76 +/- 16 versus 82 +/- 16 mg/kg per min, not significant). More importantly, during saline infusion SHR showed a significantly higher phosphorylation of insulin receptor substance-1 (IRS-1) coupled to enhanced association of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) to IRS-1 and to an increased PI 3-kinase activity compared to WKY rats. As expected, insulin exposure evoked an activation of its signalling cascade in WKY rats. In contrast, in SHR, the hormone failed to activate post-receptor molecular events.
Our data indicate that the heart of SHR shows an overactivity of the proximal steps of insulin signalling which cannot be further increased by the exposure to the hormone. This abnormality may account for the marked increase of basal cardiac glucose uptake and the loss of insulin-stimulated glucose uptake observed in SHR.
尽管心脏是胰岛素的靶器官之一，但在已观察到骨骼肌存在胰岛素抵抗的原发性高血压中，胰岛素对心肌的作用是否依然存在尚不清楚。
我们评估了自发性高血压大鼠（SHR，10 - 12周龄）和年龄匹配的正常血压Wistar - Kyoto（WKY）大鼠的心脏葡萄糖摄取及胰岛素信号传导的早期步骤。通过2 - [¹⁴C]脱氧葡萄糖法评估心脏葡萄糖摄取（微摩尔/100克每分钟）。禁食过夜后，16只WKY大鼠和17只SHR大鼠接受了高胰岛素正常血糖钳夹试验。具体而言，静脉内（i.v.）输注胰岛素（10 mU/kg每分钟）或生理盐水（0.9% NaCl）2小时，随后静脉推注2 - [¹⁴C]脱氧葡萄糖（100微居里/千克）以测量心脏葡萄糖摄取。
在输注生理盐水期间，SHR大鼠的心脏葡萄糖摄取显著高于WKY大鼠（85±18对8±3毫克/千克每分钟，P < 0.01）。此外，胰岛素能够显著增加WKY大鼠的心脏葡萄糖摄取，而在SHR大鼠中这种胰岛素作用完全被消除；因此，两种大鼠品系的心脏葡萄糖摄取变得相似（76±16对82±16毫克/千克每分钟，无显著差异）。更重要的是，在输注生理盐水期间，与WKY大鼠相比，SHR大鼠显示胰岛素受体底物 - 1（IRS - 1）的磷酸化显著更高，这与磷脂酰肌醇3激酶（PI 3激酶）的p85亚基与IRS - 1的结合增强以及PI 3激酶活性增加有关。正如预期的那样，胰岛素暴露在WKY大鼠中引发了其信号级联反应的激活。相反，在SHR大鼠中，该激素未能激活受体后分子事件。
我们的数据表明，SHR大鼠的心脏显示胰岛素信号传导近端步骤的过度活跃，这种过度活跃不能通过激素暴露进一步增加。这种异常可能解释了在SHR大鼠中观察到的基础心脏葡萄糖摄取的显著增加以及胰岛素刺激的葡萄糖摄取的丧失。
