Leighton B, Sanderson A L, Young M E, Radda G K, Boehm E A, Clark J F
Department of Biochemistry, University of Oxford, U.K.
Diabetes. 1996 Jan;45 Suppl 1:S120-4. doi: 10.2337/diab.45.1.s120.
We measured the sensitivity of glucose metabolism to insulin in soleus muscle preparations isolated from spontaneously hypertensive (SH) rats and normotensive age-matched Wistar-Kyoto (WKY) rats. SH rats were treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (1 mg/kg) and/or a second antihypertensive drug, the calcium antagonist verapamil, alone (100 mg/kg) or as combination therapy (50 mg/kg). Treatment of SH rats with trandolapril or trandolapril in combination with verapamil for 6 weeks normalized the blood pressure. The estimated concentration of insulin required for half-maximal stimulation of glycogen synthesis (i.e., EC50 values) was approximately 500 microU/ml for muscles from both WKY and SH rats. This value is five times higher than the value obtained from soleus muscle preparations isolated from insulin-sensitive Wistar rats. This indicates that glycogen synthesis is insensitive to insulin in SH and WKY rat soleus muscle. Treatment of SH rats with trandolapril with or without verapamil improved the sensitivity of glycogen synthesis to insulin in soleus muscle. Further experiments investigated whether acute exposure (1 h) of insulin-sensitive skeletal muscle with either trandolaprilat (the active metabolite of trandolapril) or bradykinin (levels of which may be raised by ACE inhibition) could affect the insulin-stimulated rate of glucose metabolism. These results show that both trandolaprilat and bradykinin caused a small but significant increase in the rates of glucose metabolism. In conclusion, 1) SH and WKY rat skeletal muscle was insulin resistant, 2) chronic treatment of SH rats with trandolapril with or without verapamil normalized blood pressure and improved the response of glycogen metabolism to insulin, and 3) bradykinin and trandolaprilat acutely caused a small but significant increase in the rate of glycogen synthesis to a submaximal physiological concentration of insulin.
我们测定了从自发性高血压（SH）大鼠和年龄匹配的正常血压Wistar-Kyoto（WKY）大鼠分离出的比目鱼肌制剂中葡萄糖代谢对胰岛素的敏感性。给SH大鼠用血管紧张素转换酶（ACE）抑制剂trandolapril（1毫克/千克）和/或第二种抗高血压药物钙拮抗剂维拉帕米单独治疗（100毫克/千克）或联合治疗（50毫克/千克）。用trandolapril或trandolapril与维拉帕米联合治疗SH大鼠6周可使血压正常化。对于WKY和SH大鼠的肌肉，刺激糖原合成达到半最大速率所需的胰岛素估计浓度（即EC50值）约为500微单位/毫升。该值比从胰岛素敏感的Wistar大鼠分离出的比目鱼肌制剂获得的值高五倍。这表明在SH和WKY大鼠比目鱼肌中糖原合成对胰岛素不敏感。用trandolapril治疗SH大鼠，无论有无维拉帕米，均可改善比目鱼肌中糖原合成对胰岛素的敏感性。进一步的实验研究了用trandolaprilat（trandolapril的活性代谢物）或缓激肽（其水平可能因ACE抑制而升高）急性暴露（1小时）胰岛素敏感的骨骼肌是否会影响胰岛素刺激的葡萄糖代谢速率。这些结果表明，trandolaprilat和缓激肽均使葡萄糖代谢速率有小幅但显著的增加。总之，1）SH和WKY大鼠骨骼肌存在胰岛素抵抗，2）用trandolapril治疗SH大鼠，无论有无维拉帕米，均可使血压正常化并改善糖原代谢对胰岛素的反应，3）缓激肽和trandolaprilat可使胰岛素的亚最大生理浓度下糖原合成速率有小幅但显著的增加。
