Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle.
Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle.
复制标题
胰岛素抵抗骨骼肌中一氧化氮/cGMP 信号级联敏感性改变的证据。
DOI：
10.1042/bj3290073
复制
发表时间：
1998
期刊：
影响因子：
--
通讯作者：
B. Leighton
中科院分区：
文献类型：
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作者：
M. Young;B. Leighton
一氧化氮激活鸟苷酸环化酶形成 cGMP，其中包含一个信号系统，该系统被认为是增加骨骼肌中葡萄糖转运和代谢的独特机制。在从胰岛素敏感（瘦 Zucker；Fa/?）和胰岛素抵抗（肥胖 Zucker；fa/fa）大鼠中分离的孵化大鼠比目鱼肌制剂中，研究了选择性 cGMP 磷酸二酯酶抑制剂扎普司特对基础葡萄糖利用的影响。 27 µM 的扎普司特显着增加了从瘦但不肥胖的 Zucker 大鼠中分离的孵化比目鱼肌中的 cGMP 水平。将肌肉与 14C 标记的葡萄糖和不同浓度的扎普司特（3、27 和 243 microM）一起孵育。 Zaprinast（27 和 243 microM）显着增加瘦 Zucker 大鼠比目鱼肌中的净乳酸和 14C 标记的乳酸释放率以及糖原合成率； 27 microM 扎普司特也增加了葡萄糖氧化。此外，无论浓度如何，磷酸二酯酶抑制剂都未能增加从肥胖 Zucker 大鼠中分离的比目鱼肌中 14C 标记的葡萄糖利用的任何方面。在胰岛素抵抗的肥胖 Zucker 肌肉中，一氧化氮合酶 (NOS) 的最大活性显着降低。因此，扎普司特对胰岛素抵抗骨骼肌缺乏作用与 NOS 活性降低是一致的。为了测试胰岛素抵抗骨骼肌中鸟苷酸环化酶内源性激活是否存在缺陷，从胰岛素敏感和胰岛素抵抗 Zucker 大鼠中分离比目鱼肌，并与不同浓度的 NO 供体硝普钠（SNP；0.1、1、5 和 15 mM）一起孵育。 SNP 显着增加了从胰岛素敏感和胰岛素抵抗大鼠中分离出的肌肉中的净乳酸和 14C 标记的乳酸释放率以及葡萄糖氧化。在胰岛素抵抗大鼠离体比目鱼肌内，观察到 cGMP 的剂量依赖性生成对 SNP 的反应降低。讨论了 NO/cGMP 信号传导受损与骨骼肌葡萄糖利用异常之间可能存在的联系。
Nitric oxide activates guanylate cyclase to form cGMP, comprising a signalling system that is believed to be a distinct mechanism for increasing glucose transport and metabolism in skeletal muscle. The effects of a selective cGMP phosphodiesterase inhibitor, zaprinast, on basal glucose utilization was investigated in incubated rat soleus muscle preparations isolated from both insulin-sensitive (lean Zucker; Fa/?) and insulin-resistant (obese Zucker; fa/fa) rats. Zaprinast at 27 microM significantly increased cGMP levels in incubated soleus muscle isolated from lean, but not obese, Zucker rats. Muscles were incubated with 14C-labelled glucose and various concentrations of zaprinast (3, 27 and 243 microM). Zaprinast (at 27 and 243 microM) significantly increased rates of net and 14C-labelled lactate release and of glycogen synthesis in lean Zucker rat soleus muscle; glucose oxidation was also increased by 27 microM zaprinast. In addition, regardless of concentration, the phosphodiesterase inhibitor failed to increase any aspect of 14C-labelled glucose utilization in soleus muscles isolated from obese Zucker rats. The maximal activity of nitric oxide synthase (NOS) was significantly decreased in insulin-resistant obese Zucker muscles. Thus the lack of effect of zaprinast in insulin-resistant skeletal muscle is consistent with decreased NOS activity. To test whether there is a defect in insulin-resistant skeletal muscle for endogenous activation of guanylate cyclase, soleus muscles were isolated from both insulin-sensitive and insulin-resistant Zucker rats and incubated with various concentrations of the NO donor sodium nitroprusside (SNP; 0.1, 1, 5 and 15 mM). SNP significantly increased rates of net and 14C-labelled lactate release, as well as glucose oxidation in muscles isolated from both insulin-sensitive and insulin-resistant rats. A decreased response to SNP was observed in the dose-dependent generation of cGMP within isolated soleus muscles from insulin-resistant rats. A possible link between impaired NO/cGMP signalling and abnormal glucose utilization by skeletal muscle is discussed.