Cyclic GMP phosphodiesterase inhibitors and facilitation of insulin-mediated capillary recruitment in muscle

现在似乎很清楚，胰岛素对肌肉内的血液流动有重大的刺激作用，以改善自身以及葡萄糖等营养物质的获取。当胰岛素的这种血流动力学效应受损时，肌肉对葡萄糖的摄取就会产生胰岛素抵抗，就有可能发展成2型糖尿病。我们的主要贡献是开发了新的技术，使这一观察成为可能，公平地说，由于这些技术，我们在这一领域处于世界领先地位。利用这些方法，我们现在希望开发基于改善肌肉毛细血管血流的治疗2型糖尿病的新药。我们将使用的方法类似于以前其他人用于治疗勃起功能障碍的药物，药物针对的是控制一种物质(环状GMP)新陈代谢的特定酶，后者反过来调节流向海绵体的血流。在我们的案例中，这些药物将针对同一酶的另一种特定亚型，即位于骨骼肌微血管控制点的环状GMP磷酸二酯酶。我们期望发现胰岛素介导的毛细血管在肌肉中的募集将被这类药物增强。因此，肌肉中的胰岛素抵抗将会减轻。

It would now seem clear that insulin has a major stimulatory effect on blood flow within muscle to improve access for itself as well as nutrients such as glucose. When this haemodynamic effect of insulin is impaired insulin resistance in terms of glucose uptake by muscle results and there is the potential for type 2 diabetes to develop. Our key contribution has been the development of new techniques to make this observation possible and it would be fair to say that we are the world leaders in this field because of these techniques. Using these methods we now wish to develop new drugs for treating type 2 diabetes based on improving muscle capillary blood flow. The approach we will use is similar to that used previously by others for the treatment of erectile dysfunction with drugs targeted at a particular enzyme controlling the metabolism of a substance (cyclic GMP) which in turn regulates blood flow to the corpus cavernosum. In our case, the drugs will be targeted at another specific isoform of the same enzyme, cyclic GMP phosphodiesterase, located at control points in the skeletal muscle microvasculature. We expect to find that insulin-mediated capillary recruitment in muscle will be enhanced by such drugs. As a consequence, insulin resistance in muscle will be lessened.