Comparison between AICAR and exercise-induced stimulation of skeletal muscle AMP-K on fat/glucose metabolism in diabetes

背景和理论：运动在糖尿病患者的生活中很重要。在控制良好的糖尿病患者中，急性运动对全身糖的利用和骨骼肌(SKM)的能量产生的比率与非糖尿病患者相似。然而，在糖尿病患者中，关于SKM如何在运动中处理糖和产生能量的信息很少。胰岛素控制久坐不动的受试者的SKM糖和能量处理。在运动中，这些过程是由非胰岛素因素控制的。化学催化剂AMP激活的蛋白激酶(AMP-K)是运动时急性糖加工和能量供应的重要替代调节剂，仅在正常运动大鼠中被研究过。目前尚无糖尿病患者AMP-K活性的研究。我们的研究将集中在：i)糖尿病患者中SKM AMP-K的刺激对SKM有效的糖加工和能量产生有多重要；ii)运动的益处是否可以通过对久坐糖尿病患者的AMP-K的药理刺激来模拟。我们的目标是：i)比较运动和药物刺激对正常和糖尿病受试者AMP-K代谢的影响；ii)确定触发AMP-K代谢反应的分子机制；iii)确定循环中的胰岛素、血糖和/或血脂水平是否影响AMP-K代谢反应。可能的结果：AMP-K的药理刺激将改善SKM的糖代谢，但对糖尿病患者影响较小。相关的AMP-K对SKM脂肪代谢的刺激可能会削弱对SKM有益的糖反应，特别是在糖尿病患者。这些信息将用于糖尿病患者未来的药物开发，旨在模拟运动对AMP-K代谢的有益影响。

Background and Rationale: Exercise is important in the life of the diabetic. In well controlled diabetes, the rates of whole body sugar usage and energy production in skeletal muscle (SkM) in response to acute exercise are similar to non-diabetics. However in diabetics, little information is available as to how SkM processes sugar and produces energy during exercise. Insulin controls SkM sugar and energy processing in sedentary subjects. During exercise, these processes are controlled by non-insulin factors. The chemical catalyst AMP activated protein kinase (AMP-K), which has been investigated only in normal exercising rats, is an important alternative regulator of acute sugar processing and energy supply for exercising SkM. No studies of AMP-K activity are available in diabetes. Our studies will focus on i) how important is the stimulation of SkM AMP-K in diabetes to efficient SkM sugar processing and energy production; ii) if the benefits of exercise can be simulated by pharmacological stimulation of AMP-K in sedentary diabetic subjects. We aim to i) compare the metabolic effects of exercise vs pharmacological stimulation of AMP-K in normal and diabetic subjects; ii) define the molecular mechanisms which trigger the AMP-K metabolic responses; iii) determine if the circulating levels of insulin, blood sugar and-or blood fat influence the AMP-K metabolic responses. Likely Outcomes: pharmacological stimulation of AMP-K will improve SkM sugar metabolism, but less so in diabetes. The associated AMP-K stimulation of SkM fat metabolism may blunt the beneficial SkM sugar responses, particularly in diabetes. This information will be used in future drug developments for diabetics which aim to simulate the beneficial AMP-K metabolic effects of exercise.