Central and peripheral actions of insulin for the control of muscle capillary recruitment

2型糖尿病在全球范围内呈上升趋势，反映了肥胖发病率的不断上升。虽然2型糖尿病的可能原因包括低体力活动和高脂肪饮食，但主要的代谢异常可能是肌肉胰岛素抵抗。这种抵抗的原因存在争议，但可能源于微血管功能障碍，即肌肉血流不足，对胰岛素招募毛细血管血流的作用没有反应。在这个项目中，我们将进一步扩展我们的开创性发现，即胰岛素在正常情况下介导毛细血管募集，并且在各种胰岛素抵抗模型中，胰岛素增加肌肉灌流的能力明显受损。我们将探索这一假设，即胰岛素通过终止于血管系统末梢小动脉的中枢神经机制来控制肌肉的微血管灌流，并努力确定这一控制的细节。我们将使用内部的新技术来研究涉及大脑的中枢控制机制的作用，以及通过局部输注各种可能增强或阻止胰岛素微血管作用的药物来研究外周机制的作用。一个积极的结果将加强我们对胰岛素作用和2型糖尿病前的胰岛素抵抗的理解。也有可能的结果是，重要的线索将被获得，从而导致可能用于治疗2型糖尿病的新的治疗剂。

Type 2 diabetes is on the increase world wide and reflects the ever-increasing incidence of obesity. Whereas the likely cause of type 2 diabetes includes low physical activity and high fat diet, the primary metabolic abnormality is likely to be muscle insulin resistance. The cause of this resistance is controversial, but may stem from microvascular dysfunction where muscle becomes poorly perfused and unresponsive to the action of insulin to recruit capillary flow. In this project we will further extend our seminal discoveries that insulin mediates capillary recruitment under normal circumstances and that in various models of insulin resistance insulin's ability to increase the perfusion of muscle is markedly impaired. We will explore the hypothesis, that insulin controls microvascular perfusion of muscle by a central neural mechanism ending at terminal arterioles on the vasculature and endeavour to identify the details of this control. We will use in-house novel techniques for examining both the role of central control mechanisms involving the brain as well as peripheral mechanisms by local infusion of various agents likely to either enhance or block insulin's microvascular action. A positive outcome will enhance our understanding of insulin action and the insulin resistance that precedes type 2 diabetes. There is also the possible outcome that important clues will be obtained leading to new therapeutic agents that could be used to treat type 2 diabetes.