Relevance of the Route of Insulin Delivery to the Develpment of Hypoglycemia

描述（由申请方提供）：低血糖是1型糖尿病（T1 DM）外源性胰岛素治疗的一种严重和常见后果，是实现最佳血糖控制的关键障碍。T1 DM患者平均每周发生2次低血糖，重度低血糖定义为患者需要他人协助给予碳水化合物或胰高血糖素的事件，发生率为每患者年1.1 - 1.5次。皮下胰岛素治疗的局限性在于胰岛素被递送到外周循环中，而不是生理性地递送到门静脉循环中。 这种不同的递送途径的可能结果是增加了对低血糖的暴露，因为血糖控制的一部分从肝脏转移到骨骼肌，在骨骼肌中有大量的组织充当“葡萄糖库”，即使在低血糖和正常血糖状态下，葡萄糖也从循环中被吸收，并且纠正低血糖的响应时间相对较慢。拟议的研究将测试这一假设，即输送胰岛素到门静脉，而不是外周静脉，减少低血糖暴露在狗模型利用两种方法。在第一种方法中，我们将应用选择性肝脏胰岛素输送的手术模型（目的1）。我们将确定通过将胰岛素输注到门静脉而不是体循环中所引起的等效过度胰岛素化在多大程度上减少了所导致的低血糖。这些实验将有助于确定恢复肝脏和体内其他组织之间的胰岛素分布平衡在多大程度上对低血糖症具有保护作用。我们将进一步研究当胰高血糖素对低血糖反应丧失时，与外周胰岛素输注相关的低血糖增加倾向被夸大的程度，如T1 DM（目的2）所示。在第二种方法中，我们将采用一种新的肝参考胰岛素类似物来评估其重现手术方法所见结果的能力（目的3）。这些研究将为胰岛素治疗的新方法奠定基础，这些新方法将允许更积极的糖尿病管理，同时限制低血糖，这是目前最佳控制的主要障碍。如果低血糖症通过使用肝参考方法减少，则可以进一步开发利用该方法的胰岛素类似物或寻求门静脉内输送胰岛素的方法。这些研究还将在一个成熟的和非常成功的导师的实验室中，使用最先进的技术，为葡萄糖调节生理学的新儿科研究者提供培训的重点。

DESCRIPTION (provided by applicant): Hypoglycemia is a serious and common consequence of exogenous insulin therapy in type 1 diabetes mellitus (T1DM) and is a key barrier to the achievement of optimal glucose control. On average, hypoglycemia occurs 2 times weekly in T1DM and severe hypoglycemia, defined as an event where a patient requires the assistance of another person to administer carbohydrate or glucagon, has an incidence of 1.1 to 1.5 episodes per patient-year. A limitation of subcutaneous insulin therapy is that insulin is delivered into the peripheral circulation rather than physiologically into the portal circulation. likely consequence of this different route of delivery is increased exposure to hypoglycemia, as a portion of glycemic control is shifted away from the liver to skeletal muscle, where there is a larger mass of tissue to act as a "glucose sink," where glucose is taken up from the circulation, even in hypoglycemic and euglycemic states, and where the response time to correct hypoglycemia is comparatively slower. The proposed research will test the hypothesis that delivery of insulin into the portal vein, as opposed to a peripheral vein, reduces hypoglycemic exposure in a canine model utilizing two approaches. In the first approach, we will apply a surgical model of selective hepatic insulin delivery (Aim 1). We will determine the extent to which equivalent overinsulinization brought about by insulin infusion into the portal rather than systemic circulation decreases resultant hypoglycemia. These experiments will help to determine how much restoring the balance of insulin distribution between the liver and other tissues in the body confers a protective effect against hypoglycemia. We will further examine how much the propensity for increased hypoglycemia associated with peripheral insulin delivery is exaggerated when the glucagon response to hypoglycemia is lost, as seen with T1DM (Aim 2). In the second approach, we will employ a novel hepatopreferential insulin analog to assess its ability to reproduce results seen with the surgical approach (Aim 3). These studies will set th stage for new approaches to insulin therapy that will permit more aggressive diabetes management while limiting hypoglycemia, a principal barrier to optimal control at present. If hypoglycemia is reduced by utilization of hepatopreferential approaches, a strong case could be made to either further develop insulin analogs that would take advantage of this approach or seek ways to deliver insulin intraportally. These studies will also provide a focus for the trainin of a new pediatric investigator in the physiology of glucose regulation using state of the art techniques in the laboratory of an established and highly successful mentor.