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

描述（由申请人提供）：低血糖是外源性胰岛素治疗1型糖尿病（T1DM）的一个严重和常见的后果，是实现最佳血糖控制的关键障碍。平均而言，T1DM患者每周发生2次低血糖，严重低血糖的发生率为1.1 - 1.5次/患者年，严重低血糖的定义是患者需要他人协助给予碳水化合物或胰高血糖素。皮下胰岛素治疗的一个局限性是胰岛素被输送到外周循环，而不是生理性地进入门静脉循环。这种不同的输送途径可能的后果是增加低血糖的风险，因为一部分血糖控制从肝脏转移到骨骼肌，那里有更大的组织充当“葡萄糖池”，葡萄糖从循环中被吸收，即使在低血糖和血糖正常的状态下，纠正低血糖的反应时间相对较慢。提出的研究将测试假设，胰岛素输送到门静脉，而不是外周静脉，减少低血糖暴露在犬模型利用两种方法。在第一种方法中，我们将应用选择性肝脏胰岛素输送的外科模型（目的1）。我们将确定胰岛素输注到门静脉而不是体循环所带来的等效胰岛素过度化在多大程度上降低了由此产生的低血糖。这些实验将有助于确定恢复肝脏和身体其他组织之间胰岛素分布的平衡对预防低血糖有多大的保护作用。我们将进一步研究，当胰高血糖素对低血糖的反应丧失时，与外周胰岛素输送相关的低血糖增加倾向在多大程度上被夸大了，正如在T1DM中所见（目的2）。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再现手术方法结果的能力（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。如果低血糖是通过肝参考途径降低的，一个强有力的案例可能是进一步开发胰岛素类似物，将利用这种方法或寻求方法输送胰岛素。这些研究也将提供一个新的儿科研究者的培训重点，在一个建立和非常成功的导师的实验室中使用最先进的技术进行葡萄糖调节的生理学。

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.