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

描述(申请人提供)：低血糖是外源性胰岛素治疗1型糖尿病(T1 DM)的一种严重和常见的后果，也是实现最佳血糖控制的关键障碍。平均而言，T1 DM患者每周发生2次低血糖，严重低血糖的发生率为1.1至1.5次/患者年。严重低血糖定义为患者需要他人帮助才能服用碳水化合物或高血糖素。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。这种不同的递送途径可能的结果是暴露于低血糖的风险增加，因为血糖控制的一部分从肝脏转移到骨骼肌，在那里有更大的组织块充当“葡萄糖接收器”，葡萄糖从循环中被吸收，即使在低血糖和正常血糖状态下，纠正低血糖的反应时间相对较慢。这项拟议的研究将利用两种方法检验这样一种假设，即门静脉注射胰岛素而不是外周静脉注射胰岛素可以减少犬模型中的低血糖暴露。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(目标1)。我们将确定由门静脉而不是全身循环注射胰岛素所带来的等量高胰岛素降低所产生的低血糖的程度。这些实验将有助于确定恢复肝脏和身体其他组织之间的胰岛素分配平衡在多大程度上可以预防低血糖。我们将进一步研究当胰升糖素对低血糖的反应丧失时，与外周胰岛素释放相关的低血糖增加的倾向在多大程度上被夸大，如T1 DM(目标2)。在第二种方法中，我们将使用一种新的肝脏参考胰岛素类似物来评估其重现手术入路结果的能力(目标3)。这些研究将为胰岛素治疗的新方法奠定基础，这种方法将允许更积极的糖尿病治疗，同时限制低血糖，这是目前最佳控制的主要障碍。如果低血糖是通过利用肝脏参照方法降低的，那么就有充分的理由进一步开发利用这种方法的胰岛素类似物，或者寻找途径在门静脉内注射胰岛素。这些研究还将提供一个重点，在已建立的和非常成功的导师的实验室中使用最先进的技术培训一名新的儿科研究人员，了解血糖调节的生理学。

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.