Effect of liver glycogen content on hypoglycemic counterregulation

 描述（由申请人提供）：医源性低血糖被公认为1型糖尿病（T1 D）患者安全、有效血糖管理的头号障碍。在之前对狗进行的实验中，我们观察到肝糖原含量的增加会增加胰岛素诱导的低血糖期间的反调节激素分泌，从而增加肝脏葡萄糖的产生。本提案中的实验将确定肝糖原含量的增加在多大程度上可以改善患有和不患有T1 D的人的低血糖反调节。犬模型将用于提高我们对这是如何发生的理解。 具体目标#1是确定在患有和不患有T1 D的人中增加肝糖原沉积对胰岛素诱导的低血糖反调节的影响。这个问题将通过研究两组人来解决;一组患有T1 D，另一组没有。这两组都将接受一项实验，其中使用果糖输注显著增加肝糖原含量，另一项实验中他们接受盐水输注，以便仅适度改变肝糖原。然后，所有受试者将接受低血糖/高胰岛素钳夹，以确定其在存在和不存在肝糖原含量增加的情况下的反调节反应。 低血糖相关自主神经功能衰竭（HAAF）是一种影响T1 D患者的暂时性疾病。因此，具体目标#2是确定增加肝糖原沉积对患有HAAF的T1 D人类中胰岛素诱导的低血糖反调节的影响。目标#2的设计与目标#1相似。然而，在代谢测试的前一天， T1 D受试者将接受低血糖/高胰岛素钳夹以征集HAAF。然后，在第2天，每个个体的肝糖原含量将增加或保持不变，随后进行与目标#1相同的低血糖/高胰岛素钳夹。 最终的目的是利用犬模型来更仔细地检查肝糖原含量增加改善低血糖反调节的机制。具体目标#3是确定胰岛素诱导的脑和肝脏低血糖对犬肝糖原含量增加导致的反调节反应改善的重要性。为了回答这个问题，我们将增加动物的肝糖原含量，然后在胰岛素诱导的低血糖期间，通过葡萄糖输注选择性地使头部或肝脏血糖正常，而动物身体的其余部分保持低血糖。

 DESCRIPTION (provided by applicant): Iatrogenic hypoglycemia is universally recognized as the number one barrier to the safe, effective management of blood glucose in people with type 1 diabetes (T1D). In previous experiments in the dog, we observed that an increase in liver glycogen content augments counterregulatory hormone secretion during insulin-induced hypoglycemia, thereby increasing hepatic glucose production. The experiments in this proposal will determine to what extant an increase in liver glycogen content can improve hypoglycemic counterregulation in humans with and without T1D. The canine model will be used to improve our understanding of how this comes about. Specific Aim #1 is to determine the effect of increasing liver glycogen deposition on insulin-induced hypoglycemic counterregulation in humans with and without T1D. This question will be addressed by studying two groups of people; one with T1D and one without. Both of these groups will undergo one experiment in which their liver glycogen content will be significantly increased using an infusion of fructose an another in which they receive a saline infusion so as to change liver glycogen only modestly. Then, all subjects will undergo a hypoglycemic/ hyperinsulinemic clamp to determine their counterregulatory responses in the presence and absence of increased liver glycogen content. Hypoglycemia-associated autonomic failure (HAAF) is a temporary condition that affects people with T1D. Therefore, Specific Aim #2 is to determine the effect of increasing liver glycogen deposition on insulin- induced hypoglycemic counterregulation in T1D humans with HAAF. The design of Aim #2 will be similar to that of Aim #1. However, on the day prior to metabolic testing, T1D subjects will undergo a hypoglycemic/ hyperinsulinemic clamp to solicit HAAF. Then, on day 2, the liver glycogen content of each individual will be either increased or remain unchanged, followed by a hypoglycemic/ hyperinsulinemic clamp identical to Aim #1. The final aim will utilize the canine model to more closely examine the mechanisms by which increased liver glycogen content improves hypoglycemic counterregulation. Specific Aim #3 is to determine the importance of insulin-induced hypoglycemia in the brain and in the liver to the improved counterregulatory responses that occur as a result of increased liver glycogen content in the dog. To answer this question we will increase the liver glycogen content of animals and then, during insulin-induced hypoglycemia, selectively make either the head, or the liver euglycemic via glucose infusion, while the rest of the animal's body remains hypoglycemic.