Effect of liver glycogen content on hypoglycemic counterregulation

 描述(申请人提供)：医源性低血糖被公认为1型糖尿病(T1D)患者安全、有效地控制血糖的头号障碍。在以前的狗实验中，我们观察到在胰岛素诱导的低血糖期间，肝糖原含量的增加会增加反调节激素的分泌，从而增加肝脏葡萄糖的产生。这项建议中的实验将确定在使用和不使用T1D的情况下，肝糖原含量的增加在多大程度上可以改善人类的低血糖反调节。犬类模型将被用来提高我们对这一现象如何发生的理解。具体目标1是确定增加肝糖原沉积对胰岛素诱导的低血糖调节的影响，在有和没有T1D的人类中。这个问题将通过研究两组人来解决；一组有T1D，另一组没有。这两组人都将接受一项实验，其中一组人的肝糖原含量将通过注入果糖显着增加，另一组人将接受生理盐水输注，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，以确定他们在存在和不存在肝糖原含量增加的情况下的反调节反应。低血糖相关的自主神经衰竭(HAF)是一种影响T1D患者的临时性疾病。因此，明确的目标2是确定增加肝糖原沉积对胰岛素诱导的低血糖反调节的影响。目标2号的设计将类似于目标1号。然而，在代谢测试的前一天， T1D受试者将接受低血糖/高胰岛素钳夹以获得HAAF。然后，在第二天，每个个体的肝糖原含量要么增加，要么保持不变，随后使用与目标1相同的降糖/高胰岛素钳夹。最终目标将利用犬模型更密切地研究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大脑和肝脏低血糖对由于狗的肝糖原含量增加而产生的改善的反调节反应的重要性。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正常血糖，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.