Effect of liver glycogen content on hypoglycemic counterregulation

肝糖原含量对降血糖反调节的影响

基本信息

批准号：
9271184
负责人：
Jason Winnick
金额：
$ 33.55万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：医源性低血糖被普遍认为是 1 型糖尿病 (T1D) 患者安全、有效控制血糖的首要障碍。在之前的狗实验中，我们观察到肝脏功能增加。肝糖原含量增加了胰岛素引起的低血糖期间的反调节激素分泌，从而增加了肝葡萄糖的产生。本提案中的实验将确定肝糖原含量的增加可以改善什么程度。患有和不患有 T1D 的人类中的低血糖反调节作用将用于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患有和不患有 T1D 的人类中胰岛素诱导的低血糖反调节作用的影响。这个问题将通过研究两组人来解决：一组患有 T1D，一组没有。另一种是接受盐水输注，仅适度改变肝糖原，然后，所有受试者都将接受低血糖/高胰岛素钳夹，以确定他们在存在或不存在与低血糖相关的自主神经衰竭的情况下的反调节反应。 (HAAF) 是一种影响 T1D 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胰岛素诱导的低血糖反调节的影响。患有 HAAF 的 T1D 人类的设计与目标 #1 相似，但是，在代谢测试的前一天， T1D 受试者将接受低血糖/高胰岛素钳夹以征求 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，然后进行与目标 #1 相同的低血糖/高胰岛素钳夹。将利用犬模型更仔细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重要性。大脑和肝脏中的低血糖是由于狗的肝糖原含量增加而发生的反调节反应的改善。为了回答这个问题，我们将增加动物的肝糖原含量，然后在胰岛素引起的低血糖期间选择性地增加。通过葡萄糖输注使头部或肝脏血糖正常，而动物身体的其余部分仍保持低血糖。