Effect of liver glycogen content on hypoglycemic counterregulation

肝糖原含量对降血糖反调节的影响

• 批准号: 9389238
• 负责人: Jason Winnick
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9389238
• 关键词: Effect; liver; glycogen; content; hypoglycemic

 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（由适用提供）：生源性低血糖普遍认为是1型糖尿病患者（T1D）患者血糖安全，有效治疗的第一障碍。在狗的先前实验中，我们观察到肝脏糖原含量的增加增加了胰岛素诱导的低血糖症期间的反调节性hors烯分泌，从而增加了肝葡萄糖的产生。该提案中的实验将确定肝糖原含量增加的额外增加可以改善有或没有T1D的人类的降血糖反调节。犬种模型将用于提高我们对这种情况的理解。具体目的＃1是确定增加肝糖原沉积对胰岛素诱导的有或没有T1D的人类胰岛素诱导的降血糖反调节的影响。这个问题将通过研究两组人来解决。一个带有T1D，一个没有。这两组都将进行一项实验，其中通过输注果糖，将显着增加其肝糖原含量，其中它们仅接受盐水输注以适度地改变肝糖原。然后，所有受试者将经历降血糖/高胰岛素夹，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。低血糖相关的自主衰竭（HAAF）是影响T1D患者的临时疾病。因此，具体目的＃2是确定增加肝糖原沉积对与HAAF T1D人类胰岛素诱导的降血糖反调节的影响。 AIM＃2的设计将类似于AIM＃1的设计。但是，在代谢测试之前的第二天， T1D受试者将经历降血糖/高胰岛素夹子以征求HAAF。然后，在第2天，每个人的肝糖原含量将增加或保持不变，然后是降血糖/高胰岛素夹，与AIM＃1相同。最终目的将利用犬种模型更仔细地检查肝糖原含量增加的机制可改善降血糖反调节。具体目的＃3是确定胰岛素诱导的大脑和肝脏中胰岛素诱导的低血糖的重要性，对狗的肝糖原含量升高而导致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，通过葡萄糖输注有选择地使头部或肝优异性产生肝优异性，而动物的其余部分仍然保持低血糖。