On the regulation of hepatic glucose metabolism during insulin-induced hypoglycemia

项目摘要 医源性低血糖被认为是安全、有效控制血糖的主要障碍 1型糖尿病（T1 D）患者中。在之前的狗实验中，我们观察到C肽输注 在胰岛素诱导的低血糖症期间增加胰高血糖素分泌和肝葡萄糖产生。的 提出的实验将确定这一发现在患有和不患有T1 D的患者中的转化影响。 我们还将使用犬模型进一步探讨这种保护作用的机制基础。 具体目的#1是在健康对照受试者中确定C肽与胰岛素共输注对胰岛素依赖性心绞痛的影响。 内源性葡萄糖产生（EGP）和反调节激素水平在低血糖症。这将 通过研究一组健康受试者两次来解决。在这两项研究中，低血糖将 通过静脉内（IV）输注胰岛素诱导。在一项研究中，C肽将在 在低血糖期，在另一项研究中，将输注生理盐水。EGP是我们的主要变量， 分析包括反调节激素和代谢底物。 具体目标#2是在T1 D患者中确定C肽与胰岛素共输注对EGP和EGP的影响。 低血糖时的反调节激素水平。该目标的研究计划与 目标#1，主要例外是我们将研究T1 D患者而不是健康对照（例如，两 低血糖钳夹研究，其中在一项研究期间施用C肽，在另一项研究期间施用盐水）。在 此外，将在此次访视前10天监测这些T1 D患者的血糖水平，以确保 他们没有出现可能混淆代谢研究数据的低血糖。类似于Aim #1，EGP是我们的主要结果变量，次要分析包括激素和底物水平。 具体目标#3是确定T1 D患者中C肽输注对葡萄糖调节反应的影响 混合餐挑战对于这个目标，我们将使用与目标#2相同的T1 D受试者。科目 将进行两次访问。在两次访视期间，他们将接受混合餐耐受试验（MMTT）。在一个 在MMTT期间，我们将输注C肽，在其他期间，我们将输注生理盐水，因为我们监测葡萄糖调节 对口服葡萄糖挑战的反应。主要变量将是对MMTT的葡萄糖反应，而 次要分析将包括激素和底物水平。 具体目标#4是确定在犬中，高胰高血糖素血症在HGP增加中的作用， 在胰岛素诱导的低血糖期间，当C肽与胰岛素共同输注时。为实现这一目标， 在范德比尔特完成，并利用犬模型更仔细地检查胰高血糖素在C- 肽诱导的低血糖反调节增强。为此，我们将使用生长抑素， 在C肽输注过程中调节胰腺激素水平，从而使我们能够确定它们的功能。

Project Summary Iatrogenic hypoglycemia is recognized as a primary 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 C-peptide infusion augmented glucagon secretion and hepatic glucose production during insulin-induced hypoglycemia. The proposed experiments will determine the translational impact of this finding in patients with and without T1D. We will also use the canine model to further explore the mechanistic basis of this protective effect. Specific Aim #1 is to determine, in healthy control subjects, the effect of C-peptide co-infusion with insulin on endogenous glucose production (EGP) and counterregulatory hormone levels during hypoglycemia. This will be addressed by studying a single group of healthy subjects two times. In both studies, hypoglycemia will be induced with an intravenous (IV) infusion of insulin. During one study, C-peptide will be infused during the hypoglycemic period, and in the other study, saline will be infused. EGP is our primary variable, with secondary analyses including counterregulatory hormones and metabolic substrates. Specific Aim #2 is to determine, in T1D patients, the effect of C-peptide co-infusion with insulin on EGP and counterregulatory hormone levels during hypoglycemia. The research plan for this Aim is very similar to that of Aim #1, with the main exception being that we will study T1D patients instead of healthy controls (e.g., two hypoglycemic clamp studies where C-peptide is administered during one study and saline during the other). In addition, the glycemic levels of these T1D patients will be monitored for 10 days prior to this visit to ensure that they do not experience hypoglycemia which could confound the data for the metabolic studies. Similar to Aim #1, EGP is our primary outcome variable, with secondary analyses including hormone and substrate levels. Specific Aim #3 is to determine, in T1D patients, the impact of C-peptide infusion on glucoregulatory responses to a mixed meal challenge. For this Aim, we will work with the same T1D subjects we did for Aim #2. Subjects will undergo two visits. During both visits they will undergo a mixed meal tolerance test (MMTT). During one MMTT we will infuse C-peptide and during the other we will infuse saline as we monitor the glucoregulatory responses to the oral glucose challenge. The primary variable will be glucose responses to the MMTT, while secondary analyses will include hormone and substrate levels. Specific Aim #4 is to determine, in canines, the role of hyperglucagonemia in the increased HGP that occurs when C-peptide is co-infused with insulin during insulin-induced hypoglycemia. Experiments for this aim will be done at Vanderbilt and utilize the canine model to more closely examine the role that glucagon plays in the C- peptide induced enhancement in hypoglycemic counterregulation. For this Aim, we will use somatostatin to regulate pancreatic hormone levels during C-peptide infusion, thereby allowing us to determine their function.