Determination of Iatrogenic Hyperinsulinemia's Contribution to Insulin Resistance and Endothelial Dysfunction in Recent-Onset Type 1 Diabetes

项目总结/摘要 胰岛素抵抗（IR）始终见于1型糖尿病（T1 DM）患者， 在病理生理学上将T1 DM与动脉粥样硬化疾病联系起来。IR和新生动脉粥样硬化，如特征 在T1 DM的早期出现。虽然动脉粥样硬化导致过度的心血管 T1 DM的心血管疾病（CVD）死亡，其早期心脏代谢过程目前还没有得到很好的表征。 T1 DM患者的血浆胰岛素水平较高，因为他们必须将胰岛素直接注射到 外周循环，绕过肝脏提取。高胰岛素血症是IR的独立危险因素， 内皮功能障碍和非糖尿病人群中的CVD。因此，我们将检验医源性 在T1 DM和健康个体中，高胰岛素血症与IR和内皮功能独立相关。 为了验证这一假设，该研究将确定短期和长期高胰岛素血症的强度 暴露量（通过平均基础胰岛素浓度[INSbasal]和胰岛素每日总剂量，TDDinsulin， 分别）与胰岛素敏感性（Aim 1）和内皮功能障碍（Aim 2）相关。在T1 DM子研究中， 我们将在诊断后的12个月内对患者进行三个阶段的研究：初步诊断，部分临床诊断， 缓解期（PCR）和PCR后。每个阶段都有不同的胰岛素暴露：1）诊断后不久（TDDinsulin> 0.5 单位/kg/天），2）PCR期间，也称为“蜜月期”（TDDinsulin<0.4单位/kg/天），和3）PCR后 （TDDinsulin>0.6单位/kg/天）。在对照子研究中，我们将研究四岁以下血糖正常的健康受试者， 高胰岛素血症的固定条件：短期高胰岛素血症，长期高胰岛素血症， 短期和长期高胰岛素血症以及正常胰岛素血症。 高胰岛素、正葡萄糖钳夹技术将在每次研究访视时量化胰岛素敏感性（目的 1）。对于目标2，将在各种血管床中确定内皮功能。作为一项主要成果， 研究将量化肱动脉内皮依赖性血流介导血管舒张。作为次要 结果，对比增强超声将量化胰岛素诱导的微血管募集。 拟议的研究将为有指导的研究培训提供一个重点。主要研究者（PI） 寻求成为一个独立的物理学家，科学家的专业知识，以调查之间的关系， 代谢失调和内皮功能障碍。一个全面的，指导性的培训计划， 为PI从犬生理学研究背景过渡到翻译人类而设计 主题研究（目标1）并提高应用先进心血管研究技术的能力， 研究临床前血管功能障碍（目标2）。该培训将使PI准备使用最先进的技术 量化未来治疗对代谢和心血管的益处，以减轻医源性高胰岛素血症。

PROJECT SUMMARY/ABSTRACT Insulin resistance (IR) is consistently found in patients with type 1 diabetes (T1DM) and pathophysiologically links T1DM with atherosclerotic disease. IR and nascent atherosclerosis, as characterized by endothelial dysfunction, are present early in T1DM. Although atherosclerosis leads to excess cardiovascular disease (CVD) death in T1DM, its early cardiometabolic processes are not well-characterized currently. People with T1DM have high plasma insulin levels because they must inject insulin directly into the peripheral circulation, which bypasses hepatic extraction. Hyperinsulinemia is an independent risk factor for IR, endothelial dysfunction, and CVD in the nondiabetic population. Thus, we will test the hypothesis that iatrogenic hyperinsulinemia independently correlates with IR and endothelial function in T1DM and healthy individuals. To test this hypothesis, the study will determine how strongly short and long-term hyperinsulinemia exposure (quantified by average basal insulin concentration [INSbasal] and total daily dose of insulin, TDDinsulin, respectively) are related to insulin sensitivity (Aim 1) and endothelial dysfunction (Aim 2). In a T1DM substudy, we will study patients during three phases over the 12 months following diagnosis: initial diagnosis, partial clinical remission (PCR), and post-PCR. Each phase has distinct insulin exposure: 1) soon after diagnosis (TDDinsulin≈0.5 units/kg/day), 2) during PCR, a.k.a. “Honeymoon phase” (TDDinsulin<0.4 units/kg/day), and 3) following PCR (TDDinsulin>0.6 units/kg/day). In a Control Substudy, we will study euglycemic, healthy participants under four fixed conditions for hyperinsulinemia: short-term hyperinsulinemia, long-term hyperinsulinemia, a combination of both short and long-term hyperinsulinemia, and euinsulinemia. The hyperinsulinemic, euglycemic clamp technique will quantify insulin sensitivity at each study visit (Aim 1). For Aim 2, endothelial function will be determined in a variety of vascular beds. As a primary outcome, this investigation will quantify brachial artery endothelium-dependent flow-mediated vasodilation. As a secondary outcome, contrast enhanced ultrasound will quantify insulin-induced microvascular recruitment. The proposed studies will provide a focus for mentored research training. The primary investigator (PI) seeks to become an independent physician-scientist with the expertise to investigate the relationship between metabolic dysregulation and endothelial dysfunction in T1DM. A comprehensive, mentored training program has been devised for the PI to transition from his background in canine physiology research to translational human subjects research (goal 1) and develop proficiency applying advanced cardiovascular research techniques to study preclinical vascular dysfunction (goal 2). This training will prepare the PI to use state-of-the-art techniques to quantify the metabolic and cardiovascular benefit of future therapies to lessen iatrogenic hyperinsulinemia.