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

项目摘要/摘要 胰岛素抵抗(IR)在1型糖尿病(T1 DM)和 从病理生理学角度讲，T1 DM与动脉粥样硬化性疾病有关。IR和新生动脉粥样硬化 通过内皮功能障碍，在T1 DM早期出现。尽管动脉粥样硬化会导致心血管过度 疾病(CVD)死亡T1 DM，其早期心脏代谢过程目前尚不清楚。 患有T1 DM的人血浆胰岛素水平很高，因为他们必须直接将胰岛素注射到 外周循环，绕过肝脏摘除。高胰岛素血症是IR的独立危险因素， 非糖尿病人群中的内皮功能障碍和心血管疾病。因此，我们将检验医源性的假设 在T1 DM和健康人中，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，这项研究将确定短期和长期高胰岛素血症的强度 暴露(通过平均基础胰岛素浓度[INS基础]和胰岛素、TDDINS、 分别)与胰岛素敏感性(目标1)和内皮功能障碍(目标2)有关。在一项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 缓解期(聚合酶链式反应)和聚合酶链式反应后。每个阶段都有不同的胰岛素暴露：1)诊断后不久(TDDINS≈0.5 单位/公斤/天)，2)在聚合酶链式反应过程中，也称为“蜜月期”(TDDIns&lt；0.4单位/公斤/天)；3)在聚合酶链式反应之后 (TDDINS&GT；0.6单位/公斤/天)。在控制子研究中，我们将研究正常血糖、健康的四岁以下受试者 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， 短期和长期的高胰岛素血症和正常胰岛素血症。 高胰岛素、正血糖钳夹技术将在每次研究访问时量化胰岛素敏感性(AIM 1)。对于目标2，将在各种血管床上测定内皮功能。作为一个主要结果，这 研究将量化肱动脉内皮依赖的血流介导的血管扩张。作为次要角色 结果，超声造影将量化胰岛素诱导的微血管募集。 拟议的研究将为指导研究培训提供重点。首席调查员(PI) 寻求成为一名独立的内科医生-科学家，拥有调查 T1 DM的代谢紊乱和内皮功能障碍。一个全面的、有指导的培训计划 是为PI从狗的生理学研究背景过渡到翻译人类而设计的 受试者研究(目标1)和熟练应用先进的心血管研究技术 研究临床前血管功能障碍(目标2)。这项培训将使私家侦探准备使用最先进的技术 量化未来治疗降低医源性高胰岛素血症的代谢和心血管益处。

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.