Plasma protein synthesis and abundance in T1 diabetes

描述(由申请人提供)： 1型糖尿病(T1D)高死亡率和高发病率的主要原因是微血管和大血管并发症，但其机制尚不清楚。T1D严格的血糖控制实质上减少了慢性微血管和急性并发症的负担，但不能减少大血管并发症。由于蛋白质是受胰岛素密切调控的关键功能分子，我们将确定循环中受T1D影响的单个蛋白质。虽然糖尿病对蛋白质代谢的整体影响已有报道，但有关个别蛋白质的信息在很大程度上是未知的。这些蛋白的鉴定可能会导致发现T1D及其并发症的标志物和/或危险因素。我们将分别使用高分辨率质谱仪和体内同位素标记来鉴定在T1 D患者血糖控制较差和严格控制期间其浓度或合成速率发生变化的血浆蛋白质。根据初步结果，我们假设，与非糖尿病对照组相比，系统性胰岛素治疗在实现血糖控制的同时，仍可能导致T1-D患者许多蛋白质合成的改变。 我们强调在这个项目中测量丰度和合成速率的重要性，以便识别浓度没有可检测到变化，但合成速率在不同状态之间有明显变化的蛋白质。第一阶段(R21)旨在测试可行性并改进分析方法。研究将在受控的短期干预期间在有限数量的受试者(T1D和非糖尿病对照组)中进行。第二阶段研究(R33)将在60名T1、D和30名临床对照中进行，分析将仅限于在第一阶段确定的候选蛋白质。研究不仅将识别血糖控制较差和严格控制状态之间变化的蛋白质，而且还将识别T1D与非糖尿病对照不同且尽管血糖控制严格但无法正常化的蛋白质。这些研究有望成为未来更详细的机制研究的基础，并有望导致T1 D的替代治疗方法。

DESCRIPTION (provided by applicant): The main causes for the high mortality and morbidity in type 1 diabetes (T1D) are microvascular and macrovascular complications but their mechanisms remain to be defined. Tight glycemic controls in T1D substantially reduced the burden of chronic microvascular and acute complications, but not macrovascular complications. Since proteins are key functional molecules that are closely regulated by insulin, we will identify the individual proteins in the circulation affected by T1D. Although the overall impact of diabetes on protein metabolism has been reported, information on the individual proteins involved is largely unknown. The identification of these proteins will potentially lead to the discovery of markers and/or risk factors for T1D and its complications. We will identify plasma proteins whose concentrations or synthesis rates are altered during both poor and tight glycemic control in T1 D patients using high resolving power mass spectrometers and in vivo isotope labeling, respectively. Based on the preliminary results, we hypothesize that systemic insulin treatment, while achieving glycemic control, may still result in altered synthesis of many proteins in T1 D patients compared to non-diabetic controls. We emphasize the importance of measuring both abundance and synthetic rates in this project, in order to identify the proteins with no detectable alterations in concentrations, but with apparent changes in synthetic rates between different states. The Phase I (R21) is designed to test the feasibility and to refine the analytical approaches. Studies will be performed in a limited number of subjects (T1D and non-diabetic controls) during controlled, short-term interventions. The Phase II studies (R33) will be conducted in sixty T1 D and 30 controls in the clinical setup, and the analysis will be confined to only the candidate proteins identified in Phase I. The studies will not only identify the proteins which are altered between poor and tight glycemic controlled states, but also the proteins which are different in T1D compared to non-diabetic controls and can not be normalized despite of tight glycemic control. These studies are anticipated to form the basis of more elaborate mechanistic studies in the future and hopefully will lead to alternative therapeutic approaches for T1 D.