Protective Factors Against the Development of Microvascular Complications

描述(由申请人提供)：确定糖尿病并发症的机制的研究主要集中在高血糖的毒性影响上。关于内源性保护性因素可以预防或中和高血糖的影响的工作很少。我们已经确定了一大群患者(奖牌获得者)的特征，他们已经依赖胰岛素50年或更长时间。临床特征显示，87%和35%的奖牌获得者没有肾病和视网膜病变。血红蛋白(Hg)水平、持续时间、胰岛素剂量和残余胰岛素产生与并发症状态无关。在初步研究中，两种晚期糖基化终末产物与减少并发症有关，两种与升高水平相关。额外的生化标记物，蛋白激酶6和酪氨酸磷酸酶(SHP-1)，与高HgA1c者缺乏增殖性糖尿病视网膜病变(PDR)相关。此外，一项对奖牌获得者的试验性后续研究确定了一组受保护的受试者，不受PDR的影响。基于支持内源性保护因素存在的试点数据，我们提出了三个协同项目，以在这一独特的队列中确定它们。这些项目是：1)利用纵向、横断面和控制组研究，扩展、描述和验证奖牌获得者队列的研究结果。增加的样本量(n=1000)将提供将传统和新因素与通过蛋白质组学(项目1)、遗传学(项目2)和诱导多能干细胞(IPSC)生物学研究(项目3)确定的并发症状态进行统计关联的能力。 2)遗传部分将包括全基因组关联研究、外周基因组测序，并与项目1合作，评估已确定的异常的细胞后果。项目1和2的结果将在没有糖尿病的年龄匹配的对照组、有或没有并发症的年轻的1型糖尿病患者组以及与我们的奖牌获得者病程相似的英国先前存在的较小的糖尿病患者队列中得到证实。3)本项目的目的是从奖牌获得者和对照组(项目1)中分离并分化为成纤维细胞、内皮细胞、肾小球系膜细胞和周细胞。这些细胞将暴露在高血糖条件和项目1和2中确定的因素中，以确定谁可以避免并发症，对照组和奖牌获得者之间的差异。获奖者的独特资质以及细胞生物学、遗传学和成人干细胞生物学领域领先团队的综合专业知识，为识别在设计1型和2型糖尿病患者血管并发症治疗方案中至关重要的保护因素带来了非凡的协同效应。 相关性：这项奖牌获得者研究的目的是在一组1型糖尿病患者中确定可以保护他们免受眼睛和肾脏疾病发展的因素，这些患者与糖尿病一起生活了50多年，没有出现任何眼睛、肾脏或神经并发症。

DESCRIPTION (provided by applicant): Studies to identify mechanisms for diabetic complications have focused on the toxic effects of hyperglycemia. There has been little work regarding endogenous protective factors that may prevent or neutralize the effects of hyperglycemia. We have characterized a large cohort of patients (Medalists) who have been insulin dependent for 50 or more years. Clinical characterization shows 87% and 35% of Medalists are free of nephropathy and retinopathy. Hemoglobin (Hg) Ale levels, duration, insulin dose, and residual insulin production did not correlate with complication status. In preliminary studies, two types of advanced glycation end products correlated with decreased complications and two with increased levels. Additional biochemical markers, protein kinase 6 and tyrosine phosphatase (SHP-1), correlated with a lack of proliferative diabetic retinopathy (PDR) in those with high HgA1c. Additionally, a pilot follow-up study of Medalists identified a group of subjects protected from PDR. Based on pilot data supporting the presence of endogenous protective factors; we propose three synergistic projects to identify them in this unique cohort. These projects are: 1) Expand, characterize and validate the findings of the Medalist cohort using both longitudinal, cross-sectional and control group studies. The increased sample size (n=1000) will provide the power to statistically relate traditional and novel factors with complication status identified through proteomic (project 1), genetic (project 2), and induced pluripotent stem cell (iPSC) biological studies (project 3). 2) The genetic component will include whole-genome association studies, exomic sequencing, and in collaboration with project 1 the evaluation of the cellular consequences of the abnormalities identified. Findings from projects 1 and 2 will be confirmed in an age-matched control group without diabetes, a younger group of type 1 diabetic patients with and without complications and a pre-existing smaller cohort of diabetic patients in the United Kingdom with similar disease duration as our Medalists. 3) The purpose of this project is to derive and differentiate IPSC from the Medalists and controls (project 1) into fibroblasts, endothelial cells, renal mesangial cells and pericytes. These cells will be exposed to hyperglycemic conditions and factors identified in projects 1 and 2 to determine the differences between who are protected from complications v controls v Medalists those not. The unique qualifies of the Medalists and the combined expertise from leading groups in cell biology, genetics and adult stem cell biology bring extraordinary synergy for identifying protective factors critical in designing therapies for vascular complications in type 1 and 2 diabetic patients. RELEVANCE: The aim of the Medalist Study is to identify factors that can protect diabetic patients from the development of eye and kidney disease in a group of type 1 diabetic patients who have survived with diabetes for more than 50 years without serious development of any eye, kidney or nerve complications.