Protective Factors Against the Development of Microvascular Complications

描述（由申请人提供）：确定糖尿病并发症机制的研究主要集中在高血糖的毒性作用上。关于内源性保护因子可以预防或中和高血糖影响的研究很少。我们研究了一大批胰岛素依赖50年或以上的患者（奖牌获得者）。临床特征显示87%和35%的获奖者无肾病和视网膜病变。血红蛋白（Hg） Ale水平、持续时间、胰岛素剂量和剩余胰岛素产生与并发症状态无关。在初步研究中，两种晚期糖基化终产物与并发症减少相关，两种与糖基化终产物水平升高相关。其他生化指标，蛋白激酶6和酪氨酸磷酸酶（SHP-1），与高HgA1c患者缺乏增殖性糖尿病视网膜病变（PDR）相关。此外，一项针对奖牌获得者的试点跟踪研究确定了一组受PDR保护的受试者。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，以确定他们在这个独特的队列。这些项目包括：1)通过纵向、横断面和对照组研究，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）确定的传统和新型因素与并发症状态的统计关联能力。

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.