Validation of Potential Protective Factors from Diabetic Complications

描述(申请人提供)：确定糖尿病视网膜病变(DR)和糖尿病肾病(DN)的保护因素可以为预防和阻止这两种毒性并发症显著降低生活质量提供重要的生物标志物和治疗剂。利用病龄超过50年的1型糖尿病(T1 DM)患者(奖牌获得者)这一独特人群，我们已经开始通过尸检研究确定糖尿病视网膜病变和糖尿病肾病的潜在保护因素。我们通过临床检查、混合餐耐受试验、广泛的眼科检查和病史问卷对600多名奖牌获得者进行了广泛的特征描述。令人惊讶的是，35%的人没有或只有轻度糖尿病视网膜病变(ETDRS&lt；53)，而只有不到14%的人有糖尿病肾病(ACR&lt；70微克/毫克)。死后组织学检查证实了这些发现。到目前为止，已经捐赠了超过16名奖牌获得者的尸检标本。来自视网膜、玻璃体和肾小球的标本的蛋白质组学图谱已经确定了第一组对DR和DN的潜在保护因素。这是通过比较受影响组织和未受影响组织的蛋白质表达来完成的。根据路径图和文献综述，肾小球分析中确定的14个候选蛋白都参与了燃料代谢。视网膜分析中确定的10个因素涉及膜循环、运输、光传导的恢复和视网膜功能。生物信息学途径分析表明，DR的候选基因与糖尿病肾病的候选基因没有重叠；然而，这两组保护因素都表明，与有相应条件的奖牌获得者相比，没有DR或糖尿病肾病的奖牌获得者存在更有活力和代谢活性的组织。这项研究建议对奖牌获得者和另一组超快进展的糖尿病患者的血浆和循环细胞中所有已识别和确认的候选对象进行测量。此外，将在培养的视网膜血管、肾小球和肾小管上皮细胞模型中研究防止高血糖暴露的能力。我们还将能够确定这些潜在的保护因子在糖尿病细胞培养模型和体内动物模型中的生物学作用。通过这些翻译研究，我们将能够识别和确认与DR和DN相关的潜在保护因素。 公共卫生相关性：临床上，对存活超过50年的糖尿病患者的研究清楚地表明，内源性保护因素可以在极端时期内预防和推迟糖尿病微血管并发症的发生。因此，未来糖尿病血管并发症的治疗方法需要减少高血糖的毒性作用，并增加保护/生存因子的作用才能有效。

DESCRIPTION (provided by applicant): The identification of protective factors for Diabetic Retinopathy (DR) and Diabetic Nephropathy (DN) could provide important biomarkers and therapeutic agents to prevent and halt these two toxic complications from significantly diminishing quality of life. Using a unique population of type 1 diabetic (T1DM) patients with more than 50 years of disease (Medalists), we have begun to identify potential protective factors for DR and DN through pre and post mortem studies. We have extensively characterized over 600 Medalists through clinical examination, mixed meal tolerance test, extensive ophthalmic examination, and medical history questionnaires. Surprisingly, 35% have no or only mild DR (ETDRS <53), and less than 14% have DN (ACR <70 mcg/mg). Post-mortem histologic examinations confirm these findings. Thus far, post-mortem specimens from over 16 Medalist Study participants have been donated. Proteomic mapping of the specimens from the retina, vitreous, and renal glomeruli have identified a first set of potential protective factors for DR and DN. This was done by comparing protein expression between affected and unaffected tissues. According to pathway mapping and literature review, the fourteen candidate proteins identified in the glomerular analysis are all involved in fuel metabolism. The 10 factors identified in the retina analysis are involved in membrane recycling, transport, recovery of phototransduction, and retinal function. Bioinformatic pathway analyses demonstrate that the candidates identified for DR do not overlap with those for DN; however, both sets of protective factors suggest that more vibrant and metabolically active tissues exist in Medalists without DR or DN compared to those with the respective conditions. This study proposes to measure all of the identified and validated candidates in the plasma and circulating cells in the Medalists and in another unusual group of diabetic patients with ultra-fast progression. Additionally, the ability to protect against hyperglycemic exposure will be studied in cultured retinal vascular and renal glomerular and tubular cell models of DR and DN. We will also be able to determine the biological actions of these potential protective factors both in cell culture models and in vivo animal models of diabetes. From these translational studies, we will be able to identify and confirm potential protective factors associated with DR and DN. PUBLIC HEALTH RELEVANCE: Clinically, studies in diabetic patients who have survived greater than 50 years of disease duration clearly have demonstrated that endogenous protective factors can prevent and delay for extreme periods of time the onset of diabetic microvascular complications. Thus, therapeutic approach in the future for diabetic vascular complications needs to decrease the toxic effects of hyperglycemia as well as increase the actions of protective/survival factors in order to be effective.