Biochemical Nature and Significance of Skin Autofluorescence in Diabetes

糖尿病皮肤自发荧光的生化性质和意义

• 批准号: 7474782
• 负责人: DAVID Raymond SELL
• 金额: $ 22.71万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474782
• 关键词: Advanced Glycosylation End Products; Am 80; Animal Model; Atherosclerosis; Autopsy; Biochemical; Biopsy; Calcium; Cardiovascular Diseases; Carotid Arteries; Cessation of life; Chemicals; Clinical Research; Collagen; Cornea; Coronary artery; Data; Deposition; Development; Diabetes Mellitus; Diabetic Angiopathies; Disease Progression; End stage renal failure; Epidemiology; Fluorescence; Future; Human; Hyperglycemia; Hyperlipidemia; Immunohistochemistry; In Situ; Individual; Insulin-Dependent Diabetes Mellitus; Intervention; Kidney Diseases; Laboratories; Leukocyte L1 Antigen Complex; Link; Literature; Lysine; Measures; Methodology; Modification; Monitor; Names; Nature; Participant; Persons; Prevention; Proteins; Recording of previous events; Research; Retinal Diseases; Risk; Risk Assessment; Rodent; Score; Severities; Skin; Structure; Time; Tissues; Vascular Diseases; cyclophosphamide/doxorubicin/lomustine protocol; diabetic; fluorophore; glycation; in vivo; novel; sugar

DESCRIPTION (provided by applicant): Excess sugars in the diabetic milieu induce proteins with slow turnover to accumulate yellow and fluorescent modifications which may serve as markers for a person's past glycemic history and potential for future complications. The objective is to elucidate the biochemical nature of skin auto-fluorescence that has been widely used in the diabetes literature as a presumptive and recently proposed noninvasive marker for advanced glycation end-product "AGE"-formation. In 1993, this laboratory was able to obtain skin biopsies from 216 participants with type 1 diabetes in the DCCT study and quantitate various AGE markers of glycemic exposure and damage. Strong correlations between skin levels and severity of micro-vascular disease as well as decrease in skin levels of AGEs were noted in subjects undergoing intensive vs. conventional therapy for hyperglycemia. Four and eight years later, these associations were reevaluated in the EDIC trial, and to our surprise, several of the markers were found to predict the risk of progression of retinopathy and nephropathy. Most surprisingly, however, only one marker of unknown chemical origin named "collagen-linked long-wavelength fluorescence" ("LW') was found to predict the risk of calcium deposition and atherosclerosis progression as measured by coronary artery calcium deposition "CAC" at all CAC scores; i.e., >0, >100, and >200. Specific aims are: (1) elucidate the structure of the novel marker of atherosclerosis progression yet elusive fluorophore "LW" in skin ; (2) To quantitate LW in skin biopsy collagen obtained at the time of DCCT closeout, and determine its ability to predict risk of macro- and micro-vascular disease in the EDIC; (3) To determine the quantitative relationship between LW in skin and carotid artery and the in situ relationship between LW formation and calcium deposition in autopsy tissue from individuals with diabetes and end-stage renal disease; and (4) to determine the in vivo mechanism of LW-1 formation and prevention of formation in animal models of diabetes and hyperlipidemia. Because LW fluorescence can be monitored non-invasively in cornea and skin, this research may have broad implications for the development of novel methodologies for assessment of the risk for macro-vascular disease progression in diabetes.

描述（由申请人提供）：糖尿病环境中的过量糖会诱导蛋白质缓慢流动率，以积累黄色和荧光修饰，这可能是一个人过去的血糖病史的标志物，并可能导致未来并发症。目的是阐明在糖尿病文献中广泛使用的皮肤自动荧光的生化性质，作为一种推定，最近提出的用于晚期糖基化末端产物“年龄”形式的无创标记。 1993年，该实验室能够在DCCT研究中从216名患有1型糖尿病的参与者中获得皮肤活检，并量化血糖暴露和损害的各种年龄标记。皮肤水平与微血管疾病的严重程度之间的密切相关性以及年龄较大的皮肤水平降低在接受高血糖的受试者与常规治疗的受试者中。四年和八年后，这些关联在EDIC试验中得到了重新评估，令我们惊讶的是，发现了一些标记可以预测视网膜病变和肾病的进展风险。然而，最令人惊讶的是，发现只有一个未知的化学起源标记为“胶原蛋白连接的长波长荧光”（“ LW'）可以预测钙沉积和动脉粥样硬化进展的风险，如冠状动脉钙钙沉积的“ CAC”在所有CAC分数中的CAC“ CAC”在所有CAC分数中; i.e.i.e.e.，> 0，> 0，> 0，> 100，> 100，以及特定的ELUC secters（1）。 atherosclerosis progression yet elusive fluorophore "LW" in skin ; (2) To quantitate LW in skin biopsy collagen obtained at the time of DCCT closeout, and determine its ability to predict risk of macro- and micro-vascular disease in the EDIC; (3) To determine the quantitative relationship between LW in skin and carotid artery and the in situ relationship between LW formation and calcium deposition in autopsy tissue from individuals糖尿病和终阶段肾脏疾病；由于可以在角膜和皮肤中非侵入性地监测LW荧光，因此这项研究可能对开发新方法的发展具有广泛的影响，以评估糖尿病中宏观血管疾病进展的风险。

项目成果

Evidence of glucuronidation of the glycation product LW-1: tentative structure and implications for the long-term complications of diabetes.

• DOI: 10.1007/s10719-017-9810-7
• 发表时间: 2018-04
• 期刊: Glycoconjugate journal
• 影响因子: 3
• 作者: Sell DR;Nemet I;Liang Z;Monnier VM
• 通讯作者: Monnier VM

Effect of chronic hypoxia on RAGE and its soluble forms in lungs and plasma of mice.

• DOI: 10.1016/j.bbadis.2015.02.003
• 发表时间: 2015-05
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
• 影响因子: 6.2
• 作者: Gopal, P.;Gosker, H. R.;de Theije, C. C.;Eurlings, I. M.;Sell, D. R.;Monnier, V. M.;Reynaert, N. L.
• 通讯作者: Reynaert, N. L.