RENAL AND CELLULAR STUDIES IN TYPE I DIABETIC PATIENTS

糖尿病肾病（DN）是肾功能衰竭的主要原因， 对发病机理的了解仍然有限。 这些研究的目的 a）根据体外研究开发风险标志物 来自个体IDDM患者的细胞，其与 肾活检终点; B）询问这些标志物是否代表遗传学 确定的过程;以及c）定义细胞之间的关系 (in体外）细胞外基质（ECM）分子的mRNA表达， 它们的酶和酶调节剂、生长因子、葡萄糖 转运蛋白和钠/氢反向转运蛋白以及肾结构和 功能终点，以探索基本的致病机制， DN.此外，为了开发一个DNA和培养细胞的储存库， 允许评估遗传的细胞功能后果， 这些变化与DN风险有关。 将有三组患者 研究：a）早期（10年）和长期（20年）IDDM持续时间 患者分为两组，具有缓慢或快速发展的 DN病变; B）与IDDM一致的同胞对;和c）同卵双胞胎 与IDDM不一致。将对糖尿病肾病进行定量 形态计量学和持续时间因子或表示为速率 是由相隔五年的两次活检决定的 主要终点将 系膜体积分数（Vv Mes/glom） 显微形态计量分析 长期的横断面研究 胰岛素依赖型糖尿病患者将允许识别细胞标志物 与DN病变的快速或非常缓慢的发展相关， 临床肾脏异常。 纵向研究（五年） 短期“快轨”和“慢轨”患者和IDDM同胞对 将允许考虑血压和其他因素 “环境变量。“培养的皮肤成纤维细胞（SF） 将评估个体患者的上述mRNA表达 使用逆转录酶聚合酶链反应列出分子。 选择皮肤成纤维细胞是因为它们的表型发生变化， “快速通道”的胰岛素依赖型糖尿病患者，并在兄弟姐妹对相关。 这些 研究将确定DN病变与SF行为的关系， 评估这一行为是否在患有糖尿病的兄弟姐妹中一致， 与DN病变一致。 非糖尿病皮肤成纤维细胞 同卵双胞胎将回答高血糖是否是必要的， DN风险的细胞标志物的表达。

Diabetic nephropathy (DN) is the leading cause of renal failure, yet pathogenetic understanding remains limited. Objectives of these studies are the following: a) to develop risk markers based on in vitro studies of cells derived from individual IDDM patients, which are related to renal biopsy endpoints; b) to ask if these markers represent genetically determined processes; and c) to define relationships between cellular (in vitro) expression of mRNA for extracellular matrix (ECM) molecules, their enzymes and enzyme regulators, growth factors, glucose transporters, and sodium/hydrogen antiporter and renal structural and functional endpoints in order to explore basic pathogenic mechanisms in DN. Also, to develop a repository of DNA and cultured cells that will allow evaluation of the cellular functional consequences of genetic variations shown to be linked to DN risk. Three patient groups will be studied: a) early (10 years) and long-term (20 years) IDDM duration patients dichotomized into two groups with slow or rapid development of DN lesions; b) sibling pairs concordant for IDDM; and c) identical twins discordant for IDDM. Diabetic nephropathy will be quantitated morphometrically and factored for duration or expressed as rate determined by two biopsies five years apart. The primary endpoint will be mesangial volume fraction (Vv Mes/glom) measured be electron microscopic morphometric analysis. Cross-sectional studies of long-term IDDM patients will allow the identification of cellular markers associated with rapid or very slow development of DN lesions and clinical renal abnormalities. Longitudinal studies (five years) in shorter-term "fast" and "slow-track" patients and IDDM sibling pairs will allow factoring for glycemia and blood pressure and other "environmental variables." Cultured skin fibroblasts (SF) from individual patients will be evaluated for mRNA expression for the above listed molecules using reverse transcriptase polymerase chain reaction. Skin fibroblasts are selected since changes in their phenotype occur in "fast-track" IDDM patients and are correlated in sibling pairs. These studies will determine the relationship of DN lesions to SF behavior and evaluate whether this behavior is concordant in IDDM sibling pairs who are concordant for DN lesions. Skin fibroblasts from nondiabetic identical twins will answer whether hyperglycemia is necessary for the expression of cellular markers of DN risk.