RENAL AND CELLULAR STUDIES IN TYPE I DIABETIC PATIENTS

糖尿病肾病是导致肾功能衰竭的主要原因，但 对病原学的理解仍然有限。这些研究的目标 以下是：a)基于体外研究开发风险标志物 来自个体IDDM患者的细胞，这与 肾活检终点；b)询问这些标志物是否在遗传上代表 确定的过程；以及c)定义细胞之间的关系 (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/氢逆向转运蛋白与肾脏结构和 功能终点，以探索其基本致病机制 DN。此外，开发DNA和培养细胞的储存库将 允许评估遗传基因的细胞功能后果 变异显示与糖尿病肾病风险有关。三个患者组将是 研究：a)早期(10年)和长期(20年)IDDM病程 患者被分成两组，进展缓慢或迅速 糖尿病肾病损害；b)符合IDDM的同胞对；c)同卵双胞胎 对IDDM不和谐。糖尿病肾病将被量化 形态计量学和因式分解的持续时间或表示为比率 由相隔五年的两次活组织检查确定。主端点将 测量的系膜体积分数(VV MES/GLOM)为Be电子 显微形态计量分析。长期的横断面研究 IDDM患者将允许识别细胞标志物 与糖尿病肾病病变的快速或非常缓慢的发展有关 临床肾脏异常。纵向研究(五年) 短期“快”和“慢”患者和IDDM同胞配对 将允许将血糖和血压等因素考虑在内 “环境变量。”培养的皮肤成纤维细胞(SF) 将对个别患者进行上述信使核糖核酸表达的评估。 用逆转录聚合酶链式反应列出分子。 选择皮肤成纤维细胞是因为它们的表型发生了变化 “快速通道”IDDM患者，并在兄弟姐妹配对中相关。这些 研究将确定糖尿病肾病病变与SF行为和 评估此行为在IDDM兄弟姐妹对中是否一致 与糖尿病肾病的病变是一致的。非糖尿病人皮肤成纤维细胞 同卵双胞胎将回答高血糖是否对 糖尿病肾病风险的细胞标记物的表达。

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.