RENAL AND CELLULAR STUDIES IN TYPE I DIABETIC PATIENTS

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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.