| The primary goal of this dissertation was to dissect the relationships between diabetes and renal disease in an animal model that spontaneously develops both pathologies.; A second question to be addressed in these studies concerns a commonly overlooked issue, pertaining to many complex diseases. Namely, the onset and later progression of a pathologic process may not represent a linear cascade of sequential events, linked simply by a chronological exacerbation of the disease features.; To test the hypotheses that diabetes and renal disease are inherited, at least partially, independently, and that the onset and progression of each disease is determined by distinct genes, I used the GK rat, a model that spontaneously develops non-insulin-dependent diabetes mellitus (NIDDM). The first step taken in the present studies was the characterization of the GK rat as a model for spontaneous renal disease. I demonstrated that GK rats mimic key features of human diabetic nephropathy.; A genome-wide scan in the F2 progeny of across between GK/Mcw and control BN/SsNHsd/Mcw (BN) rats, at 3 months of age, identified quantitative trait loci loci (QTLs) mapping to discrete genomic segments of chromosomes 1, 5 and 10, modulating hyperglycemia. Thus, onset and progression of hyperglycemia in GK rats are distinctly determined, and the impact on glycemia of the late-onset QTL occurs independently from an earlier establishment of diabetes.; Evaluation of renal disease in the same F2 progeny described identified a QTL linked to proteinuria, mapping to chromosome 5, at all ages studied. Animals carrying GK genotypes on chromosome 5 and BN genotypes on chromosome 7 become mildly proteinuric, at early ages, but do not progress by 12 months of age.; A second strain of GK rats, GK/Fl, revealed that the onset of diabetes mellitus in these rats is retarded compared to GK/Mcw rats, corroborating the findings that the QTL on chromosome 1 is important for the onset, but the major determinant of progression lies within a distinct genomic segment.; These studies demonstrated that the onset and progression of diabetes and renal disease in GK rats are distinctly determined, and identification of certain loci in linkage studies performed in those rats is possible only if the trait is assayed at specific ages. (Abstract shortened by UMI.)... |
