Abstract
We investigated the pathophysiology of diet-induced diabetes in the Cohen diabetic rat (CDs/y) from its induction to its chronic phase, using a multi-layered integrated genomic approach. We identified by linkage analysis two diabetes-related quantitative trait loci on RNO4 and RNO13. We determined their functional contribution to diabetes by chromosomal substitution, using congenic and consomic strains. To identify within these loci genes of relevance to diabetes, we sequenced the genome of CDs/y and compared it to 25 other rat strains. Within the RNO4 locus, we detected a novel high impact deletion in the Ndufa4 gene that was unique to CDs/y. Within the RNO13 locus, we found multiple SNPs and INDELs that were unique to CDs/y but were unable to prioritize any of the genes. Genome wide screening identified a novel third locus not detected by linkage analysis that consisted of a novel high impact deletion on RNO11 that was unique to CDs/y and that involved the Sdf2l1 gene. Using co-segregation analysis, we investigated in silico the relative contribution to the diabetic phenotype and the interaction between the three genomic loci on RNO4, RNO11 and RNO13. We found that the RNO4 locus plays a major role during the induction of diabetes, whereas the genomic loci on RNO13 and RNO11, while interacting with the RNO4 locus, contribute more significantly to the diabetic phenotype during the chronic phase of the disease. The mechanisms whereby the mutations on RNO4 and 11 and the RNO13 locus contribute to the development of diabetes are under continuing investigation.
Highlights
The pathophysiological basis of diabetes remains elusive, most likely because of the heterogeneity of the disease, the complexity of the pathogenesis involved and the simultaneous involvement of multiple pathways that act, interact and are regulated by a multitude of not yet fully understood variables
blood glucose level (BGL) in CDs/y-diabetogenic diet (DD) rose to a peak at 60 min, gradually dropping thereafter, with peak levels steadily increasing from 1 to 4 months, whereas in SBN/y-DD, BGL rose to a peak at 30 min to lower values than in CDs/y and did not increase over time
After 2.5 months of DD, BGL in the consomic and congenic strains were no longer different from CDs/y, yet were significantly higher than in CDr/y (Figure 6, panels C and D). These findings suggest that during the initiation phase of diabetes, the full expression of the diabetic phenotype is dependent upon the presence of CDs/y alleles at the RNO4 genomic locus, but much less so in the chronic phase of the disease, during which other genomic loci are likely to contribute more importantly to the phenotype
Summary
The pathophysiological basis of diabetes remains elusive, most likely because of the heterogeneity of the disease, the complexity of the pathogenesis involved and the simultaneous involvement of multiple pathways that act, interact and are regulated by a multitude of not yet fully understood variables. We investigated the pathophysiology of diabetes in the Cohen rodent model of diet-induced diabetes [1] In this experimental model, diabetes is induced during the initiation phase by feeding genetically susceptible animals over 1 month with a customdesigned diabetogenic diet (DD) that is copper deficient and β-casein rich, the two major dietary culprits that we have identified as contributing to the development of the disease [2]. Diabetes is induced during the initiation phase by feeding genetically susceptible animals over 1 month with a customdesigned diabetogenic diet (DD) that is copper deficient and β-casein rich, the two major dietary culprits that we have identified as contributing to the development of the disease [2] Thereafter, diabetes in this model evolves into its chronic phase over the subsequent months, as long as the animals continue to be fed with DD [3,2]
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