Transcriptional Profiling of Diabetic Neuropathy in the BKS db/db Mouse A Model of Type 2 Diabetes

OBJECTIVE-A better understanding of the molecular mechanisms underlying the development and progression of diabetic neuropathy (DN) is essential for the design of mechanism-based therapies. We examined changes in global gene expression to define pathways regulated by diabetes in peripheral nerve. RESEARCH DESIGN AND METHODS-Microarray data for 24-week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes (DEGs); DEGs were further analyzed to identify regulated biological processes and pathways. Expression profile clustering was performed to identify coexpressed DEGs. A set of coexpressed lipid metabolism genes was used for promoter sequence analysis. RESULTS-Gene expression changes are consistent with structural changes of axonal degeneration. Pathways regulated in the db/db nerve include lipid metabolism, carbohydrate metabolism, energy metabolism, peroxisome proliferator-activated receptor signaling, apoptosis, and axon guidance. Promoter sequences of lipid metabolism-related genes exhibit evidence of coregulation of lipid metabolism and nervous system development genes. CONCLUSIONS-Our data support existing hypotheses regarding hyperglycemia-mediated nerve damage in DN. Moreover, our analyses revealed a possible coregulation mechanism connecting hyperlipidemia and axonal degeneration. Diabetes 60:1981-1989, 2011