title: BTBR ob/ob mice as a novel diabetic neuropathy model: Neurological characterization and gene expression analyses.
abstract: Given the lack of treatments for diabetic neuropathy (DN), a common diabetic complication, accurate disease models are necessary. Characterization of the leptin-deficient BTBR ob/ob mouse, a type 2 diabetes model, demonstrated that the mice develop robust diabetes coincident with severe neuropathic features, including nerve conduction deficits and intraepidermal nerve fiber loss by 9 and 13 weeks of age, respectively, supporting its use as a DN model. To gain insight into DN mechanisms, we performed microarray analysis on sciatic nerve from BTBR ob/ob mice, identifying 1503 and 642 differentially expressed genes associated with diabetes at 5 and 13 weeks, respectively. Further analyses identified overrepresentation of inflammation and immune-related functions in BTBR ob/ob mice, which interestingly were more highly represented at 5 weeks, an observation that may suggest a contributory role in DN onset. To complement the gene expression analysis, we demonstrated that protein levels of select cytokines were significantly upregulated at 13 weeks in BTBR ob/ob mouse sciatic nerve. Furthermore, we compared our array data to that from an established DN model, the C57BKS db/db mouse, which reflected a common dysregulation of inflammatory and immune-related pathways. Together, our data demonstrate that BTBR ob/ob mice develop rapid and robust DN associated with dysregulated inflammation and immune-related processes.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Phillipe D
authors.initials: PD
authors.lastname: O'Brien
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Junguk
authors.initials: J
authors.lastname: Hur
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hayes
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Carey
authors.initials: C
authors.lastname: Backus
authors.affiliation: A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Sakowski
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: efeldman@umich.edu.
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010641:Phenotype; D012584:Sciatic Nerve / Q000378:metabolism*
chemical_list: D016207:Cytokines
keywords: Cytokine; Diabetic neuropathy; Functional enrichment; Gene expression analysis; Inflammation; Leptin; Matrix metalloproteinase; Mouse model; Obesity; Type-2 diabetes