Journal
NEUROBIOLOGY OF DISEASE
Volume 73, Issue -, Pages 348-355Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.10.015
Keywords
Type-2 diabetes; Obesity; Diabetic neuropathy; Mouse model; Leptin; Gene expression analysis; Functional enrichment; Inflammation; Cytokine; Matrix metalloproteinase
Categories
Funding
- National Institutes of Health [1DP3DK094292, 1R24082841]
- Juvenile Diabetes Research Foundation International
- American Diabetes Association [7-12-BS-045]
- Program for Neurology Research Discovery
- A. Alfred Taubman Medical Research Institute
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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 immunerelated 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. (C) 2015 Elsevier Inc. All rights reserved.
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