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Experimental Diabetes Research
Volume 2009 (2009), Article ID 793281, 14 pages
http://dx.doi.org/10.1155/2009/793281
Research Article

Dynamic Changes of Neuroskeletal Proteins in DRGs Underlie Impaired Axonal Maturation and Progressive Axonal Degeneration in Type 1 Diabetes

1Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
2Department of Endocrinology and Diabetes, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan
3Department of Neurology, School of Medicine, Wayne State University, Detroit, MI 48201, USA

Received 3 February 2009; Accepted 7 July 2009

Academic Editor: Jiro Nakamura

Copyright © 2009 Hideki Kamiya et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

We investigated mechanisms underlying progressive axonal dysfunction and structural deficits in type 1 BB/Wor-rats from 1 week to 10 month diabetes duration. Motor and sensory conduction velocities were decreased after 4 and 6 weeks of diabetes and declined further over the remaining 9 months. Myelinated sural nerve fibers showed progressive deficits in fiber numbers and sizes. Structural deficits in unmyelinated axonal size were evident at 2 month and deficits in number were present at 4 mo. These changes were preceded by decreased availability of insulin, C-peptide and IGF-1 and decreased expression of neurofilaments and -III-tubulin. Upregulation of phosphorylating stress kinases like Cdk5, p-GSK-3 , and p42/44 resulted in increased phosphorylation of neurofilaments. Increasing activity of p-GSK-3 correlated with increasing phosphorylation of NFH, whereas decreasing Cdk5 correlated with diminishing phosphorylation of NFM. The data suggest that impaired neurotrophic support results in sequentially impaired synthesis and postranslational modifications of neuroskeletal proteins, resulting in progressive deficits in axonal function, maturation and size.