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Diabetes 53:1556-1563, 2004
© 2004 by the American Diabetes Association, Inc.
Molecular Alterations Underlie Nodal and Paranodal Degeneration in Type 1 Diabetic Neuropathy and Are Prevented by C-Peptide
1 Department of Pathology, Wayne State University, Detroit, Michigan
2 Department of Neurology, Wayne State University, Detroit, Michigan
3 Morris Hood Jr. Comprehensive Diabetes Center, Wayne State University and Detroit Medical Center, Detroit, Michigan
To explore the molecular abnormalities underlying the degeneration of the node of Ranvier, a characteristic aberration of type 1 diabetic neuropathy, we examined in type 1 BB/Wor and type 2 BBZDR/Wor rats changes in expression of key molecules that make up the nodal and paranodal apparatus of peripheral nerve. Their posttranslational modifications were examined in vitro. Their responsiveness to restored insulin action was examined in type 1 animals replenished with proinsulin C-peptide. In sciatic nerve, the expression of contactin, receptor protein tyrosine phosphatase ß, and the Na+-channel ß1 subunit, paranodal caspr and nodal ankyrinG was unaltered in 2-month type 1 diabetic BB/Wor rats but significantly decreased after 8 months of diabetes. These abnormalities were prevented by C-peptide administered to type 1 BB/Wor rats and did not occur in duration- and hyperglycemia-matched type 2 BBZDR/Wor rats. The expression of the 
-Na+-channel subunit was unaltered. In SH-SY5Y cells, only the combination of insulin and C-peptide normalized posttranslational O-linked N-acetylglucosamine modifications and maximized serine phosphorylation of ankyrinG and p85 binding to caspr. The beneficial effects of C-peptide resulted in significant normalization of the nerve conduction deficits. These data describe for the first time the progressive molecular aberrations underlying nodal and paranodal degenerative changes in type 1 diabetic neuropathy and demonstrate that they are preventable by insulinomimetic C-peptide.
Address correspondence and reprint requests to Anders A.F. Sima, MD, PhD, Wayne State University, Department of Pathology, 540 E. Canfield Avenue, Detroit, MI 48201. E-mail: asima{at}med.wayne.edu
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