Molecular alterations underlie nodal and paranodal degeneration in type 1 diabetic neuropathy and are prevented by C-peptide.
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 beta, and the Na(+)-channel beta(1) subunit, paranodal caspr and nodal ankyrin(G) 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 alpha-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 ankyrin(G) 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.
Sima
Anders A F
AA
Wayne State University, Department of Pathology, 540 E. Canfield Avenue, Detroit, MI 48201, USA. asima@med.wayne.edu
Zhang
Weixian
W
Li
Zhen-Guo
ZG
Murakawa
Yuichi
Y
Pierson
Christopher R
CR
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D002096:C-Peptide / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics; D003929:Diabetic Neuropathies / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D009431:Neural Conduction / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011901:Ranvier's Nodes / Q000378:metabolism*; D051381:Rats; D011913:Rats, Inbred BB; D012584:Sciatic Nerve / Q000378:metabolism
D001786:Blood Glucose; D002096:C-Peptide; D006442:Glycated Hemoglobin; D007328:Insulin