Molecular alterations underlie nodal and paranodal degeneration in type 1 diabetic neuropathy and are prevented by C-peptide

Abstract

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 post-translational modifications were examined in vitro. Their responsiveness to restored insulin action was examined in type I animals replenished with proinsulin C-peptide. In sciatic nerve, the expression of contactin, receptor protein tyrosine phosphatase β, and the Na +-channel β1 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 α-Na+-cltannel 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.