Effects of proinsulin C-peptide in experimental diabetic neuropathy: vascular actions and modulation by nitric oxide synthase inhibition.
Proinsulin C-peptide treatment can partially prevent nerve dysfunction in type 1 diabetic rats and patients. This could be due to a direct action on nerve fibers or via vascular mechanisms as C-peptide stimulates the nitric oxide (NO) system and NO-mediated vasodilation could potentially account for any beneficial C-peptide effects. To assess this further, we examined neurovascular function in streptozotocin-induced diabetic rats. After 6 weeks of diabetes, rats were treated for 2 weeks with C-peptide to restore circulating levels to those of nondiabetic controls. Additional diabetic groups were given C-peptide with NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA) co-treatment or scrambled C-peptide. Diabetes caused 20 and 16% reductions in sciatic motor and saphenous sensory nerve conduction velocity, which were 62 and 78% corrected, respectively, by C-peptide. L-NNA abolished C-peptide effects on nerve conduction. Sciatic blood flow and vascular conductance were 52 and 41%, respectively, reduced by diabetes (P < 0.001). C-peptide partially (57-66%) corrected these defects, an effect markedly attenuated by L-NNA co-treatment. Scrambled C-peptide was without effect on nerve conduction or perfusion. Thus, C-peptide replacement improves nerve function in experimental diabetes, and the data are compatible with the notion that this is mediated by a NO-sensitive vascular mechanism.
Cotter
Mary A
MA
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Scotland, UK.
Ekberg
Karin
K
Wahren
John
J
Cameron
Norman E
NE
D000818:Animals; D002096:C-Peptide / Q000097:blood*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology
D002096:C-Peptide; D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019001:Nitric Oxide Synthase