title: C-peptide corrects endoneurial blood flow but not oxidative stress in type 1 BB/Wor rats.
abstract: Oxidative stress and neurovascular dysfunction have emerged as contributing factors to the development of experimental diabetic neuropathy (EDN) in streptozotocin-diabetic rodents. Additionally, depletion of C-peptide has been implicated in the pathogenesis of EDN, but the mechanisms of these effects have not been fully characterized. The aims of this study were therefore to explore the effects of diabetes on neurovascular dysfunction and indexes of nerve oxidative stress in type 1 bio-breeding Worcester (BB/Wor) rats and type 2 BB Zucker-derived (ZDR)/Wor rats and to determine the effects of C-peptide replacement in the former. Motor and sensory nerve conduction velocities (NCVs), hindlimb thermal thresholds, endoneurial blood flow, and indicators of oxidative stress were evaluated in nondiabetic control rats, BB/Wor rats, BB/Wor rats with rat II C-peptide replacement (75 nmol C-peptide.kg body wt(-1).day(-1)) for 2 mo, and diabetes duration-matched BBZDR/Wor rats. Endoneurial perfusion was decreased and oxidative stress increased in type 1 BB/Wor rats. C-peptide prevented NCV and neurovascular deficits and attenuated thermal hyperalgesia. Inhibition of nitric oxide (NO) synthase, but not cyclooxygenase, reversed the C-peptide-mediated effects on NCV and nerve blood flow. Indexes of oxidative stress were unaffected by C-peptide. In type 2 BBZDR/Wor rats, neurovascular deficits and increased oxidative stress were unaccompanied by sensory NCV slowing or hyperalgesia. Therefore, nerve oxidative stress is increased and endoneurial perfusion decreased in type 1 BB/Wor and type 2 BBZDR/Wor rats. NO and neurovascular mechanisms, but not oxidative stress, appear to contribute to the effects of C-peptide in type 1 EDN. Sensory nerve deficits are not an inevitable consequence of increased oxidative stress and decreased nerve perfusion in a type 2 diabetic rodent model.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA. stevensm@umich.edu
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Stevens
authors.forename: Weixian
authors.initials: W
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Anders A F
authors.initials: AA
authors.lastname: Sima
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002096:C-Peptide / Q000494:pharmacology*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply* / Q000294:innervation*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology; D007328:Insulin / Q000172:deficiency; D015227:Lipid Peroxidation; D008297:Male; D009046:Motor Neurons; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009417:Nerve Tissue / Q000098:blood supply* / Q000378:metabolism*; D009431:Neural Conduction / Q000187:drug effects; D009475:Neurons, Afferent; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D011913:Rats, Inbred BB; D011924:Rats, Zucker; D011930:Reaction Time / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D002096:C-Peptide; D004791:Enzyme Inhibitors; D007328:Insulin; D010088:Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester