title: Proinsulin C-peptide replacement in type 1 diabetic BB/Wor-rats prevents deficits in nerve fiber regeneration.
abstract: We recently reported that early gene responses and expression of cytoskeletal proteins are perturbed in regenerating nerve in type 1 insulinopenic diabetes but not in type 2 hyperinsulinemic diabetes. We hypothesized that these differences were due to impaired insulin action in the former type of diabetes. To test this hypothesis, type 1 diabetic BB/Wor-rats were replaced with proinsulin C-peptide, which enhances insulin signaling without lowering blood glucose. Following sciatic nerve crush injury, early gene responses such as insulin-like growth factor, c-fos, and nerve growth factor were examined longitudinally in sciatic nerve. Neurotrophic factors, their receptors, and beta-tubulin and neurofilament expression were examined in dorsal root ganglia. C-peptide replacement significantly normalized early gene responses in injured sciatic nerve and partially corrected the expression of endogenous neurotrophic factors and their receptors, as well as neuroskeletal protein in dorsal root ganglia. These effects translated into normalization of axonal radial growth and significantly improved axonal elongation of regenerating fibers in C-peptide-replaced BB/Wor-rats. The findings in C-peptide replaced type 1 diabetic rats were similar to those previously reported in hyperinsulinemic and iso-hyperglycemic type 2 BB/Z-rats. We conclude that impaired insulin action may be more important than hyperglycemia in suppressing nerve fiber regeneration in type 1 diabetic neuropathy.
authors.affiliation: Department of Pathology, Wayne State University, School of Medicine and Detroit Medical Center, Detroit, Michigan 48201, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
authors.forename: Weixian
authors.initials: W
authors.lastname: Zhang
authors.forename: Anders A F
authors.initials: AA
authors.lastname: Sima
mesh_terms: D000818:Animals; D002096:C-Peptide / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007328:Insulin / Q000172:deficiency* / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D009409:Nerve Crush; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011913:Rats, Inbred BB; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology
chemical_list: D002096:C-Peptide; D003598:Cytoskeletal Proteins; D007328:Insulin; D009414:Nerve Growth Factors; D016760:Proto-Oncogene Proteins c-fos; D017475:Receptors, Nerve Growth Factor; D007334:Insulin-Like Growth Factor I; D020932:Nerve Growth Factor; D017526:Receptor, IGF Type 1