Proinsulin C-peptide deficiency partially accounts for the differences in peripheral nerve regeneration between type 1 and type 2 diabetic polyneuropathies

Diabetic polyneuropathy is the most common chronic complication of diabetes and it is responsible for the majority of limb amputations and the increased mortality of diabetic subjects. Type 1 diabetes is characterized by insulinopenia and C-peptide deficiency secondary to destruction of pancreatic R-cells by an autoimmune process, whereas type 2 diabetes is attributed to insulin resistance in insulin responsive tissues and leads to normal or elevated levels of insulin and C-peptide. C-peptide is derived from proinsulin and current studies suggest that it and insulin exert neuroprotective effects. Recent evidence indicates that the neuropathy that develops in the two main types of primary diabetes differ. This study addressed whether nerve fiber regeneration is impaired in type 2 diabetic neuropathy and it was hypothesized that the insulin and C-peptide deficiencies of type 1 diabetes contribute to the impairment of nerve fiber regeneration in this type of diabetes. Non-diabetic, type 1 BB/W-, type 2 BB/Z- and C-peptide replaced BB/W-rats were subjected to sciatic nerve crush injury. The principle mediators of immediate early gene responses, localized neurotrophic factors and cytoskeletal elements were examined in sciatic nerve distal to the crush injury and supporting L_4–5 DRGs at the protein and mRNA levels at multiple time points.; In sciatic nerve the expression of IGF-1 and NGF, both critical players in the immediate early gene response, were less delayed and attenuated in type 2 as in type 1 diabetes and C-peptide replacement in type 1 BB/W-rats partially corrected these deficits. At latter time points NGF and IGF-1 operate as localized neurotrophic factors and they were not as delayed and attenuated in type 2 and C-peptide replaced type 1 diabetic rats as in type 1 non-C-peptide replaced rats. The same scenario was evident in the case of IGF-1R and p75 expression. IGF-1R expression remained coupled to IGF-1 expression in sciatic nerve from type 2 and C-peptide replaced type 1 diabetic animals, whereas this was not the case in the type 1 BB/W-rat. In L_4–5 DRGs the expression of TrkA, IGF-1 and p75 were less altered in type 2 and C-peptide replaced type 1 animals when compared to type 1 diabetic rats.; The expression of cytoskeletal elements were not as perturbed in type 2 and C-peptide replaced type 1 rats compared to type 1 diabetic rats in L _4–5 DRGs. The expression of β-tubulins were not as attenuated and the downregulation of neurofilament protein and mRNA in L_4–5 DRGs occurred appropriately in type 2 and C-peptide replaced type 1 animals. Sciatic nerve morphometry at 20 d after crush demonstrated significantly greater axonal size and greater myelinated fiber densities in type 2 and type 1 C-peptide replaced diabetic animals compared to non-replaced type 1 animals.; In conclusion, this study demonstrated that perturbations in immediate early gene responses, localized neurotrophic factors and cytoskeletal elements are less severe in type 2 than in type 1 diabetes and that C-peptide deficiency may account for a component of this difference.