The Effects of C‐peptide on Type 1 Diabetic Polyneuropathies and Encephalopathy in the BB/Wor‐rat

Abstract

Diabetic polyneuropathy (DPN) occurs more frequently in type 1 diabetes resulting in a more severe DPN. The differences in DPN between the two types of diabetes are due to differences in the availability of insulin and C-peptide. Insulin and C-peptide provide gene regulatory effects on neurotrophic factors with effects on axonal cytoskeletal proteins and nerve fiber integrity. A significant abnormality in type 1 DPN is nodal degeneration. In the type 1 BB/Wor-rat, C-peptide replacement corrects metabolic abnormalities ameliorating the acute nerve conduction defect. It corrects abnormalities of neurotrophic factors and the expression of neuroskeletal proteins with improvements of axonal size and function. C-peptide corrects the expression of nodal adhesive molecules with prevention and repair of the functionally significant nodal degeneration. Cognitive dysfunction is a recognized complication of type 1 diabetes, and is associated with impaired neurotrophic support and apoptotic neuronal loss. C-peptide prevents hippocampal apoptosis and cognitive deficits. It is therefore clear that substitution of C-peptide in type 1 diabetes has a multitude of effects on DPN and cognitive dysfunction. Here the effects of C-peptide replenishment will be extensively described as they pertain to DPN and diabetic encephalopathy, underpinning its beneficial effects on neurological complications in type 1 diabetes.

Early transcriptional regulation by C‐peptide in freshly isolated rat proximal tubular cells

“…Renal sensitivity to adenosine has been reported to increase in diabetes 33, and since adenosine plays a broad regulatory role, altered adenosine availability may have physiological consequences. C‐peptide has previously been shown to affect the transcription of several proteins 21–23. With the exception of nitric oxide synthase, those specific proteins were not affected in this study, possibly due to the short incubation time.…”

“…Cellular effects of C‐peptide include cell membrane binding 13, internalization 14, nucleolar localization 15, and several effects on the intracellular signalling pathways 16. C‐peptide has further been shown to affect gene transcription, including decreases in transforming growth factor (TGF)‐β‐induced alterations, 17, 18, increased expression of Na + ‐K + ‐ATPase catalytic α1 subunit 19, survival gene tumour necrosis factor receptor‐associated factor‐2, insulin receptor, insulin‐like growth factor‐1 20–22, ribosomal RNA 15, and normalization of fibronectin and nitric oxide synthase 3, 23. Normalization of pathologically altered gene transcription may provide a partial explanation for the beneficial effects of C‐peptide in diabetes.…”

Neuroprotection in Diabetic Encephalopathy

“…In addition to gene-regulatory effects of insulin and C-peptide on axonal cytoskeletal proteins and nerve fiber integrity, which are favorable in diabetic polyneuropathy, C-peptide is proposed to have some beneficial effects on primary diabetic encephalopathy [24] . It has been shown that C-peptide replacement partially prevents hippocampal neuronal apoptosis and cognitive deficits [25] .…”

Sesamol: a Treatment for Diabetes-Associated Blood-Brain Barrier Dysfunction

“…Microvascular dysfunction is a primary factor in the development and progression of disabilities most commonly associated with diabetes, including blindness, kidney failure, and peripheral neuropathies (1, 2, 3). Microangioapathy is clinically characterized by basement membrane thickening, cytoskeletal rearrangement, and increased paracellular leakage (4, 5).…”