The C-peptide Signaling

For years an assumption was made that C-peptide, a byproduct of insulin biosynthesis, possessed no appreciable physiologic role. As other contributions in this volume amply testify, the time has come to re-evaluate that notion. C-peptide either directly through interaction with its specific cell-surface receptor or indirectly through an interaction with a related membrane entity, exerts a unique effect on several intracellular processes.We review here results of studies attempting to elucidate such molecular effects of C-peptide in different cell systems and tissues. Lacking a purified C-peptide receptor, we also demonstrate C-peptide effects on distinct elements of the insulin signal transduction pathways

Structure-function interactions in the therapeutic response of diabetic neuropathy

Conventional electrophysiologic measurements such as nerve conduction velocity, compound action potential, and neuropathic symptom scores have been used to assess the severity of diabetic neuropathy and have been the major efficacy end points following pharmacologic intervention trials. Unfortunately, these measurements are not particularly sensitive and their reproducibility is, at best, good. Detailed morphometric analysis of sural nerve biopsies has evolved as a sensitive and highly reproducible method for assessing the severity and progression of diabetic peripheral neuropathy. In this study we demonstrate highly significant correlations between morphometric parameters of diabetic sural nerves and electrophysiologic and sensory score measurements of the same sural nerve. These data suggest that detailed morphometric examination is a more sensitive and reproducible method for assessing the severity of diabetic neuropathy, and that quantitative morphometric parameters provide sensitive indicators of electrophysiologic and clinically meaningful nerve damage. Morphometric analysis of sural nerve biopsies therefore constitutes a rational basis for sensitive efficacy end points in the design of future therapeutic clinical trials.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30284/1/0000686.pd

The Insulin-Like Growth Factor System and Neurological Complications in Diabetes

The IGF system plays vital roles in neuronal development, metabolism, regeneration and survival. It consists of IGF-I, IGF-II, insulin, IGF-I-receptor, and those of IGF-II and insulin as well as IGF-binding proteins. In the last decades it has become clear that perturbations of the IGF system play important roles in the pathogenesis of diabetic neurological complications. In the peripheral nervous system IGF-I, insulin, and C-peptide particularly in type 1 diabetes participate in the development of axonal degenerative changes and contributes to impaired regenerative capacities. These abnormalities of the IGF system appear to be less pronounced in type 2 diabetes, which may in part account for the relatively milder neurological complications in this type of diabetes. The members of the IGF system also provide anti-apoptotic effects on both peripheral and central nervous system neurons. Furthermore, both insulin and C-peptide and probably IGF-I possess gene regulatory capacities on myelin constituents and axonal cytoskeletal proteins. Therefore, replenishment of various members of the IGF system provides a reasonable rational for prevention and treatment of diabetic neurological complications

C-Peptide Prevents Hippocampal Apoptosis in Type 1 Diabetes

To explore mechanisms underlying central nervous system (CNS) complications in diabetes, we examined hippocampal neuronal apoptosis and loss, and the effect of C-peptide replacement in type 1 diabetic BB/W rats. Apoptosis was demonstrated after 8 months of diabetes, by DNA fragmentation, increased number of apoptotic cells, and an elevated ratio of Bax/Bcl-xL, accompanied by reduced neuronal density in the hippocampus. No apoptotic activity was detected and neuronal density was unchanged in 2-month diabetic hippocampus, whereas insulin-like growth factor (IGF) activities were impaired. In type 1 diabetic BB/W rats replaced with C-peptide, no TdT-mediated dUTP nick-end labeling (TUNEL)- positive cells were shown and DNA laddering was not evident in hippocampus at either 2 or 8 months. C-peptide administration prevented the preceding perturbation of IGF expression and reduced the elevated ratio of Bax/Bcl-xL. Our data suggest that type 1 diabetes causes a duration-dependent programmed cell death of the hippocampus, which is partially prevented by C-peptide

Avaliação por multicritérios de apoio à decisão da inovação no arranjo produtivo local de pêssego indústria.

Projeto/Plano de Ação: 11.11.11.111

Human C-peptide Dose Dependently Prevents Early Neuropathy in the BB/Wor-rat

In order to explore the neuroprotective and crossspecies activities of.C-peptide on type 1 diabetic neuropathy, spontaneously diabetic BB/W-rats were given increasing doses of human recombinant Cpeptide (hrC-peptide). Diabetic rats received 10, 100, 500, or 1000 μg of hrC-peptide/kg body weight/ day from onset of diabetes. After 2 months of hrC-peptide administration, 100 μg and greater doses completely prevented the nerve conduction defect, which was associated with a significant but incomplete prevention of neural Na+/K+-ATPase activity in diabetic rats with 500 μg or greater C-peptide replacement. Increasing doses of hrC-peptide showed increasing prevention of early structural abnormalities such as paranodal swelling and axonal degeneration and an increasing frequency of regenerating sural nerve fibers. We conclude that hrC-peptide exerts a dose dependent protection on type 1 diabetic neuropathy in rats and that this effect is probably mediated by the partially conserved sequence of the active C-terminal pentapeptid