c-peptide and Nerve-Degeneration

Diabetic polyneuropathy (DPN) is the most common late diabetic complication, and is more frequent and severe in the type 1 diabetic population. Currently, no effective therapy exists to prevent or treat this complication. Hyperglycemia remains a major therapeutic target when dealing with DPN in both type 1 and type 2 diabetes, and should be supplemented by aldose reductase inhibition and antioxidant treatment. However, in the past few years, preclinical and clinical data have indicated that factors other than hyperglycemia contribute to DPN, and these factors account for the disproportionality of prevalence of DPN between the two types of diabetes. Insulin and C-peptide deficiencies have emerged as important pathogenetic factors and underlie the acute metabolic abnormalities, as well as serious chronic perturbations of gene regulatory mechanisms, impaired neurotrophism, protein-protein interactions and specific degenerative disorders that characterize type 1 DPN. It has become apparent that in insulin-deficient conditions, such as type 1 diabetes and advanced type 2 diabetes, both insulin and C-peptide must be replaced in order to gain hyperglycemic control and to combat complications. As with any chronic ailment, emphasis should be on the prevention of DPN; as the disease progresses, metabolic interventions, be they directed against hyperglycemia and its consequences or against insulin/ C-peptide deficiencies, are likely to be increasingly ineffective.

Topics: Aldehyde Reductase; Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Hyperglycemia; Lipid Metabolism; Nerve Degeneration; Nerve Growth Factor; Oxidative Stress; Polymers

Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Hearing Loss, Sensorineural; Liraglutide; Male; Nerve Degeneration; Optic Nerve; Phenotype; Rats; Visual Pathways; Wolfram Syndrome

To explore the molecular abnormalities underlying the degeneration of the node of Ranvier, a characteristic aberration of type 1 diabetic neuropathy, we examined in type 1 BB/Wor and type 2 BBZDR/Wor rats changes in expression of key molecules that make up the nodal and paranodal apparatus of peripheral nerve. Their posttranslational modifications were examined in vitro. Their responsiveness to restored insulin action was examined in type 1 animals replenished with proinsulin C-peptide. In sciatic nerve, the expression of contactin, receptor protein tyrosine phosphatase beta, and the Na(+)-channel beta(1) subunit, paranodal caspr and nodal ankyrin(G) was unaltered in 2-month type 1 diabetic BB/Wor rats but significantly decreased after 8 months of diabetes. These abnormalities were prevented by C-peptide administered to type 1 BB/Wor rats and did not occur in duration- and hyperglycemia-matched type 2 BBZDR/Wor rats. The expression of the alpha-Na(+)-channel subunit was unaltered. In SH-SY5Y cells, only the combination of insulin and C-peptide normalized posttranslational O-linked N-acetylglucosamine modifications and maximized serine phosphorylation of ankyrin(G) and p85 binding to caspr. The beneficial effects of C-peptide resulted in significant normalization of the nerve conduction deficits. These data describe for the first time the progressive molecular aberrations underlying nodal and paranodal degenerative changes in type 1 diabetic neuropathy and demonstrate that they are preventable by insulinomimetic C-peptide.

Topics: Animals; Blood Glucose; Blotting, Western; C-Peptide; Cell Line, Tumor; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Glycated Hemoglobin; Humans; Immunohistochemistry; Insulin; Nerve Degeneration; Neural Conduction; Peripheral Nervous System Diseases; Protein Processing, Post-Translational; Ranvier's Nodes; Rats; Rats, Inbred BB; Sciatic Nerve

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.

Topics: Animals; C-Peptide; Cytoskeletal Proteins; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Disease Models, Animal; Immunohistochemistry; Insulin; Insulin-Like Growth Factor I; Male; Nerve Crush; Nerve Degeneration; Nerve Growth Factor; Nerve Growth Factors; Nerve Regeneration; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred BB; Receptor, IGF Type 1; Receptors, Nerve Growth Factor; Sciatic Nerve

The hippocampus of rats with uncontrolled insulin-dependent diabetes undergoes retraction and simplification of apical dendrites of the CA3 pyramidal neurons and synaptic rearrangements within mossy fiber terminals that could alter hippocampal connectivity and function. The intraperitoneal implantation of hydrophilic agarose macrobeads containing porcine islets for 17 days in rats with streptozotocin-induced diabetes results in normalization of body weight gain, significant control of hyperglycemia and prevention of hippocampal dendritic remodeling, and therefore, provides an effective therapeutic option.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Capsules; Dendrites; Diabetes Mellitus, Experimental; Glucagon; Graft Survival; Hippocampus; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans Transplantation; Male; Nerve Degeneration; Peritoneum; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Swine; Treatment Outcome