Hideki Kamiya

C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes.

We examined the effects of C‐peptide replacement on unmyelinated fiber function in the hind paw, sural nerve C‐fiber morphometry, sciatic nerve neurotrophins, and the expression of neurotrophic receptors and content of neuropeptides in dorsal root ganglia in type 1 diabetic BB/Wor‐rats. C‐peptide replacement from onset of diabetes had no effect on hyperglycemia, but it significantly prevented progressive thermal hyperalgesia and prevented C‐fiber atrophy, degeneration, and loss. These findings were associated with preventive effects on impaired availability of nerve growth factor and neurotrophin 3 in the sciatic nerve and significant prevention of perturbed expression of insulin, insulin growth factor–1, nerve growth factor, and neurotrophin 3 receptors in dorsal root ganglion cells. These beneficial effects translated into prevention of the decreased content of dorsal root ganglia nociceptive peptides such as substance P and calcitonin gene–related peptide. From these findings we conclude that replacement of insulinomimetic C‐peptide prevents abnormalities of neurotrophins, their receptors, and nociceptive neuropeptides in type 1 BB/Wor‐rats, resulting in the prevention of C‐fiber pathology and nociceptive sensory nerve dysfunction. The data indicate that perturbed insulin/C‐peptide action plays an important pathogenetic role in nociceptive sensory neuropathy and that C‐peptide replacement may be of benefit in treating painful diabetic neuropathy in insulin‐deficient diabetic conditions. Ann Neurol 2004

Diabetic Neuropathy Differs in Type 1 and Type 2 Diabetes

Abstract:  In this article we describe differences in early metabolic abnormalities between type 1 and type 2 diabetic polyneuropathy (DPN), and how these differences lead to milder initial functional defects in type 2 diabetes, despite the same hyperglycemic exposures. This early reversible metabolic phase is progressively overshadowed by structural degenerative changes eventually resulting in nerve fiber loss. In comparison, the late structural phase of DPN affects type 1 diabetes more severely. Progressive axonal atrophy and loss is hence expressed to a larger extent in type 1 diabetes. In addition, type 1 DPN is characterized by paranodal degenerative changes not seen in type 2 DPN. These differences can be related to the differences in insulin action and signal transduction affecting the expression of neurotrophic factors and their receptors in type 1 diabetes. Downstream effects on neuroskeletal and adhesive proteins, their posttranslational modifications, and nociceptive peptides underlie the more severe resultant pathology in type 1 DPN. These differences in underlying mechanisms should be seriously considered in the future design of interventional paradigms to combat these common conditions.

Unmyelinated fiber sensory neuropathy differs in type 1 and type 2 diabetes

Neuropathic pain is common in diabetic patients. Degeneration of sensory C‐fibers in peripheral nerve plays a prominent role in the generation of neuropathic pain. We examined degenerative changes of C‐fibers in two rat models with type 1 and type 2 diabetes.

C-Peptide Reverses Nociceptive Neuropathy in Type 1 Diabetes

We examined the therapeutic effects of C-peptide on established nociceptive neuropathy in type 1 diabetic BB/Wor rats. Nociceptive nerve function, unmyelinated sural nerve fiber and dorsal root ganglion (DRG) cell morphometry, nociceptive peptide content, and the expression of neurotrophic factors and their receptors were investigated. C-peptide was administered either as a continuous subcutaneous replacement dose via osmopumps or a replacement dose given once daily by subcutaneous injection. Diabetic rats were treated from 4 to 7 months of diabetes and were compared with control and untreated diabetic rats of 4- and 7-month duration. Osmopump delivery but not subcutaneous injection improved hyperalgesia and restored the diabetes-induced reduction of unmyelinated fiber number (P < 0.01) and mean axonal size (P < 0.05) in the sural nerve. High-affinity nerve growth factor (NGF) receptor (NGFR-TrkA) expression in DRGs was significantly reduced at 4 months (P < 0.01). Insulin receptor and IGF-I receptor (IGF-IR) expressions in DRGs and NGF content in sciatic nerve were significantly decreased in 7-month diabetic rats (P < 0.01, 0.05, and 0.005, respectively). Osmopump delivery prevented the decline of NGFR-TrkA, insulin receptor (P < 0.05), and IGF-IR (P < 0.005) expressions in DRGs and improved NGF content (P < 0.05) in sciatic nerve. However, subcutaneous injection had only marginal effects on morphometric and molecular changes in diabetic rats. We conclude that C-peptide exerts beneficial therapeutic effects on diabetic nociceptive neuropathy and that optimal effects require maintenance of physiological C-peptide concentrations for a major proportion of the day.

C-peptide improves neuropathy in type 1 diabetic BB/Wor-rats.

The spontaneously diabetic BB/Wor‐rat is a close model of human type 1 diabetes and develops diabetic polyneuropathy (DPN) similar to that seen in type 1 patients. Here we examine the therapeutic effects of C‐peptide, delivered as continuous infusion or once daily subcutaneous injections on established DPN.

Dynamic Changes of Neuroskeletal Proteins in DRGs Underlie Impaired Axonal Maturation and Progressive Axonal Degeneration in Type 1 Diabetes

We investigated mechanisms underlying progressive axonal dysfunction and structural deficits in type 1 BB/Wor-rats from 1 week to 10 month diabetes duration. Motor and sensory conduction velocities were decreased after 4 and 6 weeks of diabetes and declined further over the remaining 9 months. Myelinated sural nerve fibers showed progressive deficits in fiber numbers and sizes. Structural deficits in unmyelinated axonal size were evident at 2 month and deficits in number were present at 4 mo. These changes were preceded by decreased availability of insulin, C-peptide and IGF-1 and decreased expression of neurofilaments and β-III-tubulin. Upregulation of phosphorylating stress kinases like Cdk5, p-GSK-3β, and p42/44 resulted in increased phosphorylation of neurofilaments. Increasing activity of p-GSK-3β correlated with increasing phosphorylation of NFH, whereas decreasing Cdk5 correlated with diminishing phosphorylation of NFM. The data suggest that impaired neurotrophic support results in sequentially impaired synthesis and postranslational modifications of neuroskeletal proteins, resulting in progressive deficits in axonal function, maturation and size.

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

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.

Metabolic-Functional-Structural Correlations in Somatic Neuropathies in the Spontaneously Type 1 and Type 2 Diabetic BB-Rats

Diabetic neuropathy (DPN) is a dynamic condition affecting both type 1 and type 2 diabetic subjects. It can be divided into an early and reversible metabolic phase of nerve dysfunction. This is caused by hyperglycemia-induced activation of the polyol-pathway, redox imbalances as well as by insulin/C-peptide deficiencies resulting in impaired neural Na+/K+-ATPase activity and impairment of endoneurial blood flow. Superimposed on these metabolic abnormalities, progressive structural changes evolve which become increasingly resistant to therapeutic interventions. These affect both unmyelinated and myelinated fiber populations and consist of axonal atrophy, degeneration, and loss occurring in a dying-back fashion. The underlying mechanisms include impaired neurotrophic support including perturbed insulin/C-peptide signaling, resulting in suppressed expression of neuroskeletal protein genes, and aberrant phosphorylation of these axonal building blocks. Both the early metabolic and later occurring molecular abnormalities underlying the structural abnormalities are more severely affected in type 1 DPN relating to insulin and C-peptide deficiencies, which are not present in type 2 diabetes. This distinction between the two forms of DPN also underlies nodal and paranodal degeneration unique to both human and experimental type 1 DPN. Impaired insulin action affects the expression of nodal and paranodal adhesive molecules and their post-translational modifications. Such aberrations result in disruption of the paranodal barrier function with decreased nodal Na+-channels densities and worsening of the nerve conduction defect in type 1 DPN. In conclusion, major differences exist between type 1 and type 2 DPN, which can be directly related to the absence and presence of insulin action.