C‐peptide prevents nociceptive sensory neuropathy in type 1 diabetes

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Abstract
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