C‐peptide prevents nociceptive sensory neuropathy in type 1 diabetes

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.

C-Peptide Reverses Nociceptive Neuropathy in Type 1 Diabetes

“…Thermal plantar test. Latencies of hind paw withdrawal to thermal stimulation (42°C; 152 mW/cm 2 ) were used as measures of thermal hyperalgesia and were measured at 4 and 7 months using a UGO Biological Research apparatus (Comerio, Italy) (11,12). The time from heat source activation to the animal's self-withdrawal in seconds was measured six times in alternating hind paws.…”

“…In previous studies, we have demonstrated a relationship between impaired insulin action and suppressed neurotrophic support, decreased expression of nociceptive neuropeptides, and degeneration of their parent dorsal root ganglion (DRG) cells (11)(12)(13).…”

“…It inhibits insulin signaling at high concentrations and synergizes it at low concentrations (15)(16)(17). Previous studies have shown that it enhances the gene expression of nerve growth factor (NGF), IGF-I, and their receptors and that of the insulin receptor itself (11,18,20).…”

New insights in diabetic autonomic neuropathy in children and adolescents

“…Several experimental studies have investigated direct insulin signaling of sensory neurons in diabetic or injury models (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39): the administration of local lowdose subhypoglycemic near nerve insulin reversed ipsilateral slowing of motor conduction velocity in diabetic rats without lowering plasma glucose levels. The local injections of insulin have no impact on changes of neuropathy in other territories of the same rat (contralateral side given carrier or in the caudal nerve) (27).…”

“…A novel prospect is the possibility to administer insulin intranasally, an approach that can access the cerebrospinal fluid and has been used to treat other neurological conditions (29). Insulin is related to insulin-like growth factors in that they can cross-occupy each other's receptors and share downstream survival transduction pathways (32)(33)(34)(35).…”