Efficacy of a long‐acting C‐peptide analogue against peripheral neuropathy in streptozotocin‐diabetic mice

Aims To investigate the efficacy of a pegylated C ‐peptide ( P eg‐ C ‐peptide) against indices of peripheral neuropathy in a mouse model of type 1 diabetes and to compare efficacy of this C ‐peptide analogue against that of the native molecule. Methods C57Bl /6 mice were injected with two consecutive doses of streptozotocin ( STZ ) to induce type 1 diabetes. Mice were treated twice daily with native C ‐peptide [0.4–1.3 mg/kg subcutaneously (s.c.)] or twice weekly with P eg‐ C ‐peptide (0.1–1.3 mg/kg s.c.) for 20 weeks. Motor and sensory nerve conduction velocities, thermal and tactile responses and rate dependent H ‐wave depression were assessed after 20 weeks of diabetes. Foot skin intraepidermal fibres and corneal nerves were counted, and sciatic nerve substance P and plasma C ‐peptide levels were also determined. Results After 5 months of STZ ‐induced diabetes, mice exhibited significant motor and sensory nerve conduction slowing, thermal hypoalgesia, tactile allodynia and attenuation of rate‐dependent depression of the H reflex. These functional disorders were accompanied by nerve substance P depletion but not loss of small sensory fibres in the hind paw epidermis or the cornea. The efficacy of twice‐daily treatment with native C ‐peptide in preventing these disorders was matched or exceeded by twice‐weekly treatment with P eg‐ C ‐peptide. Both native and P eg‐ C ‐peptide also increased corneal nerve occupancy in the sub‐basal nerve plexus of control rats. Conclusions These data identify actions of C ‐peptide against novel and clinically pertinent aspects of diabetic neuropathy in mice and also establish P eg‐ C ‐peptide as a long‐acting therapeutic method of potential clinical value.