C G Jolivalt1, M Rodriguez1, J Wahren2,3, N A Calcutt1. 1. Department of Pathology, University of California, San Diego, La Jolla, CA, USA. 2. Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. 3. Cebix AB, Stockholm, Sweden.
Abstract
AIMS: To investigate the efficacy of a pegylated C-peptide (Peg-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 Peg-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 Peg-C-peptide. Both native and Peg-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 Peg-C-peptide as a long-acting therapeutic method of potential clinical value.
AIMS: To investigate the efficacy of a pegylated C-peptide (Peg-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 Peg-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 Peg-C-peptide. Both native and Peg-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 Peg-C-peptide as a long-acting therapeutic method of potential clinical value.
Authors: Corinne G Jolivalt; Katie E Frizzi; May Madi Han; Andre J Mota; Lucie S Guernsey; Lakshmi P Kotra; Paul Fernyhough; Nigel A Calcutt Journal: J Pharmacol Exp Ther Date: 2020-04-23 Impact factor: 4.030
Authors: Corinne G Jolivalt; Alexandra Marquez; David Quach; Michelle C Navarro Diaz; Carlos Anaya; Betelhem Kifle; Nabeel Muttalib; Gabriela Sanchez; Lucy Guernsey; Mike Hefferan; Darrel R Smith; Paul Fernyhough; Karl Johe; Nigel A Calcutt Journal: Diabetes Date: 2019-09-06 Impact factor: 9.461
Authors: C G Jolivalt; M R Aghanoori; M C Navarro-Diaz; M M Han; G Sanchez; L Guernsey; D Quach; K Johe; P Fernyhough; N A Calcutt Journal: J Diabetes Res Date: 2022-07-04 Impact factor: 4.061