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Diabetes 55:3581-3587, 2006
DOI: 10.2337/db06-0396
© 2006 by the American Diabetes Association
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C-Peptide Reverses Nociceptive Neuropathy in Type 1 Diabetes

Hideki Kamiya1,2, Weixian Zhang1,2, Karin Ekberg3, John Wahren3, and Anders A.F. Sima1,2,4

1 Department of Pathology, Wayne State University, School of Medicine, Detroit, Michigan
2 Morris Hood Jr. Comprehensive Diabetes Center, Wayne State University, School of Medicine, Detroit, Michigan
3 Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
4 Department of Neurology, Wayne State University, School of Medicine, Detroit, Michigan

Address correspondence and reprint requests to Dr. Anders A.F. Sima, Department of Pathology, Scott Hall 9275, 540 E. Canfield Ave., Detroit, MI 48201. E-mail: asima{at}med.wayne.edu

Abbreviations: CGRP, calcitonin gene–related peptide; DRG, dorsal root ganglion; IGF-IR, IGF-I receptor; NGF, nerve growth factor; NGFR, NGF receptor

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.


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Copyright © 2006 by the American Diabetes Association.