C-Peptide reverses nociceptive neuropathy in type 1 diabetes.
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.
Kamiya
Hideki
H
Department of Pathology, Scott Hall 9275, 540 E. Canfield Ave., Detroit, MI 48201, USA.
Zhang
Weixian
W
Ekberg
Karin
K
Wahren
John
J
Sima
Anders A F
AA
D000818:Animals; D002096:C-Peptide / Q000494:pharmacology*; D002116:Calcitonin / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000517:prevention & control*; D005727:Ganglia, Spinal / Q000503:physiopathology; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009416:Nerve Regeneration; D009443:Neuritis / Q000517:prevention & control*; D009474:Neurons / Q000502:physiology; D051381:Rats; D011913:Rats, Inbred BB; D012016:Reference Values; D013373:Substance P / Q000235:genetics
D002096:C-Peptide; D013373:Substance P; D002116:Calcitonin