Diabetic neuropathy is a debilitating disorder whose causation is poorly understood. A new theory proposes that neuropathy may arise as a consequence of loss of neurotrophic insulin-like growth factor (IGF) activity due to diabetes, superimposed on a slow continual loss due to aging. The prediction that IGF-I and IGF-II gene expression are reduced in diabetic nerves was recently tested and validated. Here we tested the prediction that IGF administration can prevent or reverse diabetic sensory neuropathy. Subcutaneous infusion of IGF-I or IGF-II, but not vehicle, halted (P < 0.01) the progression of hyperalgesia in streptozotocin-diabetic rats. Moreover, impaired sensory nerve regeneration was partially reversed within 2 weeks after treatment of diabetic rats with IGFs (P < 0.01). Impaired regeneration could also be prevented by daily subcutaneous IGF injections. The low replacement doses of IGFs were effective despite unabated hyperglycemia and weight loss. These results show that IGF replacement therapy can reverse or prevent diabetic sensory neuropathy independently of hyperglycemia or weight loss.