Insulin may have direct effects on axons through its actions on insulin receptors or through cross occupancy of insulin-like growth factor-1 receptors. We tested the hypothesis that insulin itself influences conduction of myelinated fibers independent of hyperglycemia in experimental diabetes. Low dose intermittent (0.2 units thrice weekly) Toronto (regular) insulin was injected at the sciatic notch and knee near the left sciatic nerve of rats rendered diabetic with citrate buffered streptozotocin or nondiabetic rats given citrate only. Identical volumes of normal saline were injected near the contralateral right sciatic nerve. The diabetic rats developed hyperglycemia, elevated glycosylated hemoglobin levels and had slowing of right (saline treated) sciatic tibial motor and caudal sensory conduction velocity. In contrast, local insulin treatment on the left side prevented conduction slowing, unilaterally increasing conduction velocity. In nondiabetic rats, conduction velocities were slightly higher on the insulin treated side, but the influence of insulin was less robust than in diabetics. The insulin treated sural branches of the sciatic nerves in diabetics had a higher percentage of small (< or = 9.0 microm diameter) myelinated fibers than the saline treated nerves. Local insulin has a trophic influence on myelinated fibers that is prominent in diabetic nerves and is independent of hyperglycemia.