Morphological and electrophysiological observations were made over 4 weeks on 5 groups of 8-week-old male Sprague-Dawley rats. These were comprised of controls, untreated diabetics, and diabetic animals in which sustained hypoglycemia, moderate hypoglycemia, or normoglycemia was induced by continuous subcutaneous insulin infusion (CSII) therapy. Teased fiber studies showed a marked increase in the number of myelinated fibers undergoing axonal degeneration and regeneration in the tibial nerve of severe hypoglycemic and also in moderate hypoglycemic animals but not in controls, untreated diabetic and normoglycemic groups. There was also a significant correlation between episodes of hypoglycemia (less than or equal to 2.0 mmol/l) and the prevalence of axonal degeneration and regeneration in CSII-treated diabetics. Motor nerve conduction velocity was significantly reduced in the moderate and severe hypoglycemic groups and also in untreated diabetic animals when compared with controls. However, it was significantly improved in the normoglycemic group over the untreated diabetic and severe hypoglycemic groups. In conclusion, this study has demonstrated that severe or even mild hypoglycemia produced a detrimental effect on peripheral nerve structure and function in experimental diabetes. Therefore, it may be desirable to avoid even asymptomatic hypoglycemia in the management of diabetes.