Peripheral nerve pathology related to chronic hyperinsulinemia and hypoglycemia has yet to be fully explored. Here we conducted a systematic quantitative analysis of morphological alterations in peripheral sensory and motor nerve fibers and endoneurial microvasculature in longstanding insulinoma-carrying rats (I-rats; n=12). Age-matched normal rats (n=6) served as controls. Over the 15-month observation period, two of I-rats developed paresis of the hind limbs when their blood glucose level fell below 1.7 mmol/l. These animals showed a massive myelinated fiber loss associated with active degeneration of residual myelinated fibers and multiple endoneurial microvascular occlusions at the sciatic nerve level. The rest of the non-paretic I-rats showed a decreased density of large myelinated fibers with axonal degeneration in the peroneal nerve and an increased density of small myelinated fibers with preserved morphology in the sural nerve. This was associated with endoneurial microangiopathic changes indicative of endoneurial ischemia/hypoxia in the sciatic and peroneal nerves, and an increase in endoneurial microvascular density in the sciatic and sural nerves. In conjunction with previous data, these findings suggest that the observed increase in endoneurial microvascular density may be a compensatory response to endoneurial ischemia/hypoxia induced by chronic hyperinsulinemia in I-rats without paresis. In conclusion, the present study showed characteristic morphological alterations in peripheral sensory and motor nerve fibers associated with microangiopathy indicative of endoneurial ischemia/hypoxia in the sciatic and peroneal nerves, and provides the first evidence for the occurrence of endoneurial necrosis in the sciatic nerve, to which the hind limb paresis can be ascribed in I-rats.