Insulin neuritis, or painful neuropathy following rapid improvement in glycaemic control, is well recognised but its aetiology is unclear. An understanding of the processes involved in the genesis of acute painful neuropathy of rapid glycaemic control may give an insight into the early pathogenetic factors leading to diabetic nerve damage in general. We have identified five subjects with insulin neuritis including one who developed severe autonomic neuropathy following treatment with insulin. Subjects underwent: 1) assessment of neuropathic symptom and deficit scores; 2) quantitative sensory and electrophysiological studies and 3) sural nerve epineurial vessel photography and fluorescein angiography in vivo. The sural nerve photographs were independently graded by an ophthalmologist. All subjects with insulin neuritis presented with severe sensory symptoms but clinical examination and electrophysiological tests were normal except in the subject with the severe autonomic neuropathy in whom all the tests were abnormal. On nerve photography, there was an abundance of epineurial nutrient vessels although these showed severe abnormalities including arteriolar attenuation, tortuosity and arterio-venous shunting in all subjects. Proliferating neural 'new vessels' which bear striking similarities to those found in the retina and that were more leaky to fluorescein than normal vessels, were observed in three subjects. Venous distension and/or tortuosity was also observed in three subjects and this was most marked in the subject with severe autonomic neuropathy. This study shows that epineurial nutrient vessel anatomy is abnormal in subjects with acute painful neuropathy of rapid glycaemic control, a condition previously thought to be purely metabolic in origin. The presence of epineurial arterio-venous shunting and a fine network of vessels resembling the new vessels of the retina, may lead to a 'steal' effect rendering the endoneurium ischaemic. This process may be important in the genesis of neuropathic pain, and further supports the importance of vascular factors in the pathogenesis of diabetic neuropathy.