One of the earliest papers on insulin therapy by Banting and his colleagues described a slight induration of the subcutaneous tissue and reddening of the skin immediately surrounding the point of injection. At this time Joslin and his co-workers stated that induration had been seen frequently at the site of insulin injections and described four cases of urticaria developing among the first 83 diabetic patients treated. Later, redness and swelling were observed to follow the injection of protamine insulin, and similar reactions have been described following the use of globin insulin.