The introduction of protamine insulin by Hagedorn and his co-workers1 in 1935 represented a milestone in the development of insulin therapy in diabetes. The result of extensive efforts to prolong the action of insulin, it simplified treatment in many ways. Multiple injections, even in severe cases, were reduced to one injection, glycosuria and ketosis were better controlled and hypoglycemic shocks occurred less frequently. Despite the enthusiastic reception of the new insulin preparation, many authors in Europe and America2 called attention to disadvantages caused by insolubility and slow rate of absorption of protamine insulin. In some, particularly in severe cases, the difficulties encountered were excessive glycosuria after meals and hypoglycemic reactions occurring at night and in the morning. Raising the dose to reduce the postprandial glycosuria provoked early morning shocks, while reducing the dose to avoid repeated reactions aggravated the diurnal glycosuria.
The limitations inherent in the product were
ADLERSBERG D, DOLGER H. INSULIN MIXTURES IN THE TREATMENT OF DIABETESVARIABLE VERSUS FIXED RATIOS OF INSULIN AND PROTAMINE ZINC INSULIN. JAMA. 1945;128(6):414–419. doi:10.1001/jama.1945.02860230018005