The blooming of the French lilac.

1105 The history of diabetes mellitus is replete with many therapies, nearly all, including insulin, first given without any knowledge of a mechanism of action. Beginning with early Egyptian physicians who, according to the Ebers Papyrus of 1500 B.C.E., prescribed a mixture of cakes, wheat grains, fresh grits, green lead, earth, and water, up to the more recent introduction of the thiazolidinediones, knowledge of physiologic effects preceded by years or centuries any knowledge as to what the medicament actually did. In medieval times, a prescription of Galega officinalis was said to relieve the intense urination accompanying the disease that came to have the name of diabetes mellitus. G. officinalis, also known as Goat’s rue, the French lilac or Italian fitch (Figure 1), was also given during the plague epidemics to promote perspiration and has been used as a galactogogue in cows. The active ingredient in the French lilac that produced the lowering of blood glucose was shown to be galegine or isoamylene guanidine (1). A curious chapter in the history of guanidinebased hypoglycemic agents arose from the mistaken notion that the tetany of hypoparathyroidism was due to the production of increased guanidine following parathyroidectomy, leading to the demonstration that an infusion of guanidine produced lowering of blood glucose (2). While guanidine itself and certain derivatives are too toxic for the treatment of diabetes mellitus, the biguanides (two linked guanidine rings) have proved useful, and three biguanides became available for diabetes therapy in the 1950s. Phenformin and buformin, the former becoming quite popular in the 1960s, were withdrawn from the pharmacopoeia in the early 1970s due to the emergence of frequent lactic acidosis and increased cardiac mortality (1). Metformin, a less lipophilic biguanide, proved safer and, after 20 years of use in Europe, was approved for use in the USA in 1995.