Guanidine Structure and Hypoglycemia

By a series of structural changes, Frank, Nothmann, and Wagner (1) developed synthalin, the most powerful hypoglycemic synthetic product known today. The details of their researches are not available. The increased hypoglycemic activity of agmatine over guanidine offered the first clue as to the nature of the groups which were productive of hypoglycemic activity. It may be gathered from the recent patent literature (2) that the synthesis of synthalin was accidenlal, synthalin (diguanidinodecamethylene) forming when the preparation of the homologue of agmatine (monoguanyldiaminodecane) was attempted. The enthusiasm which greeted the announcement of synthalin as a “mouth insulin” was dispelled as soon as the nature of the physiological activity was brought to light. Blatherwick et al. (3) showed in this laboratory that by parenteral administration an acute nephritis is produced in rabbits, along with injury to the liver, as shown by a decreased ability to deaminize glycine. Clinicians observed the same effects in diabetic patients on a synthalin treatment. These results suggested that synthalin might cause hypoglycemia by preventing normal glyconeogenesis. Other profound differences in the action of synthalin and insulin were brought forth by Bodo and Marks (4). They showed that synthalin causes the liver to be depleted of glycogen and brings about a breakdown of muscle glycogen in addition to a disappearance of sugar. Simola (5) found that the inorganic phosphorus does not always decrease when synthalin produces hypoglycemia, a phenomenon so characteristic of insulin hypoglycemia.