l1.e EndocrineMetabolic Clinic, Albany Hospital, iilbany, N . V .
I n froductionWith Thomas Addison's observations, in 1855, of the disease which now bears his name, great interest was generated in determining its cause and treatment. The synthesis of the first adrenal steroid, desoxycorticosterone, by Reichstein in 1937, with its strong electrolyte-regulating effects, prolonged the lives of Addisonians and led to a search for other compounds with which to correct the remaining metabolic disturbances characteristic of the adrenal deficient state. Newly isolated steroids from natural sources were shown to exert profound carbohydrate effects such as hyperglycemia, glycosuria, and hepatic glycogenesis. Inglel observed glycosuria in normal, force-fed rats given 17-hydroxycort icosterone, 11-dehydro-1 7-hydroxycorticosterone,2 ~orticosterone,~ and adrenocort icotropin h~r m o n e .~ Forshamb and Perera,6 using ll-dehydrocorticosterone, prevented hypoglycemia in fasted Addison disease patients without producing any significant increase in the fasting blood sugar or glucose tolerance. Eventually, a hierarchy of steroids was established which graded the steroids according to their electrolyte-effects on the one hand, and their carbohydrate effects on the other. Interestingly, the steroids possessed opposite degrees of potency when compared by these two standards of biological activity.The effect of certain of the adrenal steroids upon the glycogen content of the liver is very marked. According to Pabst, Sheppard, and Kuizenga? 17-hydroxycorticosterone is the most potent in causing deposition of liver glycogen, followed by 1 l-dehydro-l7-hydroxycorticosterone, corticosterone, and 11-dehydrocorticosterone. The compound 11-desoxycorticosterone is only weakly glycogenic, although it is the most potent in its effect upon electrolyte balance.With this knowledge, there developed an interest in determining other sites of action of the carbohydrate-active steroids. The ameliorating effect of adrenalectomy in diabetes of animals was shown by Long and Lukens.x The Cork suggested an inhibitory action of these steroids on the glucokinase reaction of carbohydrate synthesis. Cortical hormones participate in the synthesis of carbohydrate from proteins (gluconeogenesis), in which certain amino acids are deaminated and then combined into six-carbon chains to form glucose. A second function is to influence the reaction glucose F! glycogen towards the right, increasing the storage of glycogen in the liver at the expense of the blood sugar. In this reaction, many other hormones have an influence: insulin likewise promotes glycogen storage, while thyroxin and epinephrine mobilize glucose for use in the tissues. Anterior pituitary growth hormone antagonizes ' These studies were made possible. in part, through the help and cooperation of the Upjohn Company, lialamazoo, blirh.; Armour Laboratories, New York, N . Y.; and Ciba Pharmaceutical Produrts, Inc., Summit, N . J.
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