Mechanism of the ‘Anti-Insulin’ Action of 11,17-Oxycorticosteroids in Hypophysectomized Dogs

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Abstract
In studies employing the intravenous administration of minute amounts of C14 glucose to tag the body glucose pool, the uptake of glucose by the tissues and the output of glucose by the liver were measured in unanesthetized dogs in the postabsorptive state prior to and subsequent to a small intravenous dose of glucagon-free insulin. In this way hypophysectomized dogs treated with hydrocortisone acetate (1.2–1.5 mg/kg/day for 9–18 days) were compared with untreated hypophysectomized dogs, and three important differences were observed. The steroid regimen a) restored to normal the low glucose turnover rate and the low plasma glucose concentration seen in the untreated hypophysectomized dog prior to the administration of insulin, b) reduced the increased responsiveness of the tissues to insulin stimulation of glucose uptake which is characteristic of the untreated hypophysectomized dogs, and c) restored to near the level seen in the normal dog the decreased capacity of the hypophysectomized dog to respond to hypoglycemia with an increase in glucose output by the liver. The decreased insulin sensitivity brought about in the hypophysectomized dog by an 11, 17-oxycorticosteroid regimen is due partly to a reduced capacity of the insulin dose to lower the blood sugar concentration and partly to an increased capacity of the treated animal to restore its blood sugar concentration to the normal level. The decreased capacity of administered insulin to stimulate extra glucose uptake by the tissues is considered to be secondary to the increased glucose turnover and to a postulated increased endogenous insulin secretion existing in the steroid-treated animal prior to insulin injection. Thus all three of the observed effects of the steroid regimen may be ascribed to a single change, namely the increased capacity of the liver to put glucose into the blood.