On the Mechanism of Insulin Resistance in Toxemic States1

Abstract

Carbohydrate partitions and detns. in vitro of enzyme activity made on samples of liver removed from nembutalized dogs before and after adm. of diphtheria toxin revealed increased glycogenolysis and diminished phosphorolysis after toxin adm. Since the excessive glycogenolysis was also demonstrated in a phosphate-poor medium, and gave rise to characteristic end products not found in normal liver, amylase activity may be the abnormal process unleashed by the toxin, an activity not influenced by insulin. Hence the relative impotence of insulin (insulin resistance) in toxemic states. Glycogen synthesis is undoubtedly also interfered with. It is thus not difficult to account for the characteristically low liver glycogen, the "diabetic type" of glucose tolerance curve and the occasional hyperglycemia and glycosuria found in the initial stages of toxic liver damage. In advanced liver damage, when interference has become extreme, hypoglycemia may result. In diabetes mellitus complicated by toxemia the above effects are first seen as an increased insulin requirement: severe liver damage may cause an apparent improvement in the diabetes as the general clinical condition of the patient deteriorates. These results justify high carbohydrate therapy in liver disease and high carbohydrate therapy plus insulin in diabetes complicated by liver damage. The therapeutically increased supply of blood sugar may help to push the glycogen-glucose equilibrium in the direction of glycogen by simple mass action.