STUDIES ON THE CIRCULATING INSULIN INHIBITOR FOUND IN SOME DIABETIC PATIENTS EXHIBITING CHRONIC INSULIN RESISTANCE

Chronic insulin resistance in the diabetic patient has been arbitrarily defined as existing when the daily requirement for insulin exceeds 200 units in the absence of complicating infection or ketoacidosis (1). The general problem of insulin resistance has been the subject of several review articles (1-3). Glen and Eaton first demonstrated that serum obtained from an insulinresistant diabetic patient protected rabbits from insulin-induced hypoglycemia (4). Subsequently, the studies of Lowell (5) and Lerman (6) suggested the probable antibody nature of this humoral insulin antagonist. Marsh and Haugaard detected an insulin inhibitor in the sera of four diabetic patients requiring at least 300 units of insulin per day (7). In their experiments the ability of insulin to augment glycogen deposition by the isolated rat hemidiaphragm was utilized as the test system. The serum factor was effective only if it, insulin and the hemidiaphragm were in contact simultaneously. More recently there have been several reported cases of chronic insulin resistance in which the insulin antagonist was localized in the y-globulins and presumed to be an antibody (8-13). Colwell and Weiger (13), in an extensive study of such a patient, noted a correlation between the titer of the insulin antagonist and the serum y-globulin levels. Berson and co-workers have demonstrated the presence of an insulin binding protein in the sera of diabetic patients who have received exogenous insulin for at least three months (14). Electrophoretically this protein migrated with the fastest moving y-globulins and had many characteristics of an insulin antibody. Similar binding of insulin was not observed in the sera of diabetic patients who had never received insulin treatment, but was found in nondiabetic psychiatric patients who had been given insulin shock therapy. Furthermore, the rate of disappearance of insulin-I13l injected intravenously was found to be decreased in some diabetic patients (14, 15). Berson and associates observed that patients receiving exogenous insulin were the ones who demonstrated the decreased rate of disappearance (14). Although the binding of insulin to rat hemidiaphragm was diminished in the presence of such sera, no definite correlation existed between the insulin requirement of a patient and the amount of this insulin binding protein (15). However, increased insulin binding by plasma in cases of chronic insulin resistance has been reported previously (16, 17). Recently adrenocorticotropin (ACTH) and adrenal steroids have been used in the treatment of chronic insulin resistance with variable results (10, 12, 18-20). Howard (18) successfully treated one case whose serum contained an insulin antagonist (7). At a time when the insulin resistance was no longer apparent clinically, antagonist could still be detected in the serum by the rat hemidiaphragm assay, although later it was no longer demonstrable. Previously we have demonstrated a circulating insulin antagonist associated with diabetic acidosis (21, 22) which is quite distinct from the humoral insulin antagonist demonstrable in some chronically insulin-resistant diabetic patients not in acidosis. The present paper summarizes work which has been done concerning the insulin inhibitor occurring in chronic insulin resistance.