Lawrence Power

Serum insulin-like activity in genetic and experimental diabetes mellitus

A modification of the epididymal fat pad assay for insulin-like activity has been applied to serum from normal subjects, untreated diabetic patients, and dogs with experimentally induced diabetes. Diabetic patients exhibited abnormally elevated serum ILA levels before and after glucose loading, and also demonstrated a delay in their ILA response to glucose. Dogs with experimental diabetes did not show an elevation in their ILA values. Genetically determined diabetes is obviously different from simple insulin deficiency diabetes. The data confirm and extend previous observations that a significant degree of hyperinsulinemia exists in the garden variety of mildly diabetic pa tients. Unusually high levels of insulin like activity were found in 7 of 27 apparently normal subjects. Their ILA exceeded at most times the mean of those found in the diabetic patients. Two of these subjects later discovered a family history of diabetes. Some of the implications of these observations are discussed.

A Comparison of Insulin-like Activity Contained in the Serum Proteins of Normal Subjects and Diabetic Patients

The concentration of the insulin-like activity in serum protein fractions of normal subjects and diabetic patients was found to be (greatest in the beta globulins and in the fastermoving gamma globulins. Diabetics have nearly twice the normal Concentration of ILA in these fractions. Thus, a characteristic previously demonstrated in intact serum of diabetics has now been extended to specific protein fractions. After glucose loading, normal individuals increased the concentration of ILA in those serum protein fractions which were already most concentrated in the fasting state. The diabetics, on the other hand, increased the concentration of ILA much more slowly than normal, and this increase was in found in protien fractions different from those found to be increased in normal people. Interpretations ot these findings have been discussed.

Augmentation of Insulin Activity: Physiological Implications of a Property of Human Serum Revealed by Dilution

Dilution of human serum does not lead to the expected reduction of its insulin-like activity (ILA) as measured by the epididymal fat pad. Dilution of a solution of Crystalline Insulin does, however, reduce activity arithmetically. Because the addition of Crystalline Insulin to diluted serum results in levels of ILA greater than expected (augmentation), the failure of ILA to fall arithmetically with dilution may reflect this augmentation effect on endogenous ILA. The augmentation effect, as revealed by dilution and the addition of Crystalline Insulin, has been shown to increase in the serum of normal subjects after glucose loading, and to be deficient in fasting serum from the untreated diabetic patient.

Insulin and Insulinlike Activity in Extracts of Tumors Associated with Hypoglycemia

Insulin assays were performed on tissue extracts from ten nonpancreatic tumors and five islet-cell adenomas, all of which were associated with hypoglycemia. Acid alcohol and normal saline extractions were made from tumor tissue as well as from normal tissue. The insulin content of extracts was determined both biologically and immunologically, utilizing the rat epididymal fat pad to measure insulinlike activity (ILA) and the double antibody radioimmunoassay to estimate insulin (IRI). All five islet-cell adenomas were found to have significant concentrations of biologically and immunologically active insulin. The nonpancreatic tumors had no significant concentration of insulin or insulinlike activity, but results were equivocal in one hepatoma. The mechanism by which such tumors induce hypoglycemia remains unknown. It does not appear to result from the elaboration of insulin or of products with insulinlike activity.

Release of insulin-like activity from serum of normal subjects and diabetic patients

Exposure to acid-ethanol releases intense, previously masked insulin-like activity from the serum of both normal subjects and untreated diabetic patients. In proportion to the level of ILA in intact serum, diabetic serum contains less masked ILA than does normal serum. In terms of total ILA, however, that released from the serum of diabetics exceeds that released from normal serum, both in the fasting state and after glucose loading. The delayed increase of serum ILA after glucose loading, repeatedly observed in diabetics, has been shown to hold true for acid-alcohol releasable ILA as well.

A Globulin System from Human Serum that Augments the Activity of Crystalline Insulin on the Epididymal Fat Pad Deficiency in Diabetes Mellitus

It has been demonstrated that globulin isolated from normal serum augments the action of added crystalline insulin when assayed on the rat epididymal fat pad. This augmentation capacity is very low or absent in globulin from the serum of untreated diabetic patients. The possibility is discussed that these findings may indicate that diabetic patients produce an abnormal form of insulin.

The effect of frozen storage on serum insulin-like activity☆

Abstract Storage of serum at −20 C. is associated with an increase of its insulin-like activity in as short a period as 3 weeks. Separated serum proteins also show an increase under similar conditions. This is of practical importance for workers who make such measurements. The possibility that these observations result from alterations in a serum insulin moiety is discussed.

FURTHER STUDIES ON INSULIN AUGMENTATION CAPACITIES OF VARIOUS SERUM PROTEINS.

Abstract The ability of human serum protein to augment the action of crystalline insulin on the epididymal fat pad has been further evaluated. Serum proteins were fractionated by elution from DEAE cellulose and the capacity of individual fractions to augment insulin action determined. The property was found to be present in all fractions, but concentrated to a slightly greater extent in the fastermoving gamma globulins and beta globulins. The augmentation effect has again been found to be deficient in diabetes mellitus.

Some characteristics of the insulin augmentation phenomenon

Abstract A serum protein fraction possessing the capacity to augment insulin action on adipose tissue in vitro has been isolated and studied. Factors responsible for augmentation have been found to be nondialyzable and susceptible to destruction by ethanol, alkali and heat. The augmentation phenomenon is probably dependent upon the presence of a protein moiety.

Diabetic Insulin Antagonism

A capacity of freshly-drawn, normal serum to antagonize the action of insulin in the epididymal fat pad system has been found to be increased in the serum of untreated diabetic patients. A comparable increase has also been found in the serum of very obese subjects who are not apparently diabetic. The current status of insulin antagonism in diabetes has been briefly reviewed. Although a search for the diabetogenic insulin antagonist has been under way for several decades now, failure thus far to convincingly demonstrate its presence appears to have carried little conviction of its absence. To the several candidates currently in nomination, another has been added.