Immunologic Studies in Insulin Resistance I. Report of a Case Exhibiting Variations in Resistance and Allergy to Insulin

Lowell, Francis C.

doi:10.1172/jci101485

Cited by 48 publications

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“…These changes were correlated with the absence, and then the appearance, of insulin-neutralizing activity in the patient's serum. The allergic reactions appeared to be mediated by a mechanism quite independent of that giving rise to resistance (5).…”

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confidence: 97%

“…Lerman (4), in studying serum of 5 patients with insulin resistance, obtained evidence for the presence of an insulin antagonist in 2. One of these serums was provided by the writer, and was obtained from a diabetic patient, A. M., the subject of this and previous reports (5,6). A high degree of allergy to insulin, coupled with marked insulin resistance, combined to make the giving of insulin to this patient both disagreeable and ineffective.…”

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confidence: 99%

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Immunologic Studies in Insulin Resistance. Iii. Measurement of an Insulin Antagonist in the Serum of an Insulin-Resistant Patient by the Blood Sugar Curve Method in Mice

Lowell

1947

J. Clin. Invest.

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The detection of an insulin antagonist in the serum of insulin resistant subjects has been attempted on a number of occasions. In certain instances, the excessive quantities of insulin used in the neutralization experiments in animals may explain the failure to obtain evidence of an insulin antagonist. In the few successful experiments which have been done, little information of a quantitative nature has been obtained. Glen and Eaton (1) and Marble, Fernald and Smith (2) were able to demonstrate decreased responsiveness to insulin in rabbits injected with serum from insulin resistant patients. This change in the experimental animal was still demonstrable a week after injection of the serum. In the same year, Banting et al. (3) described experiments in which the incidence of hypoglycemic convulsions was reduced in mice injected with mixtures of serum and varying amounts of insulin. The serum was obtained from a patient with schizophrenia who developed insulin resistance during insulin shock therapy. This case is especially interesting because diabetes was not present, suggesting that the resistance was directed against prepared insulin only. When the same serum was retested a week later in mice maintained on a high carbohydrate diet, practically no insulin neutralization could be demonstrated. Lerman (4), in studying serum of 5 patients with insulin resistance, obtained evidence for the presence of an insulin antagonist in 2. One of these serums was provided by the writer, and was obtained from a diabetic patient, A. M., the subject of this and previous reports (5,6). A high degree of allergy to insulin, coupled with marked insulin resistance, combined to make the giving of insulin to this patient both disagreeable and ineffective. A further important feature was the presence of a relatively mild degree of diabetes, making possible prolonged periods during which insulin therapy could be omitted without immediate danger to the patient's life. A number of hospital admissions provided opportunity to show that: a. At the end of a period of 5 months or more without insulin therapy, small doses of insulin would give rise to urticaria, constriction in the chest, and, on one occasion, collapse. b. After desensitization with graded doses of insulin, a period of 3 to 5 days followed during which the injection of relatively small doses of insulin would be followed by a fall in blood sugar. c. Within about 11 to 15 days of starting desensitization and treatment with insulin, a solid resistance to insulin developed. These changes were correlated with the absence, and then the appearance, of insulin-neutralizing activity in the patient's serum. The allergic reactions appeared to be mediated by a mechanism quite independent of that giving rise to resistance (5).The method previously used for the demonstration of insulin-neutralizing activity of the patient's serum (6) consisted in observing the incidence of hypoglycemic symptoms in mice injected with a mixture of serum and insulin. This method had a number of disadvantages whic...

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confidence: 99%

Immunologic Studies in Insulin Resistance. Iii. Measurement of an Insulin Antagonist in the Serum of an Insulin-Resistant Patient by the Blood Sugar Curve Method in Mice

Lowell

1947

J. Clin. Invest.

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“…One patient, A. M., exhibited susceptibility to this preparation at a time when she was resistant to crystalline insulin. The other, C. S., was apparently resistant to human as well as crystalline insulin (10). The potency of this preparation of human insulin was approximately 25 units per ml.…”

Section: Experiments With Normal Human Serummentioning

confidence: 81%

“…Furthermore, the "glucose effect" in such tests is also diminished. A few tests were done on a serum (Table V) obtained from a second insulin-resistant patient whose clinical course has also been briefly described (10). Two of 11 (Table IV).…”

Section: Experiments With Normal Human Serummentioning

confidence: 99%

Immunologic Studies in Insulin Resistance Ii. The Presence of a Neutralizing Factor in the Blood Exhibiting Some Characteristics of an Antibody

Lowell

1944

J. Clin. Invest.

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The huge doses of insulin required by some insulin-resistant patients have led many observers to postulate the presence of an insulinneutralizing factor in the blood of such individuals. In attempts to demonstrate this factor, the usual procedure has been to inject insulin mixed with the patient's serum into laboratory animals and then to look for a decrease or absence of insulin effect. Some studies have given entirely negative results (1 to 4), possibly because of the large amounts of insulin used in carrying out the tests. However, a few workers have obtained evidence indicating some insulinneutralizing activity (5 to 7).The interpretation of experiments to be reported here, as well as those reported by others, is made difficult by the wide variations in response to insulin exhibited by different animals and even by the same animal at different times. Also, factors other than the injection of insulin may possibly affect the animal's response. Irritation from the injected foreign protein (human serum), the presence of high concentrations of glucose in the injected serums, and delay in the absorption of the insulin (if mixture is not injected intravenously), may all combine to interfere with insulin effect and produce the impression that neutralization has taken place.Earlier experiments in mice with blood obtained from a case of insulin resistance, A. M., provided evidence for the presence of an insulinneutralizing factor (8, 9). It was believed at that time that this was an antibody. Additional evidence has been obtained from a study of a series of 25 blood specimens obtained from the same patient. Tests have also been made with blood from a second insulin-resistant patient. These studies leave little doubt that an insulinneutralizing factor was present and that this factor was an antibody for crystalline insulin. TESTS FOR INSULIN-NEUTRALIZING ACTIVITY Materials and methodsAdult albino mice were starved for 24 hours without bedding but with access to water. Each animal was then injected intra-abdominally with 0.5 ml. of a mixture of 2 or more of the following: U 40 crystalline insulin (Lilly), saline, human serum, and glucose. The mice were observed continuously for 90 minutes in an incubator measuring approximately 7 X 4 X 5 feet. The thermostats were set for a temperature of 350 C. to 37.5°C., but because the incubator door was opened at intervals during the tests, the temperature averaged slightly lower than this. The number of mice showing insulin effect was recorded. No animal was used more than once.Insulin effect was considered to be present when one or more of the following symptoms appeared: convulsions, extreme irritability and overactivity, coma, loss of equilibrium, and marked weakness or paralysis of the hind legs. These symptoms disappeared quickly when a glucose solution was injected intra-abdominally. During the test, the mice were kept under continuous observation because sumptoms of insulin effect were sometimes transitory.All dilutions of insulin were freshly made. The human serum was obta...

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“…Diminution of hypoglucemic effect of insulin in the intact animal when mixed with antagonist serum. 8 . 9 > 10 2.…”

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confidence: 99%

Humoral Antagonism to Insulin

Stetten

Field

1956

Diabetes

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Immunologic Studies in Insulin Resistance I. Report of a Case Exhibiting Variations in Resistance and Allergy to Insulin

Cited by 48 publications

References 9 publications

Immunologic Studies in Insulin Resistance. Iii. Measurement of an Insulin Antagonist in the Serum of an Insulin-Resistant Patient by the Blood Sugar Curve Method in Mice

Immunologic Studies in Insulin Resistance. Iii. Measurement of an Insulin Antagonist in the Serum of an Insulin-Resistant Patient by the Blood Sugar Curve Method in Mice

Immunologic Studies in Insulin Resistance Ii. The Presence of a Neutralizing Factor in the Blood Exhibiting Some Characteristics of an Antibody

Humoral Antagonism to Insulin

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