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Biomedical subjects

C R Kahn

Publications and source records attributed to C R Kahn.

At least 361 records · Page 20Linked to original sources
PubMed1980

Characterization of insulin receptors in patients with the syndromes of insulin resistance and acanthosis nigricans.

This report analyzes the in vitro characteristics of 125I-insulin binding to the monocytes of nine patients with the syndromes of acanthosis nigricans and insulin resistance. The 3 Type A patients (without demonstrable autoantibodies to the insulin receptor) had decreased binding of insulin due to a decreased concentration of receptors. In these patients the residual receptors demonstrated normal dissociation kinetics, negative cooperativity, and were blocked by anti-receptor antibodies in a manner similar to normal cells. In contrast, monocytes from the 6 Type B patients (with circulating anti-receptor autoantibodies) had decreased binding of insulin due to a decrease in receptor affinity. Insulin binding to monocytes of Type B patients demonstrated accelerated rates of dissociation with no evidence of cooperative interactions among insulin receptors. When coupled with previous data, the present studies further suggest that different mechanisms account for the defects in insulin binding and insulin resistance observed in these patients.

Acanthosis Nigricans↗
PubMed1980

Role of insulin receptors in insulin-resistant states.

The interaction of insulin with its receptor represents one of the key intermediate steps between secretion of insulin and its final biologic effects. Alterations in this interaction have been found in a number of disease states, including obesity, non-insulin-dependent diabetes mellitus (NIDDM), glucocorticoid excess, and acromegaly, as well as several rare forms of severe insulin resistance. The major factor regulating the receptor in obesity and NIDDM appears to be insulin. In obesity this alteration in normal regulation occurs secondary to overeating, whereas in the diabetic state the nature of the primary defect is uncertain. The role of the receptor in insulin resistance and methods for its evaluation are discussed.

Acromegaly↗
PubMed1980

The riddle of tumour hypoglycaemia revisited.

In summary, hypoglycaemia due to non-pancreatic tumour is relatively common among the causes of fasting hypoglycaemia in the adult. Most of the neoplasms are large, and present as masses in the mediastinum or retroperitoneal space. Although therapy is difficult, successful palliation by surgery or radiotherapy has been achieved in a number of cases. Although many theories have been advanced to explain the hypoglycaemia, the best documented mechanism is production of an insulin-like substance by the tumour. Both low molecular weight (NSILA-s) and high molecular weight (SNILP) peptides have been reported to be elevated in some cases of tumour hypoglycaemia. Further study of this class of peptides will no doubt lead to assays that may facilitate diagnosis of tumour hypoglycaemia, as well as offer new approaches to the therapy of this disease.

Amino Acid Sequence↗
PubMed1980

Direct demonstration of separate receptors for growth and metabolic activities of insulin and multiplication-stimulating activity (an insulinlike growth factor) using antibodies to the insulin receptor.

Insulin and such insulinlike growth factors as multiplication stimulating activity (MSA) are related polypeptides that have common biological activities. Both insulin and MSA produce acute metabolic responses (stimulation of glucose oxidation in isolated fat cells) as well as growth effects (stimulation of [(3)H]thymidine incorporation into DNA in cultured fibroblasts). In addition, most cells have separate receptors for insulin and insulinlike growth factors, and both peptides have weaker affinity for each other's specific receptors than for their own. To determine, therefore, whether these effects are mediated by receptors for insulin, insulinlike growth factors, or both, we have selectively blocked insulin receptors with a specific antagonist, namely Fab fragments derived from naturally occurring antibodies to the insulin receptor. In rat adipocytes, 10 mug/ml of antireceptor Fab inhibited insulin binding by 90%, whereas it inhibited MSA binding <5%. The anti-insulin receptor Fab is without intrinsic biological activity, but acts as a competitive inhibitor of insulin receptors. Blockade of insulin receptors with Fab fragments produced a 30-fold rightward shift in the dose response for stimulation of glucose oxidation by both insulin and MSA. The dose-response curves for stimulation of oxidation by vitamin K(5) and spermine, agents that stimulate glucose oxidation through noninsulin receptor pathways, were not affected by the blockade of insulin receptors with Fab antibody fragments. These data suggest that this acute metabolic effect of both insulin and MSA is mediated via the insulin receptor. In cultured human fibroblasts, 10 mug/ml of Fab inhibited insulin binding by 90% and MSA binding by 15%. In fibroblasts, however, blockade of the insulin receptor did not alter the dose response for stimulation of thymidine incorporation into DNA by either insulin or MSA. Furthermore, intact antireceptor antibody immunoglobulin (Ig)G, which produces multiple other insulinlike effects, and Fab fragments of antireceptor antibody did not stimulate thymidine incorporation. These data demonstrate directly that the insulin receptor mediates the metabolic effects of insulin and MSA, whereas the growth-promoting action of both peptides is mediated by the MSA receptor or other growth factors.

Adipose Tissue↗
PubMed1980

Antibody-induced desensitization of the insulin receptor. Studies of the mechanism of desensitization in 3T3-L1 fatty fibroblasts.

Antibodies against the insulin receptor (Anti-R), which are found in the serum of type B patients with the syndrome of insulin resistance and acanthosis nigricans, inhibit the binding of insulin to its receptor and mimic the actions of insulin when studied acutely in vitro. After prolonged exposure of 3T3-L1 cells to Anti-R, the insulinomimetic activity is lost, and the cells show a marked decrease in their maximal response to insulin (antibody-induced desensitization), thus providing a model for the insulin resistance seen in vivo. This study explores in detail the mechanism and specificity of desensitization in 3T3-L1 cells.Desensitization, like the insulinomimetic activity of Anti-R, requires bivalence. Monovalent preparations of Anti-R inhibit insulin binding and shift the insulin biological dose-response curve to the right, but do not decrease the maximal insulin response. The affinity of monovalent Anti-R is less than that of the native antibody. Cross-linking of monovalent Anti-R reconstitutes its insulinomimetic activity and partially reconstitutes desensitization. Desensitized cells are resistant to the insulinomimetic actions of concanavalin A, which interacts with the insulin receptor, but are not desensitized to spermine and vitamin K(5), insulinomimetic agents that are thought to act independently of the insulin receptor. Glucose, pyruvate, or certain hexoses are required in the incubation media for desensitization to occur. Although Anti-R is taken up into cells and degraded by lysosomes, chloroquine, cycloheximide, colchicine, and cytochalasin E have little influence on the induction of or recovery from antibody-induced desensitization. These data suggest that desensitization is not merely due to the inhibition of insulin binding, but is a complex process involving a decreased ability of the receptor to generate a biological response.

Animals↗
PubMed1980

Virus-induced decrease of insulin receptors in cultured human cells.

Viral infections may produce abnormalities in carbohydrate metabolism in normal subjects and profound changes in glucose homeostasis in insulin-dependent diabetics. Using an in vitro radio-receptor assay with 125I-labeled insulin and human-amnion (WISH) cells, the effect of viral infections on insulin receptors was examined. Both herpes simplex virus and vesicular stomatitis virus produced a 50% decrease in insulin binding. There was no evidence that this decrease was due to degradation of insulin. On quantitative analysis, this decrease in binding was found to be the result of a decrease in receptor concentration with no change in receptor affinity. The decrease in receptors occurred between 4 and 12 h, at the time viral antigens were being inserted into the plasma membrane of infected cells. Because the t 1/2 of insulin receptors in uninfected cells was between 14 and 24 h, the decrease in insulin receptors cannot be explained solely by virus-induced shut-off of macromolecular synthesis. Moreover, viruses such as encephalomyocarditis that do not insert new antigens into the plasma membrane, did not cause changes in the number of insulin receptors. The most likely explanation is that virus-induced changes in the plasma membrane altered or displaced insulin receptors. It is concluded that the insulin receptor assay is a sensitive and quantitative method for studying the effect of viral infections on cell membranes. These data also suggest that abnormalities in glucose metabolism associated with some viral infections may be due, in part, to changes in the concentration of insulin receptors.

Amnion↗
PubMed1980

Demonstration of a primary (? genetic) defect in insulin receptors in fibroblasts from a patient with the syndrome of insulin resistance and acanthosis nigricans type A.

We have studied insulin binding to cultured skin fibroblasts from a patient with the Type A syndrome of insulin resistance and acanthosis nigricans. Insulin binding was decreased aobut 50% at low insulin concentrations. This was due to a decrease in receptor affinity and in increase in the rate of dissociation of insulin from the receptor. In addition, there was a loss of negative cooperativity, as measured by the ability of unlabeled insulin to accelerate dissociation. This defect in the receptor was stable for up to 16 passages of the cells. By contrast, binding of epidermal growth factor did not differ from control. These data suggest that the Type A syndrome of insulin resistance is due to a primary, and possibly genetic, defect in the insulin receptor.

Acanthosis Nigricans↗
PubMed1980

Insulin activates glycogen synthase in cultured human fibroblasts.

To develop a technique for examining short term insulin effects in cultured human fibroblasts, the effect of insulin on glycogen synthase was determined. Fibroblasts contain detectable glycogen synthase activity which can be converted from the D form, dependent on glucose-6-phosphate for activity, to the 1 form, which is independent of glucose-6-phosphate, in the presence of insulin. In the basal state, about 6-20% of the glycogen synthase is independent activity. This increases to between 30 and 60 %1 activity after insulin stimulation. Stimulation is seen with insulin concentrations as low as 10-9 M, although maximal stimulation requires 10-7 - 10-6 M insulin. The effect of insulin is rapid, reaching a maximum within 20 min of incubation. Incubation the cells in fresh media without serum and glucose for up to 24 h before assay enhances the cellular response to insulin. Glucose has only a small, transient effect on the conversion of the enzyme from the D to the I form in the absence of insulin. These data demonstrate that human fibroblasts possess insulin-sensitive glycogen synthase, which may be used as a marker of metabolic response in disease states.

Adult↗
PubMed1979

Radioimmunoassay of the insulin receptor: a new probe of receptor structure and function.

A sensitive and specific radioimmunoassay for the insulin receptor has been developed employing receptor autoantibodies from the serum of a patient with insulin-resistant diabetes. The assay detects insulin binding sites at concentrations as low as 0.1 nanomolar; distinguishes between receptors originating from human placental membranes, human lymphoblastoid cells, and mouse liver membranes; and measures the receptor independently of its binding function. Down-regulation, or loss of binding after exposure to insulin, is associated with loss of immunoreactive receptor.

Animals↗