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C R Kahn

Publications and source records attributed to C R Kahn.

At least 379 records · Page 21Linked to original sources
PubMed1979

Desensitization of the insulin receptor at an early postreceptor step by prolonged exposure to antireceptor antibody.

We have used an adipocyte-like cell line, the 3T3-L1 fatty fibroblasts, to compare acute and chronic effects of autoantibodies directed against the insulin receptor. Acute exposure of the cells in tissue culture to the antibodies resulted in a blockade of insulin binding and stimulation of 2-deoxy-glucose transport and glucose oxidation. Maximal acute effects were reached within 30-120 min. Subsequently, the stimulatory response decayed and, after 6 hr in the continuous presence of the antibodies, basal glucose metabolism had returned to the level observed with unexposed cells and a state of severe insulin resistance prevailed. In contrast to the decay of bioresponse, no change in insulin binding was detectable over the same time period. The mechanism of desensitization seemed to involve events early after insulin binding to receptor because cells exposed to antibody for prolonged periods of time, although unresponsive to insulin and antireceptor antibodies, responded normally to both spermine and vitamin K(5), agents that stimulate glucose metabolism independently of the insulin receptor. These data suggest that prolonged or continuous occupancy of the insulin receptor by a ligand, in this case antireceptor antibodies, does not produce a continuous biological response. Instead, there is desensitization at some early step in the pathway for insulin action. These observations have important implications with respect to the mechanism of insulin action and to other situations in which there is long-term exposure of cells to antibodies that react with membrane components.

Adipose Tissue↗
PubMed1979

Amino acid deficiency and the skin rash associated with glucagonoma.

A 47-year-old white man had a malignant glucagonoma and severe necrolytic migratory erythema. His plasma glucagon levels were markedly elevated at 50 ng/mL and plasma amino acids diminished to 45% of normal. To test the hypothesis that the skin rash associated with a glucagonoma is secondary to an amino acid deficiency, we obtained 2 d of fasting baseline laboratory data from the patient while he consumed his usual diet. He was then given 3 L/d of supplemental intravenous amino acids for 3 d. His plasma amino acid levels increased slightly, and there was some improvement in his skin rash. Immediately thereafter, total parenteral nutrition was administered for 3 d without added zinc or fatty acids. During total parenteral nutrition, 14 of 17 plasma amino acids became normal, and the patient's skin rash rapidly disappeared. These findings suggest that the skin rash associated with a glucagonoma is most likely due to an amino acid deficiency and can be reversed by parenteral nutrition.

Amino Acids↗
PubMed1979

Regulation of insulin receptors in normal and abnormal physiology in humans.

Insulin receptors in human tissue undergo marked changes in both their concentration and their affinity for insulin. In general, alterations in receptor affinity are associated with rapidly changing metabolic environments and can occur within hours, whereas alterations in receptor concentration appear to require longer time periods for their induction. The association of a given type of receptor alteration (i.e., change in affinity or concentration) with a given clinical state indicates the presence of distinct modulators of the insulin-receptor interaction. We have presented evidence for 2 specific modulators, i.e., insulin itself and anti-insulin-receptor antibodies. In several clinical states, especially those associated with changes in receptor affinity, receptor alterations are unrelated to either ambient insulin levels or anti-receptor antibodies, suggesting the presence of several as yet unknown mediators of the insulin receptor. The direct metabolic consequences of these receptor events are not well established. In several states, the receptor alteration correlated quite well with the clinical sensitivity of the whole organism to insulin, indirectly implicating the receptor as the major control point for insulin sensitivity. In contrast, specific examples were cited in which receptor events are not consonant with observed biologic responses to insulin, thereby suggesting a predominance of postreceptor processes. Finally, it should be emphasized that the study of hormone receptors and their relationship to disease states is in the formative stage. With new and improved methodology we hope we will be able to investigate the entire pathway of insulin action at its target tissues, from the initial receptor binding to the final biologic effect.

Acanthosis Nigricans↗
PubMed1979

Direct inhibition of growth and antagonism of insulin action by glucocorticoids in human breast cancer cells in culture.

We have examined the interaction of dexamethasone with the ZR75-1 human breast cancer cell line to determine if glucocorticoids might directly inhibit growth of breast cancer cells. Growth of these cells in serum-free medium was stimulated significantly by physiological concentrations of insulin (0.1 to 1.0 nM). Pharmacological concentrations of dexamethasone (10 nM) reduced cell number below that found in controls and nearly abolished the effect of insulin after several days in culture. Thymidine and uridine, but not leucine, incorporation into macromolecules or acetate incorporation into fatty acids were similarly inhibited by dexamethasone in the presence of absence of insulin. Dexamethasone did not inhibit insulin effects by altering insulin receptor affinity or concentration, as determined by Scatchard analyses of insulin binding. Net thymidine uptake into the trichloroacetic acid-soluble fraction of the cell was stimulated by insulin and inhibited by dexamethasone also inhibited thymidine kinase activity multiple potential sites of glucocorticoid action that directly oppose the effects of insulin. They also suggest that glucocorticoids have a direct inhibitory effect on proliferation of human breast cancer cells, which may help explain breast tumor regression following pharmacological glucocorticoid therapy.

Acetates↗
PubMed1978

Autoantibodies to the insulin receptor activate glycogen synthase in rat adipocytes.

Autoantibodies to the insulin receptor mimic the effects of insulin on glycogen synthase and phosphorylase. The interaction of antibodies with adipocyte cell surface insulin receptors seems sufficient to promote stable changes in the activities of these intracellular enzymes, suggesting that internalization or processing of insulin is not important in the generation of these biological responses.

Adipose Tissue↗
PubMed1978

Properties and partial purification of the detergent-solubilized insulin receptor: a demonstration of negative cooperativity in micellar solution.

Turkey erythrocytes possess insulin receptors with binding properties very similar to those of mammalian insulin receptors. In the present study, the insulin receptor of the avian erythrocyte has been solubilized in Triton X-100, extensively characterized and partially purified, and its properties compared to those of the membrane-bound receptor. The solubilized insulin receptor has a Stokes radius of 70 A and an apparent molecular weight of 300 000 in 0.05% Triton. The binding of insulin to the soluble receptor was very similar to the binding observed with the membrane-bound receptor. Thus, binding was markedly temperature dependent for both the soluble and membrane-bound forms, although the kinetics of binding were slower with the soluble receptor. Both forms of the receptor also showed a sharp pH optimum; however, solubilization produced a shift from maximal binding at pH 7.8 to pH 7.3. The soluble receptor also retained insulin analog specificity, ion sensitivity and negative cooperativity. The soluble receptor did not appear to degrade either bound or free insulin. On DEAE-cellulose chromatography the receptor eluted as a single peak. The specific activity of this partially purified preparation was 25--30 pmol/mg protein (about 500-fold enrichment over crude extract and 5-fold over highly purified membranes). Extensive attempts to purify further the receptor by gel filtration, carboxymethyl-cellulose chromatography and affinity chromatography resulted in either a very low yield or only modest enrichment. Purification was also complicated because the receptor was easily denatured; about 40% of the activity was lost after a 90-min exposure to 3 M urea or pH 4.5. These data suggest that the insulin receptor retains its properties in the absence of the lipid bilayer of the membrane. Complete purification will be difficult due to a lack of stability under a number of conditions.

Animals↗
PubMed1978

Anti-insulin receptor antibodies inhibit insulin binding and stimulate glucose metabolism in skeletal muscle.

Autoantibodies against the insulin receptor are found in the serum of some patients with severe insulin resistance. The effects of one of these sera on insulin binding and on glucose transport and metabolism were investigated in the isolated mouse soleus muscle. Preincubation of muscles with the patient's serum resulted in an inhibition of subsequent 125I-insulin binding (half-maximal effect at 1:500 dilution) and in a two to three-fold stimulation of glucose transport and metabolism (half-maximal effect at 1:2000 dilution). The insulin-like effects were blocked by anti-human IgG, but not by anti-insulin antibodies. The magnitude of the serum effects on 2-deoxyglucose uptake and glycolysis was similar to that of insulin, but the effect on glycogen synthesis was smaller than that of insulin. It is suggested that the patient's serum and insulin promote glucose transport and glycolysis through a common pathway, but act differently on glycogen synthesis.

Animals↗
PubMed1978

Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction.

Insulin resistance may be said to exist whenever normal concentrations of insulin produce a less than normal biologic response. Hormone resistant states may be divided into those due to decreased sensitivity to a hormone (i.e., a shift in the dose-response curve to the right), those due to a decrease in the maximal response to the hormone, and those that are combinations of decreased sensitivity and decreased responsiveness. This distinction is important, since the molecular mechanisms that produce these various forms of insulin resistance may be different. Disorders associated with alterations prior to the interaction of insulin with its receptor are more likely to produce states of decreased sensitivity, where disorders associated with alterations at the intracellular steps in insulin action are more likely to produce decreased responsiveness. Alterations in the insulin receptor itself may produce either, although most frequently changes in receptor affinity as well as in receptor number will be manifest as changes in sensitivity. This is a result of the large number of "spare" receptors for most insulin effects. In many studies, the differential diagnosis between states of altered sensitivity and altered responsiveness is difficult due to the complicated and interrelated nature of the metabolic pathways of insulin action. This is frequently further complicated by incomplete data (usually the result of studying response to only one hormone concentration rather than a full dose-response) and change in rates of basal metabolism in different diseases. The latter is a particularly difficult problem, but it is clear that use of "fold-" or "percent-" stimulation may further obscure the nature of the change when complete data are not provided. With more precise use of these terms and a more complete understanding of insulin action, it will be possible to begin to segregate the roles of the various prereceptor, receptor and postreceptor factors that are involved in producing the differing patterns of metabolism observed in disease.

Adipose Tissue↗