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J Roth

Publications and source records attributed to J Roth.

At least 739 records · Page 41Linked to original sources
PubMed1976

Site-site interactions among insulin receptors. Characterization of the negative cooperativity.

By studying the dissociation of 125I-instulin from its receptors in the absence and phe negatively cooperative type for the insulin receptors. In the present study we extend oy purified mouse and rat liver membranes as well as in human circulating monocytes and human cultured lymphocytes demonstrated negative cooperativity that was extraordinarily simn membranes more slowly than it does from its receptors on whole cells. The dissociaty a small percentage of the receptor sites (1 to 5%), are sufficient to accelerate dissociation of hormone from receptor. At these insulin concentrations insulin is entirely monomeric, and in fact at higher concentrations of insulin (greater than 10(-7) M) where insulin dimers predominate, the cooperativity effect is progressively lost. The dissociation rate of 125I-insulin alone (that is at very low fractional saturation of receptors) was markedly accelerated by dripping the pH from 8.0 to 5.0, whereas the dissociation of 125I-insulin at high receptor occupancy was only slightly accelerated by the fall in pH. The dissociation rate was directly related to temperature, but the dissociation rate of 125I-insulin at low receptor occupancy was much more affected by reduction in temperature and showed a sharp transition at 21 degrees. Urea at concentrations as low as 1 M produced a marked acceleration of 125I-insulin dissociation. Divalent cations (calcium and magnesium) appear to stabilize the insulin-receptor interaction, since higher degrees of receptor occupancy were required to achieve a given rate of dissociation of 125I-insulin. These data make it likely that the insulin receptors exist as oligomeric structures or clusters in the plasma membrane. Insulin receptor sites appear to switch from a "slow dissociating" state to a "fast dissociating" state when their occupancy increases; the proportion of sites in each state is a function of occupancy of the receptor sites by the insulin monomer as well as of the physiochemical environment. Other models which could explain apparent negative cooperativity besides site-site interactions, i.e. polymerization of the hormone, steric or electrostatic hindrance due to ligand-ligand interactions, or unstirred (Noyes-Whitney) layers are considered unlikely in the case of insulin receptors on both experimental and theoretical grounds.

Animals↗
PubMed1976

The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man.

In six patients with acanthosis nigricans variable degrees of glucose intolerance, hyperinsulinemia and marked resistance to exogenous insulin were found. Studies of insulin receptors on circulating monocytes suggest that the insulin resistance in these patients was due to a marked decrease in insulin binding to its membrane receptors. When these patients were fasted, there was a fall in plasma insulin but no increase in insulin binding, suggesting that the receptor defect was not secondary to the hyperinsulinemia. The clinical features shared by these cases and several similar ones previously reported may be divided into two unique clinical syndromes: Type A, a syndrome in younger females with signs of virilization or accelerated growth, in whom the receptor defect may be primary, and Type B, a syndrome in older females with signs of an immunologic disease, in whom circulating antibodies to the insulin receptor are found.

Acanthosis Nigricans↗
PubMed1976

Insulin receptors in normal and transformed fibroblasts: relationship to growth and transformation.

The insulin receptors in normal and transformed lines of mouse Balb/3t3 fibroblasts have been studied. In the normal fibroblasts, the binding of insulin was low in growing cells and increased 2-9 fold in confluent stationary cells. Insulin binding was increased whether growth arrest was due to contact inhibition of growth or serum starvation. When serum-starved cells were stimulated to grow by the addition of fresh serum, insulin binding declined. In cells transformed by simian virus 40, Kirsten, Moloney, and Harvey sarcoma viruses, methylcholanthrene, X rays, or spontaneously, the binding was low, in the same range as growing normal cells. In simian virus 40-transformed cells, insulin binding increased 4 fold as the cells reached higher densities in culture. No relationship to changes in cell size was found. The differences in binding were due to changes in the concentration of the receptors, without changes in their affinity for the hormone.

Blood↗
PubMed1976

[Radiation dose to the head, and particularly to the lens of the eye, during tomography with EMI scanner].

Radiation dose to the lens of the eye was estimated using thermoluminescence and film dosimetry on patients undergoing computerised axial skull tomography with the EMI scanner, and also on various phantoms. The dose decreases from the lateral margin of the right eye to the lateral margin of the left eye. During conventional three layer tomography, maximal exposure to the eye is about 0.6 R (1.55 X 10 10-4 C.kg-1), produced entirely by scatter. Direct irradiation of the plane of orbits produces maximal exposure rate of 3 R (7.7X 10-4 C.kg-1). Maximal dose to the head depends on skull size and is about 4 R (approximately 10-3 C.kg-1). The local dose dependence of the eyes was confirmed theoretically by drawing up a computer programme, and was related to the method used by the EMI scanner.

Film Dosimetry↗
PubMed1976

Direct method for detection and characterization of cell surface receptors for insulin by means of 125I-labeled autoantibodies against the insulin receptor.

Autoantibodies directed against the cell surface receptors for insulin are found in some patients with extreme insulin resistance. These antibodies specifically inhibit the binding of insulin to its receptor. A purified IgG fraction from one patient's plasma was labeled with 125I. The 125I-labeled antireceptor antibody, which initially represented about 0.3% of the total 125I-IgG, was enriched by selective adsorption and subsequent elution from cells rich in insulin receptors. The 125I-antireceptor antibody bound to cells and the binding was inhibited by whole plasma and purified IgG from this patient, as well as whole plasma from another patient with autoantibodies to the insulin receptor. Insulins that differed 300-fold in biological potency and affinity inhibited binding of 125I-antireceptor antibody in direct proportion to their ability to bind to the insulin receptor. The binding of 125I-antireceptor antibody was closely correlated with the binding of 125I-insulin over a wide range of receptor concentrations on different cell types. Experimentally induced reduction of the insulin receptor concentration was associated with parallel decreases in the binding of 125I-antireceptor antibody and 125I-insulin. The preparation of 125I-antireceptor antibody with a high specific activity by cytoadsorption and elution has provided a sensitive method for the detection of receptors and autoantibodies to cell surface components.

Antigen-Antibody Reactions↗
PubMed1976

Effects of fast neutrons on the eye.

The study of 93 eyes receiving neutron irradiation establishes the character of the ophthalmic complications of neutron. Significant changes are produced in the eyelids, conjunctiva, and cornea, but the production of cataract is relatively unimportant. No reaction was seen after neutron treatment that had not already been seen after chi or gamma radiation. That the unavoidable damage is similar to that reported with other forms of radiation, and not worse, is an important finding in view of the statistically significant benefit of neutron treatment to patients in a controlled clinical trial of advanced tumours of the head and neck (Catterall and others, 1975). The observations indicate that the improved cure rates with neutrons are not obtained at the expense of inflicting greater damage to normal structures. This investigation has also shown that the neutron effects of treating these very extensive tumours are acceptable and that, with carefully measured doses, they are predictable. The dose-response relationship in categories of clinical effect for a smaller series of patients, reported in Table 1 of our preliminary communication (Brown and other, 1976), is confirmed.

Adult↗
PubMed1976

Nonsuppressible insulin-like activity of human serum. A potent inhibitor of insulin degradation.

Nonsuppressible insulin-like activity soluble in acid ethanol (NSILA-s) is a well-characterized peptide derived from human serum which has previously been shown to have insulin-like bioactivity and react with both insulin and NSILA-s receptor sites in liver plasma membranes. In the present study we find that NSILA-s is also a potent competitive inhibitor of the insulin-degrading system of the liver plasma membrane. The most purified NSILA-s preparation tested was 20-fold more potent than insulin itself, and significant inhibition of insulin degradation occurred at concentrations of NSILA-s similar to those found in plasma.

Binding, Competitive↗
PubMed1976

Fluctuations in the affinity and concentration of insulin receptors on circulating monocytes of obese patients: effects of starvation, refeeding, and dieting.

The binding of 125I-insulin to insulin receptors on circulating monocytes of obese patients and normal volunteers has been determined under various dietary states. In the basal, fed state the monocytes of obese patients with clinical insulin resistance (n= 6) bound less insulin than normals (n =10) because of a decrease in insulin receptor concentration (obese = 6,000-13,000 sites per monocyte versus normals 15,000-28,000 sites per monocyte). The single obese patient without evidence of clinical insulin resistance demonstrated normal binding of insulin with 16,000 sites per monocyte. In all patients, the total receptor concentration was inversely related to the circulating levels of insulin measured at rest after an overnight fast. For the obese patients with basally depressed insulin binding, a 48-72-h fast lowered circulating insulin and increased binding to normal levels but only at low hormone concentrations; this limited normalization of 125I-insulin binding was associated with increased receptor affinity for insulin without change in receptor concentration. Refeeding after the acute fasting periods resulted in return to the elevated plasma insulin levels, the basal receptor affinity, and the depressed insulin binding observed in the basal, fed state. Chronic diet restored plasma insulin levels, insulin binding, and receptor concentration to normal without change in affinity. When the data from this study are coupled with previous in vivo and in vitro findings they suggest that the insulin receptor of human monocytes is more sensitive to regulation by ambient insulin than the receptors of obese mice and cultured human lymphocytes. The results further indicate than an insulin receptor undergoes in vivo modulation of its interaction with insulin by changing receptor concentration and by altering the affinity of existing receptors.

Adolescent↗
PubMed1976

Characterization of antibodies to the insulin receptor: a cause of insulin-resistant diabetes in man.

We have characterized the circulating inhibitor of insulin receptor binding found in several patients with a new syndrome of extreme insulin resistance. The inhibitor is an immunoglobulin by multiple criteria, including precipitation by 33% ammonium sulfate, migration on G-200 Sephadex gel filtration and DEAE chromatography, and immuno-precipitation with specific anti-human immuno-globulins. Although predominantly IgG, some activity is found in the IgM fraction of the immunoglobulins in one patient. The inhibitory immunoglobulins reacted with antisera to both kappa and lambda light chain determinants and are therefore polyclonal. In addition, activity is retained in the F(ab')2 fraction of pepsin-digested IgG. Evidence suggests that these antibodies are directed at determinants on or near the insulin receptor, and that they are responsible for the observed clinical insulin resistance.

Antibodies↗
PubMed1976

Water-soluble specific growth hormone binding sites from cultured human lymphocytes: preparation and partial characterization.

Cultured human lymphocytes (IM-9 cell line) have specific binding sites or receptors for human growth hormone (hGH). Under appropriate conditions, this specific binding material is spontaneously released into the incubation medium and is solubilized without the use of detergents. This water-soluble preparation binds [125I]iodo-hGH with the same specifictiy as receptors on the intact cell. Unlabeled hGH, but not porcine growth hormone or insulin, competes with labeled hGH for binding to the soluble preparation. Growth hormone preparations of varying purity compete for binding to the soluble binding preparation in the same rank order as they compete for binding to the intact IM-9 lymphocyte. [125I]iodo-hGH incubated with, but not bound to, the soluble preparation is partially degraded, while the [125I]iodo-hGH that is bound to the soluble preparation is protected from degradation, and its ability to rebind to fresh cells is enhanced. The [125I]iodo-hGH-soluble binding preparation complex can be dissociated by the addition of large quantities of unlabeled hGH or by lowering the pH, and [125I]iodo-hGH in both instances remains intact and undegraded. The soluble binding preparation did not sediment when centrifuged at 200,000 X g for 4 hours and was not retained on 0.20 micron Millipore filters. The soluble binding preparation was not retarded on Sephadex G-200. Binding activity was abolished by tryptic digestion. These studies demonstrate that hGH-binding sites, like previously reported insulin binding sites, can be spontaneously solubilized from cultured human lymphocytes, without the use of detergents; these soluble binding preparations are of high molecular weight and are, at least in part, protein in nature.

Animals↗
PubMed1976

Evidence for higher proportion of "little" growth hormone with increased radioreceptor activity in acromegalic plasma.

Plasma growth hormone (GH) from both normal and acromegalic patients comprises multiple immunoreactive components that can be separated by G-100 Sephadex gel filtration and measured by radioimmunoassay (RIA) and radioreceptor assay (RRA). The higher molecular weight immunoreactive components, from both normal and acromegalic subjects, have a lower RRA/RIA than does the lower molecular weight "little" GH component. The "little" GH component comprises a higher proportion of the total immunoreactive GH in acromegalic plasma than in normal plasma whether the data are expressed only in terms of the "big" and "little" components (89 vs. 71%), or as a function of total immunoreactive GH (76 vs. 55%), or whether the plasma is obtained in the basal or stimulated state for the acromegalic patients. When the RRA/RIA x 100 is determined for the isolated "little" component, the acromegalic has a significantly greater ratio than the normal (110 vs. 75%). We conclude that acromegalic plasma contains a higher proportion of the more radioreceptor active "little" GH component than does the normal and, in addition, that the "little" component from the acromegalic is more radioreceptor-active than the normal.

Acromegaly↗
PubMed1976

The immunology of the insulin receptor.

We have detected and characterized anti-insulin-receptor autoantibodies which circulate in several patients with insulin resistance diabetes. These antibodies are predominantly IgG and are polyclonal. They inhibit insulin binding to its receptor on a variety of tissues from widely separated species. Antibodies obtained from different patients appear to bind to different determinants on the receptor and alter receptor function in several ways. Some anti-receptor antibodies are capable of stimulating insulin-like effects on target tissues, while others block insulin-stimulated effects. Direct labeling of anti-receptor antibody with 125I permits use of these antibodies as an assay and probe of insulin receptors.

Adipose Tissue↗
PubMed1976

[Relation between manifest bronchial obstruction and bronchial hyperreactivity (author's transl)].

Based on the inquiry of 252 patients an investigation was carried out concerning the frequency of manifest bronchial obstruction in dependence on the bronchial hyperreactivity. Patients with bronchial hyperreactivity showed more frequently with a high significance as well a decrease in the FEV1 as an increase of resistance. Therefore in dependence on the occurrence of a manifest bronchial obstruction also the probability of a simultaneous presence of bronchial hyperreactivity increases. The results are important for understanding the functional dynamics of the bronchopulmonary system, especially the evocation of dyspnea by irritation of the respiratory tract.

Adolescent↗
PubMed1976

[Isodose computations of linear and circular interstitial radiation sources].

A new program for computation and representation of isodoses around interstitial radiation sources is presented. The sources can be arranged in a line or circularly. The choice for the location of the isodose plane is restricted by a sole condition: It has to be positioned parallel to a given axis. The program comprises different possibilities for an optimal description of the isodoses.

Electronic Data Processing↗