Insulin interactions with its receptors: experimental evidence for negative cooperativity.
01 Nov 1973-Biochemical and Biophysical Research Communications (Academic Press)-Vol. 55, Iss: 1, pp 154-161
TL;DR: A simple method is reported to detect cooperative interactions in the binding of polypeptide hormones to their membrane receptors, and Insulin receptors on cultured lymphocytes and liver plasma membranes show negative cooperative interactions.
About: This article is published in Biochemical and Biophysical Research Communications.The article was published on 1973-11-01. It has received 711 citations till now. The article focuses on the topics: Hormone receptor & Receptor.
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936 citations
TL;DR: Hyperinsulinemia is often both a result and a driver of insulin resistance, and situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance are examined.
Abstract: Insulin resistance, recently recognized as a strong predictor of disease in adults, has become the leading element of the metabolic syndrome and renewed as a focus of research. The condition exists when insulin levels are higher than expected relative to the level of glucose. Thus, insulin resistance is by definition tethered to hyperinsulinemia. The rising prevalence of medical conditions where insulin resistance is common has energized research into the causes. Many causes and consequences have been identified, but the direct contributions of insulin itself in causing or sustaining insulin resistance have received little sustained attention. We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance. 1) Mice transfected with extra copies of the insulin gene produce basal and stimulated insulin levels that are two to four times elevated. The mice are of normal weight but show insulin resistance, hyperglycemia, and hypertriglyceridemia. 2) Somogyi described patients with unusually high doses of insulin and hyperglycemia. Episodes of hypoglycemia with release of glucose-raising hormones, postulated as the culprits in early studies, have largely been excluded by studies including continuous glucose monitoring. 3) Rats and humans treated with escalating doses of insulin show both hyperinsulinemia and insulin resistance. 4) The pulsatile administration of insulin (rather than continuous) results in reduced requirements for insulin. 5) Many patients with insulinoma who have elevated basal levels of insulin have reduced (but not absent) responsiveness to administered insulin. In summary, hyperinsulinemia is often both a result and a driver of insulin resistance.
666 citations
Cites background from "Insulin interactions with its recep..."
...At increasing concentrations of insulin, occupancy of receptor sites increases, but average affinity diminishes (“negative cooperativity”) (39)....
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TL;DR: This new procedure permitted an analysis of insulin binding activity and cellular responsiveness to insulin during adipocyte conversion in vitro and found that cells appeared to be adipocytes by morphological and biochemical criteria and the specific insulin binding was 6to lo-fold greater than in undifferentiated control cells.
651 citations
TL;DR: It is likely that the insulin receptors exist as oligomeric structures or clusters in the plasma membrane 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.
591 citations
TL;DR: The rate of dissociation of 125I-betaNGF from the higher affinity binding site I is accelerated by unlabeled betaNGF under conditions where the occupancy is both increased and decreased.
590 citations
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TL;DR: The number and variety of known compounrjs between proteins and small molecules are increasing rapidly and make a fascinating story as discussed by the authors, and there are many compounds of serum albumin, which was used during the war by many chemists, most of whom found at least one 6ew compound.
Abstract: The number and variety of known compounrjs between proteins and small molecules are increasing rapidly and make a fascinating story. For instance, there are the compounds of iron, which is carried in our blood plasma by a globulin, two atoms of iron to each molecule of globulin held in a rather tight salt-lie binding? which is stored as ferric hydroxide by ferritin much as water is held by a sponge? and which functions in hemoglobin, four iron atoms in tight porphyrin complexes in each protein molecule. Or, there are many compounds of serum albumin, which was used during the war by many chemists, most of whom found at least one 6ew compound. This molecule, which has about a hundred carboxyl radicals, each of which can take on a proton, and about the same number of ammonium radicals, each of which can dissociate a proton, has one single radical which combines with mercuric ion so firmly that two albumin molecules will share one mercury atom if there are not enough to go a r ~ u n d . ~ At the present stage of rapid growth of known compounds, it seems more profitable for me to make no attempt to catalogue the various classes of compounds, but to discuss the general principles involved, in the hope that this will make more useful the information which is accumulating so rapidy from so many laboratories. We want to know of each molecule or ion whicb can combine with a protein molecule, /‘How many? How tightly? Where? Why?” The answer to the first two questions, and sometimes to the third, can be furnished by the physical chemist, but he will often need to team with an organic chemist to determine the effect of altering specified groups to find if they are reactive. The determination of function iç a complicated problem which may be the business of the physiologist or physiological chemist. But the answers to both of the more complicated problems will depend on the answers to the simpler questions, “HOW many?” and “How tightly bound?” If the various groups on a protein molecule act independently, we can apply the law of mass action as though each group were on a separate molecule,4 and the strength of binding can be expressed as the constant for each group. Often, a single constant will express the behavior of severa1 groups. If the constants are widely spread, as those for the reaction of hydrogen ion with carboxylate ions, with imidazoles and with amines, the interpretation is simple. If the separation is less, it is very difficult to distinguish the case of different intrinsic affinities from the case of interaction among the groups. We know that such interaction occurs in simple moleculeç in which a reac-
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