Modulation of hexose uptake and insulin action by cell membrane fluidity. The effects of temperature on membrane fluidity, insulin action, and insulin binding.
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Adipose Tissue↗
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Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding.
Insulin binding to monocytes and insulin action in vivo was examined in 14 obese subjects during the postabsorptive state and after starvation and refeeding. Tissue sensitivity to insulin was evaluated with the euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained 100 muU/ml above the fasting level, and plasma glucose is held constant by a variable glucose infusion. The amount of glucose infused is a measure of tissue sensitivity to insulin and averaged 285+/-15 mg/m(2) per min in controls compared to 136+/-13 mg/m(2) per min in obese subjects (P <0.001). (125)I-Insulin binding to monocytes averaged 8.3+/-0.4% in controls vs. 4.6+/-0.5% in obese subjects (P < 0.001). Insulin binding and insulin action were highly correlated in both control (r = 0.86, P < 0.001) and obese (r = 0.94, P < 0.001) groups. Studies employing tritiated glucose to measure glucose production indicated hepatic as well as extrahepatic resistance to insulin in obesity. After 3 and 14 days of starvation, insulin sensitivity in obese subjects decreased to 69+/-4 and 71+/-7 mg/m(2) per min, respectively, whereas (125)I-insulin binding increased to 8.8+/-0.7 and 9.0+/-0.4%. In contrast to the basal state, there was no correlation between insulin binding and insulin action. After refeeding, tissue sensitivity increased to 168+/-14 mg/m(2) per min (P < 0.001) whereas insulin binding fell to 5.0+/-0.3%. We conclude that (a) in the postabsorptive state insulin binding to monocytes provides an index of in vivo insulin action in nonobese and obese subjects and, (b) during starvation and refeeding, insulin binding and insulin action changes in opposite directions suggesting that postreceptor events determine in vivo insulin sensitivity.
Adolescent↗
Effect of cytochalasin B and D on groups of insulin receptors and on insulin action in rat adipocytes. Possible evidence for a structural relationship of the insulin receptor to the glucose transport system.
The possible physiological importance of the groups of insulin receptors on rat adipocytes and the relationship of these groups to insulin action were investigated. The effect of cytochalasin B and D on biological actions of insulin was measured and compared with the effect of these agents on the ultrastructural distribution of groups of insulin receptors. Cytochalasin B had no effect on epinephrine-stimulated lipolysis, insulin inhibition of epinephrine-stimulated lipolysis, or insulin stimulation of protein synthesis. Cytochalasin B, over a concentration range of 50 nM to 5 muM, progressively inhibited the basal glucose transport system, as measured by glucose oxidation, 2-deoxyglucose transport, and 3-O-methylglucose transport. Insulin was capable of fully stimulating remaining basal transport at submaximal concentrations of cytochalasin B. Insulin pretreatment of adipocytes partially protected the glucose transport system from inhibition by cytochalasin B. Cytochalasin B markedly altered the distribution pattern of insulin receptors, which caused an increase in the number of single receptor molecules by decreasing the number of larger groups. A significant correlation (r = 0.964; P < 0.001) was found between the percent increase in single receptors and the percent decrease in glucose transport. Ferritin-insulin pretreatment of adipocytes prevented disruption of the groups of insulin receptors by cytochalasin B. Cytochalasin D had no effect on the biological actions of insulin or on the groups of insulin receptors. These data suggest that the ability of insulin to affect adipocyte metabolism is independent of the hormone occupying adjacent, grouped receptor sites. The marked contrast in effects of cytochalasin B and D on groups of insulin receptors and glucose transport suggests that the microfilament system is not involved in insulin action or in holding the groups of insulin receptors together, as both agents are known disrupters of microfilaments and inhibitors of actin gelation. The correlation between the effects of cytochalasin B on insulin receptor distribution and glucose transport leads to the speculation that the glycoprotein molecules containing the insulin receptor are functionally linked with the glucose transport system.
Adipose Tissue↗
Insulin action in isolated fat cells. II. Effects of divalent cations on stimulation by insulin of protein synthesis, on inhibition of lipolysis by insulin, and on the binding of 125I-labelled insulin to isolated fat cells.
The effects of ommission of Ca2+ and Mg2+ from the incubation medium on three aspects of insulin action in isolated fat cells have been investigated. In the (Ca2+ + Mg2+)-free incubation medium incorporation of L-[14C]leucine into fat cell protein was reduced in the absence of insulin. Insulin stimulated L-[14C]leucine incorporation only in the presence of added CaCl2 or MgCl2. Incubation of the cells in the (Ca2+ + Mg2+)-free medium reduced but did not abolish the ability of adrenaline to stimulate lipolysis or the ability of insulin to inhibit the adrenaline-stimulated lipolysis. Specific binding of 125I-labelled insulin to the fat cells was reduced in the absence of Ca2+ and Mg2+ but was not abolished, even in the presence of EDTA. Ca2+ was routinely the most effective divalent cation in supporting these aspects of insulin action, but similar responses were obtained with Mg2+, Sr2+ and Ba2+. Since insulin still binds to the cells under conditions in which some of the cellular effects of the hormone are abolished, it is suggested that divalent cations may have a role, either direct or indirect, in the processes linking the insulin-insulin receptor complex to certain effector systems in the cells. It is tentatively suggested that this action occurs at the level of the fat cell plasma membrane.
Adipose Tissue↗
Mode of insulin action.
A unifying hypothesis is proposed for the mechanism of insulin action in adipose tissue. Insulin both induces displacement of Ca++ from a membrane-bound pool and inhibits efflux of the ion, thereby facilitating a rise in intracellular free Ca++ concentration. The former effect could enhance the transport of substrates and ions into the cell, while the latter modulates the activity of some intracellular enzymes to stimulate glycogenesis, lipogenesis, and decrease lipolysis and glycogenolysis. The calcium ion might act as the missing second messenger for insulin action.
Adenosine Triphosphate↗
Modulation by calcium of the insulin action and of the insulin-like effect of ocytocin on isolated rat lipocytes.
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Adipose Tissue↗
Insulin action on Escherichia coli. Regulation of the adenylate cyclase and phosphotransferase enzymes.
Insulin on Escherichia coli was studied using wild type E. coli B/r and K12 strains and a number of phosphoenolpyruvate phosphotransferase mutants. In vivo, the effects of insulin on the differential rate of tryptophanase synthesis, the rate of alpha-methylglucoside uptake and the rate of growth on glucose were determined in E. coli B/r. In vitro, the effect of insulin on the adenylate cyclase and the phosphotransferase activities was determined using toluenized cell preparations of E. coli B/r, E. coli K12 and phosphotransferase mutant strains. The specificity of insulin action on E. coli was determined using glucagon, vasopressin and somatropin as well as insulin antisera. Results show the specific action of insulin on E. coli, inhibiting tryptophanase induction and adenylate cyclase activity, while stimulating growth on glucose and uptake and phosphorylation of alpha-methylglucoside.
Adenylyl Cyclases↗
Effects of estrogen to alter amino acid transport in R3230AC mammary carcinomas and its relationship to insulin action.
The effects of estrogens on transport and incorporation of amino acids into the R3230AC mammary adenocarcinoma were studied in vivo and in vitro. Dissociated tumor cells from ovariectomized rats, like those from diabetic rats, displayed elevated transport of proline, representing entry by the A system; transport of phenylalanine (L system) was unaltered, as was glucose transport and its utilization. Administration of estradiol valerate decreased the entry of proline into tumor cells from intact, diabetic, or ovariectomized animals; the response to the steroid hormone was greater in ovariectomized or diabetic rats compared to intact animals. The time course of the effects of estrogen treatment was examined in diabetic rats. By 72 hr, transport of both proline and leucine was significantly decreased; incorporation of leucine into proteins and uridine into RNA was significantly reduced by 24 hr after injection of estradiol valerate. The effects of estrogen in vivo to reduce transport of amino acids and their incorporation into proteins appeared to correlate with the reduced tumor growth observed. Experiments were performed to examine the effects of 17 beta-estradiol in vitro on amino acid transport into dissociated cells from ovariectomized or diabetic rats. Under these experimental conditions, 17 beta-estradiol (10(-6)M) inhibited proline transport with little or no effect on leucine transport in cells from ovariectomized rats; in cells from diabetic rats, proline transport and leucine incorporation were significantly reduced by estradiol, whereas phenylalanine transport was slightly inhibited (approximately 20%). The effect of estradiol in vitro was also manifest in tumor cells obtained from diabetic rats treated in vivo with estradiol valerate; estradiol in vitro caused a further reduction in proline transport but not in leucine transport, results that imply some specificity to the action of estrogen on the A system. Since we had earlier shown that insulin action on transport in these tumor cells were directed towards the A system, we examined the effects of insulin, estradiol, and their combination in vitro on proline and leucine transport. Insulin (10(-8) M) stimulated proline transport; 17 beta-estradiol, at a selected lower level of 10(-8) M, inhibited proline transport. When both were added in vitro, estradiol (10(-8 M) was capable of significantly reducing the insulin (10(-8) M)-induced increase in proline transport. Leucine transport was not altered in any of these experiments. Together, these data suggest that estrogens are capable of inhibiting amino acid transport into the R3230AC mammary carcinoma, an effect that is compatible with reduced tumor growth. The possible relationship of estrogen and insulin at the level of amino acid transport remains to be elucidated.
Adenocarcinoma↗
Lack of a gastrointestinal mediator of insulin action in maturity-onset diabetes.
It is suggested that hepatic uptake of orally ingested glucose depends not only on insulin secretion but also on the release of a gastrointestinal factor which mediates insulin action on the liver. In maturity-onset diabetes characterised by hyperinsulinaemia and insulin resistance, deficiency of this gastrointestinal factor may be the primary pathogenetic event leading to postprandial hyperglycaemia. Postprandial hyperglycaemia brings about an increase in insulin secretion; and hyperinsulinaemia, in turn, results in decreased binding of insulin to its receptor and in peripheral (extrahepatic) resistance to insulin.
Administration, Oral↗
Phospholipases of plasmic membranes of adipose tissue. Possible intermediaries for insulin action.
In the present investigation we have shown that cytoplasmic membranes of adipocytes contain A1 and A2 phospholipase activities which are optimal in a buffer with 5 mM Ca2+ (pH 8.5). Insulin enhances these activities within phosphatidylethanolamine. Insulin increases also the amount of free fatty acids in membranes. Rodbell and Blecher have already shown an insulin-like action of phospholipases towards the uptake of glucose and amino-acids by adipocytes. Shier and Asakawa have recently described that lysolecithin and unsaturated fatty acids can change nucleotide-cyclase activities of cytoplasmic membranes towards GTP and ATP; lysolecithins and Triton X 100 seem to react in an identical way. Results from these studies give new suggestions on insulin action; phospholipase activation changes membrane physiochemical properties inducing an increase of glucose carrier mobility and leading the membrane cyclase enzyme (s) towards GMP cyclic synthesis.
Adipose Tissue↗
Studies on the mechanism of insulin action. IV. The isolation and determination of a low insulin receptor activity.
After passing the membrane protein dissolved in 1% DOC over a Sepharose 4B column, a peak with insulin receptor binding activity has been shown in the void volumn. After treating this single peak fraction with 6M guanidine HCl and again passing over a Sepharose 4B column preequilibrated with guanidine HCl, four absorbing peaks at 280 nM have been observed. In addition to the first peak representing the void volume, the 4th absorbing peak has been found to display an obvious binding activity as well. This low molecular biologically active unit has also been demonstrated by means of gel electrophoresis. Its molecular weight has been determined with Sepharose 6B to be about 50,000 daltons.
Animals↗
Syneristic and antagonistic effects of glucocorticoids on insulin action.
HTC cells, an established line of rat hepatoma cells in tissue culture, provide a useful experimental model system for studying the interaction of glucocorticoids and insulin in the regulation of protein metabolism. The actions of insulin and glucocorticoids on amino acid transport and protein degradation are antagonistic in this cell line. In contrast, the actions of these two hormones are additive with regard to the induction of tyrosine aminotransferase. The addition of insulin to HTC cells previously incubated with dexamethasone causes a rapid further doubling in the cellular concentration of this enzyme. The properties of the induction by insulin differ in several respects from the induction by glucocorticoids. The former occurs immediately, without the characteristic lag observed during induction by steroids. Insulin induction of transaminase does not require concomitant RNA synthesis, and does not cause the accumulation of specific mRNA for this enzyme as do glucocorticoids. Using specific immunoprecipitation techniques, we have demonstrated that insulin stimulates a nonselective increase in the rate of total protein synthesis in HTC cells, and a selective decrease in the rate of degradation of tyrosine aminotransferase relative to total protein. Thus the induction of transaminase by insulin involves two distinct actions of the hormone, affecting both synthesis and degradation of protein.
Animals↗
Insulin action on adipocytes. Evidence that the anti-lipolytic and lipogenic effects of insulin are mediated by the same receptor.
1. The dose-response relationships of insulin stimulation of lipogenesis and inhibition of lipolysis were studied simultaneously by using rat adipocytes to determine whether these different effects of insulin are mediated through the same or different sets of receptors. 2. The sensitivity (defined as the concentration of insulin required to produce a half-maximal effect) of the stimulated lipogenic response to insulin was not significantly different from the sensitivity of the anti-lipolytic response to insulin. The addition of different adrenaline and glucose concentrations did not alter the half-maximal concentration of insulin required to inhibit lipolysis. 3. The specificities of the lipogenic and antilipolytic responses were studied by using insulin analogues. The sensitivities of the lipogenic and anti-lipolytic responses were the same for five chemically modified insulins and hagfish insulin, which have potencies compared with bovine insulin of between 3 and 90%. 4. Starving rats for 48h significantly increased the sensitivities of both the antilipolytic and lipogenic responses to insulin, but the changes in the sensitivities of both lipogenesis and anti-lipolysis returned to that of fed rats. 5. We conclude that insulin stimulates lipogenesis and inhibits lipolysis over the same concentration range. These observations provide powerful evidence that the different effects of insulin are mediated through the same set of receptors.
Adipose Tissue↗
The role of calcium in insulin action. V. Importance of cyclic guanosine 3':5' monophosphate and calcium ions in insulin stimulation of lipoprotein lipase activity and protein synthesis in adipose tissue.
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Adipose Tissue↗
Alterations in insulin action by endotoxin in vitro.
Fat cells isolated from epididymal fat pads of Sprague-Dawley rats were exposed to E coli endotoxin in vitro, and after washing the ensuing alterations in glucose oxidation and antilipolysis were studied. Although endotoxin (500 microgram/ml) exhibited an insulin-like effect on basal glucose oxidation, it diminished insulin stimulation of glucose oxidation, seemingly inducing an insulin-resistant state. On the other hand, identical doses of insulin elicited significantly greater antilipolytic effects in endotoxin-treated cells, than in untreated cells. Thus, endotoxin exposure (in a range of 0.05-200 microgram/0.5 ml cell suspension) rendered adipocytes more sensitive to the antilipolytic effect of insulin. Results of this study indicate that the different physiologic actions of insulin on adipocytes are not affected in a uniform manner by endotoxin exposure in vitro.
Adipose Tissue↗
Insulin action in isolated fat cells. I. Effects of divalent cations on the stimulation by insulin of glucose uptake.
The effects of divalent cations, in particular Ca2+ and Mg2+, on glucose uptake by rat isolated fat cells in the presence and absence of insulin have been studied. EDTA (disodium salt) was used to deplete the bovine serum albumin present in the incubation medium of endogenous divalent cations prior to incubation with the cells, but was not present in the incubation medium during the incubation of the cells. The removal of Ca2+ and Mg2+ from the incubation medium did not affect the basal glucose uptake, but abolished the ability of insulin to stimulate glucose uptake by the cells. Addition of 25 microM MgCl2 or CaCl2 to the incubation medium restored a significant insulin stimulation, and this stimulation was maximal when 0.1 mM MgCl2 or CaCl2 had been added. SrCl2 and BaCl2 were also effective in restoring the insulin stimulation, but did not substitute fully for Ca2+ and Mg2+ in the incubation medium. Possible explanation for these observations are discussed.
Adipose Tissue↗
Direct demonstration that receptor crosslinking or aggregation is important in insulin action.
Exposure of adipocytes to antibodies to the insulin receptor results in a blockade of (125)I-labeled insulin binding, stimulation of glucose oxidation, and many more insulin-like effects. Allowing for differences in purity, antireceptor antibody is equipotent with insulin on a molar basis. Both the bivalent F(ab')(2) and monovalent Fab' fragments of the antireceptor antibody are fully active in inhibiting (125)I-labeled insulin binding. Bivalent F(ab')(2) also retains its insulin-like effects. In contrast, the monovalent Fab' loses almost all ability to stimulate glucose oxidation and acts as a competitive antagonist of insulin-stimulated glucose oxidation. Addition of anti-F(ab')(2) antisera, which crosslink the Fab'-receptor complexes, results in a restoration of the insulin-like activity of the antibody. Similarly, when cells are exposed to submaximal doses of insulin, addition of anti-insulin antibodies at low concentration enhances the biological activity of insulin. These data suggest that receptor occupancy by ligand is not sufficient for signal generation and that the insulin-like effects of antireceptor antibody (and perhaps insulin itself) require receptor aggregation or clustering. This aggregation, however, appears to be independent of microfilaments or microtubules because the insulin-like effects of antireceptor antibody, and in fact, of insulin itself, are unaffected by agents that are known to disrupt these structures.
Adipose Tissue↗
Cellular uptake and nuclear binding of insulin in human cultured lymphocytes: evidence for potential intracellular sites of insulin action.
Human cultured lymphocytes (IM-9) were used to demonstrate that insulin can enter the intact cell and bind to the nucleus. When these lymphocytes were incubated with 125I-labeled insulin, specific cellular uptake reached a maximum within 2 min and remained at a plateau for 90 min or longer. Partially purified nuclei from such cells contained approximately 15-20% of the total cellular radioactivity. Nuclei freed of all other cellular fractions (by washing the partially purified nucleic with Triton X-100) bound approximately 7% of the total cellular radioactivity. In contrast to the rapid uptake of labeled insulin into the intact cell, specific binding to the nucleus was half-maximal after 5 min of incubation and maximal after 90 min. Both the cellular uptake and subsequent nuclear binding of labeled insulin were progressively inhibited by increasing concentrations of unlabeled hormone. Independent evidence for the nuclear binding of insulin was obtained by preparing autoradiographs of lymphocytes incubated for various times with labeled insulin. Such preparations strongly suggest that insulin binds to the plasma membrane, enters the cytosol, and then binds to the nucleus.
Biological Transport↗