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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Skeletal muscle sensitivity and responsiveness to insulin and their relationship to overall glucose disposal and insulin binding were determined in 89 premenopausal women of varying body fat topography (waist/hips girth ratio [WHR] 0.64-1.02) and obesity level (percentage of ideal body weight 92-230). As a marker of insulin action, the percentage of total glycogen synthase present in the I form (glucose-6-phosphate independent) was measured in quadriceps muscle biopsies. The increase in percentage of synthase I 1 h after oral glucose loading was not significantly different between nonobese and obese weight-matched subgroups of increasing WHR, but this response was maintained at the expense of increasing plasma insulin levels as the WHR rose. The increase in percentage of synthase I in response to submaximal steady state plasma insulin (SSPI) of approximately 100 microU/ml achieved by the infusion of somatostatin, insulin, and glucose, however, was significantly lower in obese than in nonobese subjects, and was inversely correlated with WHR. The increase in percentage of synthase I correlated inversely with the steady state plasma glucose (SSPG) concentration, which is an index of the efficiency of overall glucose disposal, and directly with insulin binding to circulating monocytes. Insulin binding also correlated inversely with WHR and with fasting plasma insulin levels. When obese subjects were separated into three weight-matched subgroups on the basis of increasing WHR, significant trends to decreased percentage of synthase I response, increased SSPG, and decreased insulin binding were found. In women with predominantly upper body obesity (WHR greater than 0.85), the increase in percentage of synthase in response to submaximal SSPI was diminished, but there was no impairment of percentage of synthase I responsiveness to supramaximal SSPI of approximately 1,000 microU/ml. At supramaximal SSPI levels, SSPG in four obese women was normal, whereas in five women, SSPG concentrations were markedly increased. Our results suggest that in premenopausal women, impaired skeletal muscle insulin sensitivity that results in decreased glucose storage capacity may contribute to the diminished efficiency of glucose disposal and insulin resistance that are associated with upper body obesity. The impairment in skeletal muscle sensitivity may be overcome in vivo at the expense of increasing plasma insulin levels, with maximal responsiveness remaining unimpaired. This defect may result from a reduction in insulin receptor number which could, in turn, be secondary to persistently elevated fasting plasma insulin levels. In some upper body segment obese women, however, an additional defect affecting other insulin-sensitive pathways may also be present.
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PMID:Relationship between skeletal muscle insulin resistance, insulin-mediated glucose disposal, and insulin binding. Effects of obesity and body fat topography. 614 58

An increasing body of evidence supports the regulation of hormone action by changes in receptor concentration and affinity. Down and up regulation of insulin and somatomedin receptors by changes in hormone concentration explains the alterations in receptor numbers in obesity or diabetes. However, the changes in receptor affinity that have been described have no known mechanism. In most cases, they occur in vivo, but changes can be produced in vitro by ketone bodies and calcium ions. Calcium ions have also been implicated in insulin action, thus strengthening this relationship. Evaluation of the control of receptor affinity must take into account the effects of metabolites such as glucose and minerals, as well as multiple other factors. The relationship between binding and the biological effect of insulin has to be resolved before the full understanding of insulin action can be reached. The controversial areas of insulin receptor research are becoming clearer, but much more information is required before these questions can be resolved.
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PMID:Receptors for insulin and insulin-like molecules. 624 82

An insulin-sensitive subcellular system was developed from rat adipocytes consisting of plasma membranes and mitochondria. Direct addition of insulin, concanavalin A or anti-insulin receptor antibody to this system resulted in the production of a mediator substance from the plasma membrane that caused dephosphorylation of the alpha subunit of pyruvate dehydrogenase in the mitochondria with concomitant activation of the enzyme. The mediator activated pyruvate dehydrogenase by activating the pyruvate dehydrogenase phosphatase and not by inhibiting the pyruvate dehydrogenase kinase. This was similar to the mechanism by which insulin causes activation of the enzyme in the intact cell. The insulin-sensitive mediator material from the adipocyte plasma membrane was acid-stable with a molecular weight of 1,000 to 1,500. Our laboratory has shown that the mediator that activates pyruvate dehydrogenase was present in intact adipocytes, hepatoma cells, and IM-9 lymphocytes. Insulin altered the amount or activity of the mediator consistent with the effect of the hormone on the cell. Other laboratories have shown similar effects on skeletal muscle and liver. We have shown the mediator to mimic insulin action on the low Km cyclic adenosine monophosphate (AMP) phosphodiesterase and the (calcium++-magnesium++)-adenosine triphosphatase (Ca++-Mg++)-ATPase of adipocyte plasma membranes in addition to pyruvate dehydrogenase. Other laboratories have shown the mediator to activate glycogen synthase. A body of direct and indirect evidence exists that demonstrates that more than one mediator exists. The chemical nature of the mediator is unknown but probably represents a new family of intracellular mediators of hormone action. These mediators may have clinical relevance in postreceptor defects of obesity and type II diabetes (noninsulin-dependent diabetes mellitus).
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PMID:The chemical mediators of insulin action: possible targets for postreceptor defects. 633 85

[125I]Insulin binding to insulin receptors on circulating monocytes was studied in 9 patients with acromegaly associated with fasting hyperglycemia and was compared to previously reported studies of 11 patients with acromegaly who had normal or nearly normal glucose tolerance and 29 normal volunteers. In the hyperglycemic acromegalic, as had been found in the normoglycemic acromegalic, the total receptor concentration per cell was decreased in proportion to the hyperinsulinemia, i.e. the receptor concentration was inversely related to the basal level of insulin, similar to what is found in patients with obesity, diabetes, and insulin-secreting tumors. However, the acromegalic patients with hyperglycemia failed to show the increase in affinity of the empty receptor that had previously been found in their normoglycemic counterparts. The failure to increase receptor affinity causes the cells of the hyperglycemic acromegalic patients to bind less insulin at each insulin concentration than do the cells of normoglycemic patients. Again, the abnormalities in the patients correlates very closely with abnormalities at the level of the insulin receptor, though the sequence of the molecular events that produce these changes remains to be determined.
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PMID:Insulin receptor on monocytes from patients with acromegaly and fasting hyperglycemia. 633 36

Insulin binding was studied in fibroblasts and monocytes from nondiabetic subjects with a range of body mass indices (BMI). Binding was compared in fibroblasts from extremely obese subjects and normal weight subjects. The [125I] insulin displacement curve for the obese subjects was shifted to the right. Scatchard analysis suggested that cells from the obese group have an increased number of receptors with decreased affinity. Significant correlations were observed between the cell donor's BMI and the concentration of insulin required to inhibit half of the [125I]insulin specifically bound to fibroblasts (r = 0.8; P less than 0.005), the high affinity dissociation constant (r = 0.8; P less than 0.005), and the number of receptors (r = 0.6; P less than 0.05). Insulin binding to monocytes was measured for nondiabetic Pima Indian subjects with a range of BMI values. Scatchard analysis of the data indicated that the high affinity dissociation constant was positively correlated with BMI (r = 0.6; P less than 0.02). The number of receptors was also positively correlated with BMI (r = 0.6; P less than 0.05). The observation that both cultured cells and monocytes exhibit changes in insulin binding that correlate with the obesity of the cell source suggests that the insulin resistance of obesity may be partially a reflection of genetic differences at the site of the insulin receptor.
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PMID:Altered insulin binding to monocytes and diploid fibroblasts from obese donors. 634 14

Resistance to the action of insulin plays a central role in many important disease states, including diabetes and obesity. Many insights into the mechanism and significance of insulin resistance in these and other disorders have followed upon our expanding knowledge regarding insulin receptors. In this article, we review our current understanding of insulin receptors and their regulation, and we assess the role of insulin receptor pathology in the various syndromes characterized by insulin resistance.
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PMID:Insulin receptors and insulin resistance. 634 53

The insulin-binding isotherms and the structural composition of human liver insulin receptors were examined by using plasma membranes that were prepared from liver biopsies of nine non-obese and 10 obese subjects undergoing elective surgery. The insulin-binding characteristics of liver membranes from non-obese subjects were quite similar to those previously described in rat liver membranes. However, when the membranes from obese subjects were compared with the non-obese group, insulin-binding activity was reduced by 50% (P less than 0.01). The reduction in obesity resulted primarily from a decrease in total receptor number, although a small decrease in receptor affinity was also observed. Insulin binding was not correlated with sex or with the fasting plasma insulin level. The insulin-binding sites of liver membranes were affinity-labeled with 125I-insulin and the cross-linking reagent, disuccinimidyl suberate. The liver membranes from both the non-obese and the obese group had heterogenous (nonreduced) insulin-binding species of 300,000, 260,000, and 150,000 mol wt, which were again comparable to the findings reported in rat liver. Sulfhydryl reduction demonstrated a major sub-unit of 125,000 and a minor component of 40,000-45,000 in both groups. These results indicate a close similarity between the hepatic insulin receptor of man and the more intensely studied rat hepatic receptor. Obesity in human subjects is associated with a loss of hepatic insulin receptors. This alteration may contribute to the insulin resistance reported in this organ as well as to obesity-mediated glucose tolerance.
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PMID:Studies of liver insulin receptors in non-obese and obese human subjects. 635 85

The Prader-Willi syndrome is among other features characterized by obesity and a high prevalence of glucose intolerance. The fasting plasma insulin concentration and the insulin response to glucose are often increased, indicating some insulin resistance in this disease. To investigate whether this could be due to an insulin receptor defect 7 patients with Prader-Willi syndrome, 10 normal weight subjects and 8 obese subjects were tested for the binding of [125I]insulin to monocytes. Monocytes from patients with Prader-Willi syndrome bound significantly less insulin than cells from normal subjects (P less than 0.01). However, no difference was found between Prader-Willi patients and the obese controls (P greater than 0.1). It is concluded that the insulin resistance found in Prader-Willi patients, similar to that found in obese subjects, in part, may be explained by an insulin receptor defect on target cells for insulin action.
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PMID:A reduced number of insulin receptors in patients with Prader-Willi syndrome. 635 45

This report describes a 55-year-old diabetic patient with severe insulin resistance due to obesity and hepatic cirrhosis. Anti-insulin antibodies were responsible for only a minor part of the insulin resistance. Insulin resistance was mediated primarily at the target tissue level by a combination of insulin receptor deficiency and a postreceptor defect. When the patient was treated with U-500 regular pork insulin subcutaneously, her insulin requirement was only one third to one half of that during U-100 NPH or regular insulin treatment. The reasons for the greater efficacy of U-500 insulin are unknown. U-500 insulin may have a place in the optimization of therapy for patients with insulin resistance of nonimmunologic origin.
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PMID:Enhanced efficacy of U-500 insulin in the treatment of insulin resistance caused by target tissue insensitivity. 636 60

The antilipolytic effect of insulin was studied in 9 obese and 10 age- and sex-matched subjects of normal weight. Isolated fat cells were taken before and 1 h after an 100 g oral glucose load. Insulin inhibition of basal and isoprenaline-induced rates of lipolysis were determined by using a sensitive bioluminescent glycerol assay. When compared with the controls, the obese group showed a lower glucose tolerance, a higher insulin secretion, and a lower specific insulin receptor binding per adipocyte surface area, which would suggest an insulin-resistant state. Before oral glucose, however, the sensitivity of the antilipolytic effect of insulin was enhanced 10-fold in obesity (P less than 0.01), but the maximum antilipolytic effect was not altered. Glucose ingestion induced a 10-25-fold increase in insulin sensitivity (P less than 0.01) and a 10% but not significant increase in specific adipocyte insulin receptor binding in the nonobese group. In the obese group, however, neither the insulin binding nor the antilipolytic effect of the hormone was increased by oral glucose. After oral glucose, insulin sensitivity was similar in the two groups. The concentration of the hormone which produced a half maximum effect was about 1 microU/ml. Similar results were obtained with insulin inhibition of basal and isoprenaline-stimulated glycerol release. It is concluded that, after an overnight fast, the sensitivity of the antilipolytic effect of insulin is markedly enhanced in adipocytes of "insulin-glucose resistant" obese subjects, presumably because of alterations at postreceptor levels of insulin action. In obesity, the antilipolytic effect of insulin seems normal after glucose ingestion. Furthermore, in adipocytes of subjects of normal weight, oral glucose rapidly stimulates the sensitivity of the antilipolytic effect of insulin, apparently because of changes at postreceptor sites. This short-term regulation of insulin action following the ingestion of glucose does not seem to be present in obesity.
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PMID:Influence of obesity on the antilipolytic effect of insulin in isolated human fat cells obtained before and after glucose ingestion. 636 86


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