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

We have previously shown that in the insulin-resistant obese hyperglycemic mouse (ob/ob) there is a deficiency in the number of insulin receptor sites on hepatocytes, adipocytes, and thymic lymphocytes. We now find that concentration of insulin receptors on liver plasma membranes is decreased in the db/db mouse, another form of inherited obesity, and in normal mice that became obese after treatment with gold thioglucose, while thin mice, heterozygous for the ob mutation (ob/+), have normal insulin binding. With acute and chronic food restriction of the ob/ob and gold thioglucose obese mice, there is reduction in hyperinsulinemia and an associated increase in the insulin receptor concentration toward normal. In contrast, when fasting ob/ob mice were given exogenous insulin to maintain the hyperinsulinemia, insulin receptors failed to increase. Thus, in all cases, there was a consistent relationship between the degree of hyperinsulinemia and of insulin receptor loss. These findings suggest that decreased insulin binding is a characteristic feature of the insulin resistance of obesity, and that sustained hyperinsulinemia is a major factor in the control of the concentration of insulin receptors on target cells.
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PMID:Insulin receptor deficiency in genetic and acquired obesity. 16 96

When insulin or any peptide hormone binds to its receptor on the surface of a target cell, it initiates a series of biochemical steps that ultimately lead to the characteristic action of the hormone. The strength of the signal generated by the hormone depends equally on the hormone concentration, the receptor concentration, and the receptor affinity. Not only do hormone concentrations change rapidly and widely in vivo but so do receptor concentration and affinity. In hormone resistant states, any step in the biochemical pathway of hormone action at the target cell may be involved. Studies of insulin receptors in people indicate that the insulin receptor is altered in many common disorders such as obesity and diabetes, as well as in rare disorders such as extreme insulin resistance due to circulating antibodies directed at the insulin receptor itself. By responding to both intracellular and extracellular events, the insulin receptor is, therefore, a major site for the regulation of target cell responsiveness in vivo.
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PMID:Insulin receptor status in disease states of man. 19 62

The effects of hormones on human adipose tissue are reviewed with respect to the pathogenesis, prevention and therapy of obesity. Insulin. The insulin-resistance in the obese is associated with a decrease of the number of insulin receptor sites, which is likely to be secondary to increased insulin levels. Catecholamines. Human adipose tissue contains alpha- and beta-adrenergic receptors. Alterations in the relation of alpha- and beta-adrenergic responsiveness may be important in the pathogenesis of regional forms of obesity. Gastrointestinal hormones. As opposed to adipose tissue of other species lipolytic effects of gastrointestinal hormones were as yet not clearly demonstrated in human fat cells. Prostaglandins were implicated in the pathogenesis of metabolic obesity. However, the effects of these C-20 fatty acids on human adipose tissue remain to be elucidated. Parathyroid hormone has been shown to possess lipolytic activity in vitro. This property may be important under physiological conditions too. Triglyceride storage diseases and lipomatoses are discussed as models for studying impaired hormonal responsiveness in human adipose tissue.
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PMID:[Obesity and adipose tissue. 2. Hormonal regulation of adipose tissue metabolism]. 21 12

Previous studies have shown that the sensitivity of tissues to insulin is diminished in states of glucocorticoid and GH excess and is increased when these hormones are deficient. To evaluate the role of the insulin receptor in these states, we have studied [125I]insulin binding to purified liver plasma membranes obtained from rats with a variety of perturbations of both glucocorticoids and GH. Glucocorticoid excess was produced in rats by administration of ACTH (40 U/day for 4 days) or dexamethasone (1 mg/day for 4 days). This resulted in an insulin-resistant state. Associated with this insulin resistance, there was a 50-60% decrease in insulin binding to its specific receptors in liver. Conversely, adrenalectomy, which produces an increase in insulin sensitivity, was associated with an increase in insulin binding to liver. Computer-assisted Scatchard analysis using a negative cooperative model for the inulin-receptor interaction indicated that, in contrast to our findings with obesity, the changes in insulin binding in these states were most likely due entirely to changes in receptor affinity, with no change in receptor concentration. GH administration also produced mild insulin resistance and a decrease in receptor concentration. This was associated with a reciprocal increase in receptor affinity and thus, no major alteration in insulin binding occurred at low physiological insulin concentrations. Hypophysectomized rats, on the other hand, showed an increase in receptor concentration and a decrease in affinity, and GH treatment only partially corrected these changes. Rats implanted with the MtT tumor (which secretes ACTH, GH, and PRL) have the combined effects of excess glucocorticoids and GH and are very insulin resistant. Liver membranes prepared from these rats showed a decrease in insulin binding and receptor affinity similar to that observed in other states of glucocorticoid excess. Further, adrenalectomy of the tumor-bearing rats resulted in an increase in insulin binding despite the persistence of the elevated levels of GH, ACTH, and PRL. These findings suggest that alterations in insulin receptor affinity and number may play a major role in the states of altered insulin sensitivity which accompany glucocorticoid excess and deficiency, and follow hypophysectomy. In contrast, the insulin resistance associated with GH excess is mediated at either a site on the receptor distal to the insulin-binding site (i.e. transduction) or at one or more of the intracellular reactions important in insulin action.
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PMID:Alterations in insulin binding induced by changes in vivo in the levels of glucocorticoids and growth hormone. 21 65

A longitudinal in vivo and in vitro analysis of the genesis of insulin resistance has been carried out in mice made obese by chemical made obese by chemical lesion (goldthioglucose, GTG) of the hypothalamus. Six weeks after GTG administration, glycemia and glucose disposal were normal but associated with increased insulin concentration, suggesting incipient insulin resistance. The in vitro counterpart of the latter in obese mice was observed in soleus muscle that was somewhat less responsive to insulin than controls, in liver that had increased basal lipogenesis but was uninfluenced by insulin, and in hepatic plasma membranes in which a slight decrease of insulin binding was measured. At this stage of obesity, basal adipose tissue lipogenesis was increased but the tissue responded in a normal fashion to insulin. These relatively discrete early metabolic changes were corroborated in vivo by a normal hypoglycemic effect of exogenous insulin. Sixteen weeks after GTG administration, hyperglycemia and gross hyperinsulinemia were recorded. This insulin resistance was evidenced in vivo by the lack of hypoglycemic effect of exogenous insulin unless considerable amounts of the hormone were administered. It coincided in vitro with a poor response of soleus muscle to insulin, an absence of a stimulatory effect of the hormone upon both adipose tissue and liver tissue, and a marked decrease in insulin binding to liver plasma membranes. It appears that insulin resistance is a multifactorial and progressive abnormality that might involve both insulin receptor and intracellular metabolic alterations.
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PMID:Longitudinal study on the establishment of insulin resistance in hypothalamic obese mice. 36 21

In an attempt to determine whether the decreased number of insulin's receptors in obesity is a result of downregulation of the receptors, diazoxide (5 mg/kg/d) was given to 10 obese subjects. Insulin's suppression by diazoxide in these 10 subjects resulted in a mild glucose intolerance and an increase in insulin's receptors in seven of the 10 subjects. The subjects could be divided into three groups by analyzing the Scatchard plots of their insulin receptor studies before and after diazoxide. Four subjects exhibited an increase in both high affinity and low affinity receptors, three showed an increase only in high affinity receptors, and three failed to demonstrate any change in receptors in response to diazoxide. These studies support the concept that the decreased number of insulin's receptors observed in obesity is a result of the downregulation of the receptors and is not the primary, underlying cause of insulin resistance in obesity, although a contributory role cannot be ruled out.
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PMID:Downregulation of insulin receptors in obese man. 43 66

The isolated mouse soleus muscle is a suitable system to measure specific insulin binding and insulin effects. Studies in obese mice have pointed to discrete sites of insulin resistance of skeletal muscle in obesity: (1) A decrease in the number of insulin receptors, which may result in diminished insulin sensitivity (i.e., impaired responses to submaximally stimulating doses of insulin); and (2) Alterations that lay apart from, or beyond, the insulin receptor: thus, glucose transport (and/or phosphorylation) appears to be intrinsically altered and the stimulation by insulin of glycogen synthesis is markedly depressed. These alterations are responsible for the marked resistance to maximally stimulating doses of insulin. The serum from a patient with the syndrome of insulin resistance and acanthosis nigricans contains antibodies that inhibit insulin binding and exert insulin-like effects in muscle; this serum is, however, less effective than insulin in maximally stimulating glycogen synthesis, which suggests some differences in their mechanisms of action.
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PMID:Studies of insulin insensitivity in soleus muscles of obese mice. 72 46

Insulin sensitivity of insulin dependent tissues (muscle, adipose tissue, liver) is subject to a variety of influences. Any change in insulin sensitivity is compensated in healthy subjects by a dynamic change in insulin secretion, which will decrease following a rise in insulin sensitivity and increase if insulin sensitivity is impaired (i.e. during insulin resistance induced by obesity, pregnancy, oral contraceptives, dehydration, saturated fatty acids, fever, drugs, etc.). In contrast to secondary insulin resistance idiopathic insulin resistance in type 2 diabetic individuals is associated with impaired insulin secretion, which thus is unable to overcome impaired insulin sensitivity. Idiopathic insulin resistance in type 2 diabetes is additionally characterized by reduced glucose storage, the basis of which may reside in an insulin receptor defect, in the presence of insulin receptor antibodies, in a postreceptor defect or in the synthesis of abnormal insulin molecules.
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PMID:[Insulin resistance]. 129 Mar 22

Early after lesion of the ventromedial hypothalamus nuclei (VMH), insulin-induced glucose utilization is increased in white adipose tissue (WAT), whereas oxidative and glycolytic muscles are, respectively, normoresponsive or resistant to insulin. Five weeks later, all of the muscles are resistant, whereas WAT returns to normal responsiveness. The aim of this study was to characterize the insulin receptor kinase activity in WAT and muscles 1 and 6 wk after lesion. The number and affinity of insulin receptors were not modified in any of the tissues studied. Autophosphorylation and phosphorylation of an exogenous substrate were similar in oxidative and glycolytic muscles of VMH and control rats both 1 and 6 wk after the lesion. Insulin receptors from WAT of 1-wk VMH rats exhibited a 2.5-fold increase in insulin-stimulated autophosphorylation and phosphorylation. Six weeks after the lesion, both autophosphorylation and phosphorylation returned to normal values. This suggests that insulin receptor tyrosine kinase activity does not play a significant role in the insulin resistance of skeletal muscles but has a crucial role in mediating the variations of insulin action on WAT observed during the development of VMH obesity.
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PMID:Insulin receptor kinase activity in muscles and white adipose tissue during course of VMH obesity. 131 7

Obesity is a multifactorial disease with a marked genetic component. The situation is further complicated by the heterogeneity of obesity demonstrated by the topographical distribution of body fat, e.g. upper body (central) and lower body (gluteal) obesity. Furthermore, the distribution of fat shows a stronger heritable tendency compared with total body fat. Central obesity is characterized by hyperinsulinaemia and insulin resistance, a feature in common with non-insulin dependent diabetes mellitus, hypertension and atherosclerosis. In order to study the molecular genetics of central obesity we have examined 56 severely obese (mean body mass index 40), unrelated British Caucasoid young non-diabetic women for associations of restriction fragment length polymorphism of candidate genes with anthropometric measurements and indices of insulin secretion and resistance. The candidate genes examined were insulin receptor, insulin sensitive glucose transporter and insulin. An association of the class 3 allele of the hypervariable region in the 5' flanking region of the insulin gene was found with upper segment obesity (P = 0.005). Furthermore, the class 3 allele was also associated with fasting hyperinsulinaemia (P = 0.01), stimulated insulin secretion (P = 0.01) and insulin resistance as calculated from the homeostatic model of assessment (HOMA; P = 0.008). No such associations were found with the other candidate genes studied. This data suggests that polymorphisms in the 5' flanking region of the insulin gene may affect expression of the gene and thereby modulate insulin production in severely obese female subjects.
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PMID:Central obesity and hyperinsulinaemia in women are associated with polymorphism in the 5' flanking region of the human insulin gene. 135 60


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