Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy. We have examined restriction fragment length polymorphisms (RFLPs) near "candidate diabetogenic genes" as one approach to identify molecular markers for GDM genes. Genotypes for insulin hypervariable region (HVR), insulin-like growth factor II (IGF2), insulin receptor (INSR), and glucose transporter (GLUT1) RFLPs were studied in 96 GDM and 164 control subjects, matched to GDM for race, age, and gravidity. Logistic regression analysis was used to explore the relationship between genotypes at these candidate gene loci and GDM, while adjusting for the effects of potential confounding variables. Among black subjects, the INSR allele 1 (P = 0.001) and interactions between INSR allele 1 with body mass index (BMI) (P = 0.002) and history of DM in subject's mother (P = 0.004) contributed significantly to GDM risk. Among Caucasian subjects, a similar relationship between the INSR allele 1 (P = 0.007) and INSR allele 1-BMI interactions (P = 0.011) on GDM risk were observed. In Caucasians, an additional significant risk factor was determined by an INSR allele 1-IGF2 allele 2 interaction (P = 0.018). No risk factors were identified in Hispanic subjects. These data continue to support the hypothesis that GDM is a heterogeneous disorder with respect to phenotypic and genotypic features. Furthermore, our data suggest that risk for GDM in black and Caucasian subjects is not due to obesity perse but to interactions between obesity and INSR alleles. In Caucasian women, INSR and IGF2 alleles interact to confer additional risk for GDM. Thus genes underlying susceptibility to GDM in some women may be similar to genes conferring risk to NIDDM, while in others novel genes may contribute to GDM risk.
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PMID:Increased risk for gestational diabetes mellitus associated with insulin receptor and insulin-like growth factor II restriction fragment length polymorphisms. 257 27

Insulin action in vivo and insulin binding to monocytes in vitro were correlated in patients with myotonic dystrophy (MyD) and compared with healthy controls. Confirming our previous studies and those of others, the present results show that the glucose infusion rate (DR), an estimate of in vivo insulin sensitivity, was significantly diminished in MyD. At the same per cent of ideal body weight DR in MyD patients was considerably less than controls suggesting that obesity could not solely account for decreased insulin sensitivity in MyD. The relative capacity (RC), and relative affinity (ED50) of the insulin receptor in monocytes was significantly less in patients. The relative affinity (ED50) was improved by changing environmental insulin levels while receptor numbers (RC) were not. Insulin sensitivity and RC showed a trend toward a positive correlation although this did not reach statistical significance. Our data suggest that the alteration of the insulin receptor in MyD is different from obesity and from other disorders of the motor unit such as amyotrophic lateral sclerosis, where insulin sensitivity and RC are reduced but ED50 is unchanged. Thus, in MyD the receptor may be one of the loci where the resistance occurs.
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PMID:Environmental influence on altered receptor function in a genetic disease: insulin and glucose affect insulin receptors in myotonic dystrophy. 264 9

The tyrosine kinase activity of the insulin receptor was investigated in skeletal muscle biopsies from insulin-resistant males with obesity or with Type 2 (non-insulin-dependent) diabetic males who were lean or overweight. The kinase activity of the receptor from all three groups of insulin-resistant subjects was 40% less when compared to the activity of lean control subjects. This alteration was present in the absence of changes in the level of the insulin receptor on its insulin binding characteristics. We conclude that the tyrosine kinase activity of the skeletal muscle insulin receptor is defective in obesity and Type 2 diabetes, and that this alteration contributes to the insulin-resistant characteristics of both disorders.
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PMID:Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and type 2 (non-insulin-dependent) diabetes mellitus. 282 66

We studied insulin binding, receptor autophosphorylation, and insulin action in isolated adipocytes from 23 Pima Indians with varying degrees of obesity over a range of glucose tolerance. [125I]Insulin binding varied widely and did not correlate with fasting plasma immunoreactive insulin levels or insulin sensitivity, as assessed by the ED50 values of insulin stimulation of glucose transport or insulin inhibition of lipolysis in isolated abdominal wall adipocytes obtained by biopsy from the patients. In contrast there was a significant correlation between loss of stimulation of autophosphorylation in solubilized receptors and loss of insulin sensitivity for both stimulation of glucose transport (r = -0.59; P less than 0.005) and inhibition of lipolysis (r = -0.54; P less than 0.01). There was also a significant inverse correlation between insulin's ability to stimulate receptor autophosphorylation and in vivo insulin resistance, as assessed by fasting plasma insulin levels (r = -0.46; P less than 0.05). These data indicate a significant correlation between changes in sensitivity of glucose transport and antilipolysis to insulin and receptor kinase activity in those patients and suggest that defective coupling of insulin binding to insulin action at the level of phosphorylation of the insulin receptor may cause the insulin resistance in this group of patients.
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PMID:Alterations in insulin receptor autophosphorylation in insulin resistance: correlation with altered sensitivity to glucose transport and antilipolysis to insulin. 283 14

The effect of a new type of antidiabetic agent, BRL 26830A, has been tested in obese mice. Since this drug increases thermogenesis, insulin receptor binding and kinase activity were studied in brown adipose tissue and skeletal muscle of mice made obese by gold thioglucose. At 1 mg.kg-1.day-1, a 3-wk treatment normalized the glycemia and increased the uncoupling protein content of brown adipose tissue. The insulin receptor number and its associated kinase activity increased only in brown adipose tissue. At 2 mg.kg-1.day-1, additional effects, i.e., a 20% reduction in body weight and a normalization of insulin receptor number both in brown adipose tissue and in skeletal muscle, were observed. All those results were obtained even though hyperinsulinemia was not corrected. At the higher drug dosage, insulin receptor kinase activity evolved in direct proportion to the receptor number in brown adipose tissue. By contrast, in skeletal muscle, the receptor kinase activity toward exogenous substrates increased more than the receptor number, suggesting that the alteration of insulin receptor kinase activity previously reported in skeletal muscle of obese mice was partly reversed by BRL 26830A. None of these parameters was modified by the drug in lean mice. These results show that, even without affecting obesity, BRL 26830A improves insulin resistance in obese mice, probably through its effect on insulin receptors. This action prevails in brown adipose tissue, supporting the idea that this tissue plays an important role in glucose homeostasis. Thermogenic drugs could thus be powerful agents for the treatment of noninsulin-dependent diabetics.
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PMID:Effect of a thermogenic agent, BRL 26830A, on insulin receptors in obese mice. 284 63

Obese (ob/ob) mice were treated with the thermogenic beta-adrenoceptor agonist BRL 26830 for 14 days. White adipocytes prepared from these animals showed significant increases in insulin receptor number, with no change in the affinity for these receptors. Increased receptor number was accompanied by increased glucose transport, as measured by 2-deoxyglucose uptake in vitro.
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PMID:Increased insulin binding and glucose transport in white adipocytes isolated from C57B1/6 ob/ob mice treated with the thermogenic beta-adrenoceptor agonist BRL 26830. 286 64

The insulin receptor is a glycoprotein with a molecular weight in the order of 300,000. There are probably two pairs of subunits joined together by disulphide bonds. The distribution of receptors appears to be tissue-specific. On liver plasma membranes they are found predominantly as singletons, whereas on adipocytes they occur mainly in groups. The groups of receptors are held together by disulphide bonds, but these are different from the bonds holding the subunits together. When insulin binds to the receptor, the hormone-receptor complex is internalised in pinocytotic invaginations in the adipocyte, and in coated pits in fibroblasts. Half the receptors are transported to lysosomes where they are degraded, and the other half are recycled to the cell surface presumably for further re-utilisation. Obese patients and those with type II diabetes have in common both a reduced number of insulin receptors and a post-receptor defect. However the degree of insulin resistance in type II diabetes cannot be accounted for on the basis of obesity alone. Moreover many type II diabetics are not obese. The insulin receptor is also altered in certain physiological states. Fasting and exercise lead to increased binding of insulin to its receptor. Pregnancy, on the other hand, may either increase or reduce binding. The effects of glucocorticoids are heterogeneous, and it is probable that the insulin resistance they induce is post-receptor in nature. Auto-antibodies to the insulin receptor is a rare cause of severe insulin-resistant diabetes, but the condition has given considerable insight into the nature of the insulin receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The insulin receptor. 299 44

We have studied the structure and function of the insulin receptors in obese patients with and without noninsulin dependent diabetes mellitus (NIDDM) and in nonobese controls using partially purified receptors from muscle biopsies. Insulin binding was decreased in obesity due to reduced number of binding sites but no differences were observed in insulin binding between obese subjects with or without NIDDM. The structural characteristics of the receptors, as determined by affinity labeling methods and electrophoretic mobility of the beta-subunit, were not altered in obese or NIDDM compared to normal weight subjects. Furthermore, the ability of insulin to stimulate the autophosphorylation of the beta-subunit and the phosphoamino acid composition of the phosphorylated receptor were the same in all groups. However, insulin receptor kinase activity was decreased in obesity using Glu4:Tyr1 as exogenous phosphoacceptor without any appreciable additional defect when obesity was associated with NIDDM. Thus, our data are supportive of the hypothesis that in muscle of obese humans, insulin resistance is partially due to decreased insulin receptors and insulin receptor kinase activity. In NIDDM the defect(s) in muscle is probably distal to the insulin receptor kinase.
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PMID:Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes. 303 21

Recent studies have led to an enhanced understanding of cellular alterations that may play an important role in the pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM). The insulin receptor links insulin binding at the cell surface to intracellular activation of insulin's effects. This transducer function involves the tyrosine kinase property of the beta-subunit of the receptor. It was found that adipocytes from subjects with NIDDM had a 50 to 80 percent reduction in insulin-stimulated receptor kinase activity compared with their non-diabetic counterparts. This defect was relatively specific for the diabetic state since no decrease was observed in insulin-resistant non-diabetic obese subjects. The reduction in kinase activity was accounted for by changes in the ratio of two pools of receptors, both of which bind insulin but only one of which is capable of tyrosine autophosphorylation and subsequent kinase activation; 43 percent of the receptors from non-diabetic subjects were capable of autophosphorylation compared with only 14 percent in the NIDDM group. A major component of cellular insulin resistance in NIDDM involves the glucose transport system. Exposure of cells to insulin normally results in enhanced glucose transport mediated by translocation of glucose transporters from a low-density microsomal intracellular pool to the plasma membrane. It was found that cells from NIDDM subjects had a marked depletion of glucose transporters in both plasma membranes and low-density microsomes, relative to obese non-diabetic control participants. Obese non-diabetic persons had a normal number of plasma membrane transporters but a reduced number of low-density microsome transporters in the basal state compared with lean control volunteers; insulin induced the translocation of relatively fewer transporters from the low-density microsome to the plasma membrane in the obese subgroups. In addition to the diminished number of glucose transporters, cells from both NIDDM and obese subjects had impaired functional activity of glucose carriers since decreased whole-cell glucose transport rates could not be entirely explained by the magnitude of the decrement in the number of plasma membrane transporters. Thus, impaired glucose transport is due to both a numerical and functional defect in glucose transporters. The cellular content of high-density microsomal transporters was the same in lean and obese control volunteers and NIDDM subjects, suggesting that transporter synthesis is normal and that cellular depletion results from increased protein turnover once transporters leave the high-density microsomal subfraction.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cellular mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes. 305 97

To study the relationship between childhood obesity, weight loss, hyperinsulinaemia and the erythrocyte insulin receptor, we measured the plasma concentrations of immunoreactive insulin (IRI) and C-peptide and the binding of 125I-insulin to erythrocytes in 12 obese children with a mean age +/- SD of 11.4 +/- 2.5 years and a mean relative weight score +/- SD of 4.8 +/- 1.4 and 12 age-matched normal-weight children. Eight obese children were re-evaluated after 1 year's participation in a weight reduction programme. The obese children had higher fasting plasma concentrations of IRI (P less than 0.01) and C-peptide (P less than 0.05) and a lower C-peptide to IRI molar ratio (P less than 0.01) than the normal-weight children. The obese children had in addition a reduced erythrocyte insulin binding (P less than 0.05 or less) over the physiological range of circulating insulin concentration. There was a negative correlation (r = -0.60; P less than 0.01) between the insulin tracer binding and the relative weight. The weight reduction programme resulted in a decrease of 1.0 SD (P less than 0.05) in the mean relative weight score. At the end of the therapy the obese children had lower fasting blood glucose levels (P less than 0.05) and lower plasma IRI concentrations at 90 min (P less than 0.05) after an oral glucose load than at the onset of therapy. There were no significant differences between the insulin binding characteristics at the commencement and at the end of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reduced insulin removal and erythrocyte insulin binding in obese children. 306 31


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