Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The metabolic syndrome usually goes along with abdominal obesity: diabetes type II, hypertension, dyslipidemia, and gout are often associated. The common characteristic is the resistance to insulin action. Reasons for the metabolic syndrome are--besides a genetic determination--overnutrition, physical inactivity, and alcohol consumption. Therefore, a causal therapy aims at the elimination of these factors. Consequently, the non-pharmacological therapy of the metabolic syndrome should be emphasized. The most important treatment is the reduction of body weight in the presence of obesity which is relevant for almost 90% of the patients. Body weight can rapidly be diminished by hypocaloric diets. Both, conventional reducing diets or formula diets may be used for weight reduction. Total fasting should not be performed for several reasons. For minor weight reduction or weight maintenance following a period of rapid weight loss with a hypocaloric diet, increased physical activity also lowers weight or prevents relapsing. Aims of therapeutical procedures are the elimination or amelioration of insulin resistance and subsequently the diseases of the metabolic syndrome. Both methods, reducing diet and physical training, act on various factors related to insulin resistance. For example, hypocaloric diets activate thyroxine kinase of the insulin receptor and reduce glucose and insulin in plasma. Physical training reduces not only insulin and glucose in plasma but also free fatty acids in addition and increases capillary density in skeletal muscle. Using the glucose clamp technique, diets and training are equally effective in improving glucose metabolism. Compared to these non-pharmacological methods drugs are less convincing. Since the non-pharmacological treatment implies behavioral changes with regard to nutrition, physical activity and alcohol consumption, simple instructions are not sufficient. Usually long-lasting changes in life style are necessary in order to achieve health improvement. Therefore, health care programs on individual or social basis are required in order to improve nutrition and increase physical activity. However, long-acting effects are difficult to achieve in adults; more promising is the prevention of insulin resistance.
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PMID:[Non-pharmacological therapy of metabolic syndrome]. 771 78

Insulin binding has been reported to be decreased in non-insulin-dependent diabetes mellitus (NIDDM). Although elevated basal insulin concentrations have been correlated with decreased insulin binding in obesity, this relationship has not been found in NIDDM. To determine the potential cause(s) of the decrease, we measured 125I-insulin binding to circulating monocytes isolated from 31 non-insulin-treated patients with NIDDM who had a fasting plasma glucose (FPG) concentration greater than 7.8 mmol/L and 13 control subjects. We examined the influence of obesity, insulin concentration, glycemic control, and treatment with oral hypoglycemic agents on insulin binding in a cross-sectional study. Insulin binding was significantly decreased in the entire NIDDM group (mean +/- SEM, %/10(7) monocytes: 4.65 +/- 0.33) as compared with controls (6.45 +/- .70, P < .02). Subgroups defined by obesity (relative body weight > 1.2) and poor glycemic control (FPG > 11.1 mmol/L) and those not taking oral hypoglycemic agents had significantly lower insulin binding (P < .02). However, neither relative body weight nor insulin concentrations (basal or stimulated) correlated with insulin binding. Stepwise linear regression analysis showed that only FPG significantly correlated with insulin binding (r = -.45, P = .002) even when oral hypoglycemic agent-treated patients were removed from the analysis (r = -.50, P = .003). There was no significant contribution to explain insulin binding by the other variables, including diagnosis of diabetes, obesity, insulin concentration, or treatment with oral hypoglycemic agents. We conclude that poor metabolic control is associated with an alteration in insulin receptor regulation in NIDDM.
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PMID:Insulin binding in non-insulin-dependent diabetes mellitus (NIDDM) is correlated with glycemic control: clinical evidence for abnormal receptor regulation in NIDDM. 772 74

Obesity is considered to be one of the major risk factors for developing non-insulin dependent diabetes mellitus (NIDDM). Our cohort study for NIDDM in Aito, Shiga 1980-1990 confirmed that aging, higher body mass index (obesity) and high blood pressure were independent risk factors for developing NIDDM in Japan. In Pima Indians, decreased glucose disposal rate (GDR) is significantly related to percentage of body fat (%fat). Insulin signaling for glycogen synthesis in the skeletal muscles is impaired in the early stages of obesity. Although the molecular mechanism for insulin resistance in obesity is still unknown, hyperinsulinemia induces insulin receptor loss by means of the down regulation mechanism, and prolonged hyperglycemia may induce the impairment of insulin receptor kinase in the skeletal muscles in obese subjects. These dysfunctions in insulin signaling may cause the deterioration of insulin sensitivity, resulting in worsening glycemic control. Thus dysfunction of insulin receptor signaling in skeletal muscles may be a target for preventing diabetes in obese subjects.
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PMID:[Obesity as a risk factor for developing non-insulin dependent diabetes mellitus--obesity and insulin resistance]. 775 Jun 30

Protein-tyrosine phosphatases (PTPases) have an essential role in the regulation of the steady-state phosphorylation of the insulin receptor and other proteins in the insulin signalling pathway. To examine whether increased PTPase activity is associated with adipose tissue insulin resistance in human obesity we measured PTPase enzyme activity towards the insulin receptor in homogenates of subcutaneous adipose tissue from a series of six lean and six nondiabetic, obese (body mass index > 30) subjects. The obese subjects had a mean 1.74-fold increase in PTPase activity (P < 0.0001) with a striking positive correlation by linear regression analysis between PTPase activity and body mass index among all of the samples (R = 0.918; P < 0.0001). The abundance of three candidate insulin receptor PTPases in adipose tissue was also estimated by immunoblot analysis. The most prominent increase was a 2.03-fold rise in the transmembrane PTPase LAR (P < 0.001). Of the three PTPase examined, only immunodepletion of LAR protein from the homogenates with neutralizing antibodies resulted in normalization of the PTPase activity towards the insulin receptor, demonstrating that the increase in LAR was responsible for the enhanced PTPase activity in the adipose tissue from obese subjects. These studies suggest that increased PTPase activity towards the insulin receptor is a pathogenetic factor in the insulin resistance of adipose tissue in human obesity and provide evidence for a potential role of the LAR PTPase in the regulation of insulin signalling in disease states.
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PMID:Increased abundance of the receptor-type protein-tyrosine phosphatase LAR accounts for the elevated insulin receptor dephosphorylating activity in adipose tissue of obese human subjects. 776 20

The polyunsaturated fatty acid regulation of lipogenic enzyme gene expression in genetically obese rats (Wistar fatty, non-insulin-dependent diabetes mellitus) has been investigated. The hepatic mRNA concentrations and activities of lipogenic enzymes in the fatty and lean rat were greatly increased by feeding a hydrogenated fat diet to fasted rats, and also reached similar maximum levels with similar time courses. By feeding a corn oil diet, however, the increases were markedly reduced in the lean rats, but were not significantly reduced in the fatty rats. Consequently, when the animals were fed corn oil, the mRNA concentrations and activities in the fatty rats were higher than those in the lean. Thus, it appeared that the higher gene expression in the fatty rats can be ascribed to the defects of polyunsaturated fatty acid suppression. On the other hand, insulin binding to receptors in the liver was reduced by the corn oil diet in the lean rats but was not reduced in the fatty rats (although the insulin binding level was lower in the Wistar fatty rats than in the lean). Changes in the insulin receptor autophosphorylation and kinase activity toward exogenous substrate were similar to the insulin binding. It is suggested that the polyunsaturated fatty acids may not suppress insulin binding activity to receptors in the livers of the fatty rats, probably due to down regulation by hyperinsulinemia. The defects of polyunsaturated fatty acid suppression of lipogenic enzyme gene expression may be one of the factors of obesity.
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PMID:Polyunsaturated fatty acid regulation of lipogenic enzyme gene expression in liver of genetically obese rat. 789 32

IRS-1 (insulin receptor substrate-1) is a major substrate for the insulin receptor tyrosine kinase. After phosphorylation by the insulin receptor, IRS-1 binds to the specific molecules which possess SH2 (src homology 2) domain such as 85 kDa subunit of phosphatidylinositol 3 kinase and may mediate insulin signals. The regulation of IRS-1 has been analyzed in animal models of insulin resistance, and its mechanism has been studied in culture cells. In animal models of insulin resistance, phosphorylation of IRS-1 was mainly regulated by the insulin receptor tyrosine kinase both in liver and muscle. However, IRS-1 protein level was differently regulated in muscle and liver. In muscle, IRS-1 protein decreased with dexamethasone treatment and in hypoinsulinemic states such as starvation and streptozotosine-induced diabetes and showed no change in hyperinsulinemic states such as obesity. In liver, IRS-1 protein increased with dexamethasone treatment and hypoinsulinemic states and decreased in hyperinsulinemic states. In cultured cell such as 3T3-L1 or 3T3-F442A adipocytes, IRS-1 was negatively regulated both by insulin and dexamethasone by different mechanisms. Insulin regulates the IRS-1 expression at protein level mainly by decreasing the half life of IRS-1 protein, and dexamethasone regulates it at mRNA level mainly by decreasing the half life of IRS-1 mRNA.
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PMID:[The expression of the insulin receptor substrate-1 (IRS-1) and analysis of its mechanism]. 789 62

1. Recent molecular genetic studies have implicated the low-density-lipoprotein receptor gene locus (LDLR, at chromosome 19p13.2) in obesity in essential hypertensive patients and in the atherogenic lipoprotein phenotype. The present study examined genotypes for the obesity-associated ApaLI restriction fragment length polymorphism of LDLR, and genotypes for a hypertension-associated RsaI restriction fragment length polymorphism at the insulin receptor gene (INSR) locus, which is linked to LDLR, in relation to plasma lipids, body mass index and blood pressure in 27 obese and 57 non-obese Caucasians with severe essential hypertension, selected on the basis of having parents who were both hypertensive, and in 25 obese and 45 non-obese normotensive subjects selected on the basis of having parents who were both normotensive after the age of 50 years. 2. Plasma triacylglycerol and low-density-lipoprotein-cholesterol were elevated in hypertensive patients, but did not differ between the obese and non-obese hypertensive groups. Significant positive correlations were seen between body mass index and triacylglycerol and low-density-lipoprotein-cholesterol in the obese and non-obese hypertensive patients, respectively. In addition, obese hypertensive patients had significantly higher diastolic blood pressure than non-obese hypertensive patients. 3. The eight obese hypertensive patients who were homozygous for the obesity-associated 6.6 kb allele of the ApaLI restriction fragment length polymorphism of LDLR ('6.6. kb homozygotes') had a significantly higher body mass index [34 +/- 6.0 (SD) kg/m2] than the 18 heterozygotes (29 +/- 2.7 kg/m2) and the single subject who was homozygous for the 9.4 kb allele (29 kg/m2) (P = 0.012 by one-way analysis of variance). The body mass index of the eight hypertensive 6.6 kb homozygotes was also greater than the body mass index of 29 +/- 2.4 kg/m2 observed for the eight obese normotensive 6.6 kb homozygotes. In addition, the eight obese hypertensive 6.6 kb homozygotes had a higher plasma triacylglycerol [4.2 +/- 0.77 (SEM) mmol/l] than the 18 obese hypertensive heterozygotes (2.4 +/- 0.33 mmol/l; P = 0.045). Non-obese hypertensive patients showed no significant genotypic differences in relation to the LDLR restriction fragment length polymorphism. 4. In the normotensive group, however, the frequency of the 6.6 kb allele of the LDLR ApaLI restriction fragment length polymorphism in obese subjects (0.54) was not significantly greater than in non-obese subjects (0.48) [cf. the significantly (P = 0.004( different values of 0.63 and 0.39, respectively, in obese and non-obese hypertensive patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Significant relationships of plasma lipids and body mass index with polymorphisms at the linked low-density-lipoprotein receptor gene and insulin receptor gene loci (19p13.2) in essential hypertensive patients. 803 1

Recent data have suggested a key role for tumor necrosis factor (TNF)-alpha in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus (NIDDM). TNF-alpha expression is elevated in the adipose tissue of multiple experimental models of obesity. Neutralization of TNF-alpha in one of these models improves insulin sensitivity by increasing the activity of the insulin receptor tyrosine kinase, specifically in muscle and fat tissues. On a cellular level, TNF-alpha is a potent inhibitor of the insulin-stimulated tyrosine phosphorylations on the beta-chain of the insulin receptor and insulin receptor substrate-1, suggesting a defect at or near the tyrosine kinase activity of the insulin receptor. Given the clear link between obesity, insulin resistance, and diabetes, these results strongly suggest that TNF-alpha may play a crucial role in the systemic insulin resistance of NIDDM. This may allow for new treatments of disorders involving resistance to insulin.
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PMID:Tumor necrosis factor alpha: a key component of the obesity-diabetes link. 792

Many clinical observations have suggested that there is a strong relationship between hyperinsulinemia and hyperandrogenism. HAIR-AN syndrome is defined as a constellation of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN). Two major mechanisms could account for this syndrome: (i) hyperinsulinemia induced by insulin resistance causes hyperandrogenism, and (ii) hyperandrogenism causes insulin resistance and hyperinsulinemia. Acanthosis nigricans is considered to be an epiphenomenon caused by hyperinsulinemia. The causes of HAIR-AN syndrome include syndromes of extreme insulin resistance due to mutations in the insulin receptor gene, lipoatrophic diabetes, obesity, some endocrinopathies, and genetic and acquired ovarian hyperandrogenism.
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PMID:[HAIR-AN syndrome]. 798 93

To assess the role of insulin receptor (IR) tyrosine kinase in human insulin resistance, we examined the kinase activity of IR of skeletal muscle biopsies from eight lean and five obese nondiabetics and six obese subjects with noninsulin-dependent diabetes mellitus (NIDDM). Biopsies were taken during euglycemic clamps at insulin infusion rates of 0, 40, 120, and 1200 mU/m2.min. IRs were immobilized on insulin agarose beads, and autophosphorylation and histone 2B phosphorylation were measured. Phosphatase and protease inhibitors preserved the in vivo phosphorylation state of the IRs. Glucose disposal rates (GDR) were reduced according to insulin dose by 23-30% in the obese (P < 0.05) and 43-64% in the NIDDM subjects (P < 0.0005). IR autophosphorylation was increased up to 9-fold in controls and was reduced (P = 0.04) in NIDDM compared to obese subjects. Histone-2B kinase was increased up to 6-fold in controls and was reduced by 50% in NIDDM. Kinase values by both methods were similar in lean and obese controls. In vivo stimulation of kinase was well correlated to the increase in GDR, as was the decrement in kinase in NIDDM to the decrement in GDR. These results suggest that defects in muscle IR kinase are significant in the in vivo insulin resistance of NIDDM, but not that of obesity.
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PMID:Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes mellitus and obesity. 810 37


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