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

1. Skeletal muscle is a major glucose-utilizing tissue in the absorptive state and alterations in muscle insulin-stimulated glucose uptake lead to derangements in whole body glucose disposal. 2. Furthermore, muscle GLUT4 overexpression in transgenic animals ameliorates insulin resistance associated with obesity or diabetes, which suggests that increasing GLUT4 in muscle by pharmacological intervention may be an effective therapy in insulin-resistant states. 3. This highlights the importance of understanding the pathways that upregulate GLUT4 glucose transporter expression in muscle. 4. We review studies describing the regulation of GLUT4 and the information currently available on the mechanisms that control GLUT4 expression in muscle.
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PMID:Searching for ways to upregulate GLUT4 glucose transporter expression in muscle. 980 66

Insulin resistance is commonly associated with obesity in rodents. Using mice made obese with goldthioglucose (GTG-obese mice), we have shown that insulin resistance results from defects at the level of the receptor and from intracellular alterations in insulin signalling pathway, without major alteration in the number of the Glut 4 glucose transporter. Activation of phosphatidylinositol 3-kinase (PI 3-kinase) was found to be profoundly affected in response to insulin. This defect appears very early in the development of obesity, together with a marked decrease in IRS 1 tyrosine phosphorylation. In order to better understand the abnormalities in glucose transport in insulin resistance, we have studied the pathway leading from the insulin receptor kinase stimulation to the translocation of the Glut 4 containing vesicles. This stimulation involves the activation of PI 3-kinase, which in turns activates protein kinase B. We have then focussed at the mechanism of vesicle exocytosis, and more specifically at the role of the small GTPase Rab4 in this process. We have shown that Rab4 participates, first in the intracellular retention of the Glut 4 containing vesicles, second in the insulin signalling pathway leading to glucose transporter translocation.
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PMID:From insulin receptor signalling to Glut 4 translocation abnormalities in obesity and insulin resistance. 1007 60

The mouse ob gene encodes leptin, an adipocyte hormone that regulates body weight and energy expenditure. Leptin has potent metabolic effects on fat and glucose metabolism. A mutation of the ob gene results in mice with severe hereditary obesity and diabetes that can be corrected by treatment with the hormone. In lean mice, leptin acutely increases glucose metabolism in an insulin-independent manner, which could account, at least in part, for some of the antidiabetic effect of the hormone. To investigate further the acute effect of leptin on glucose metabolism in insulin-resistant obese diabetic mice, leptin (40 ng x g(-1) x h(-1)) was administered intravenously for 6 h in C57Bl/6J ob/ob mice. Leptin increased glucose turnover and stimulated glucose uptake in brown adipose tissue (BAT), brain, and heart with no increase in heart rate. A slight increase in all splanchnic tissues was also noticed. Conversely, no increase in skeletal muscle or white adipose tissue (WAT) glucose uptake was observed. Plasma insulin concentration increased moderately but neither glucose, glucagon, thyroid hormones, growth hormone, nor IGF-1 levels were different from phosphate-buffered saline-infused C57Bl/6J ob/ob mice. In addition, leptin stimulated hepatic glucose production, which was associated with increased glucose-6-phosphatase activity. Conversely, PEPCK activity was rather diminished. Interestingly, hepatic insulin receptor substrate (IRS)1-associated phosphatidylinositol 3-kinase activity was slightly elevated, but neither the content of glucose transporter GLUT2 nor the phosphorylation state of the insulin receptor and IRS-1 were changed by acute leptin treatment. Hepatic lipid metabolism was not stimulated during the acute leptin infusion, since the content of triglycerides, glycerol, and citrate was unchanged. These findings suggest that in ob/ob mice, the antidiabetic antiobesity effect of leptin could be the result of a profound alteration of glucose metabolism in liver, BAT, heart, and consequently, glucose turnover. Insulin resistance of skeletal muscle and WAT, while not affected by acute leptin treatment, could also be corrected in the long term and account for some of leptin's antidiabetic effects.
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PMID:Acute intravenous leptin infusion increases glucose turnover but not skeletal muscle glucose uptake in ob/ob mice. 1034 14

The earliest defect in developing type 2 diabetes is insulin resistance, characterized by decreased glucose transport and metabolism in muscle and adipocytes. The glucose transporter GLUT4 mediates insulin-stimulated glucose uptake in adipocytes and muscle by rapidly moving from intracellular storage sites to the plasma membrane. In insulin-resistant states such as obesity and type 2 diabetes, GLUT4 expression is decreased in adipose tissue but preserved in muscle. Because skeletal muscle is the main site of insulin-stimulated glucose uptake, the role of adipose tissue GLUT4 downregulation in the pathogenesis of insulin resistance and diabetes is unclear. To determine the role of adipose GLUT4 in glucose homeostasis, we used Cre/loxP DNA recombination to generate mice with adipose-selective reduction of GLUT4 (G4A-/-). Here we show that these mice have normal growth and adipose mass despite markedly impaired insulin-stimulated glucose uptake in adipocytes. Although GLUT4 expression is preserved in muscle, these mice develop insulin resistance in muscle and liver, manifested by decreased biological responses and impaired activation of phosphoinositide-3-OH kinase. G4A-/- mice develop glucose intolerance and hyperinsulinaemia. Thus, downregulation of GLUT4 and glucose transport selectively in adipose tissue can cause insulin resistance and thereby increase the risk of developing diabetes.
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PMID:Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. 1121 42

The effects of extracts isolated from Lagerstroemia speciosa L. (banaba) on glucose transport and adipocyte differentiation in 3T3-L1 cells were studied. Glucose uptake-inducing activity of banaba extract (BE) was investigated in differentiated adipocytes using a radioactive assay, and the ability of BE to induce differentiation in preadipocytes was examined by Northern and Western blot analyses. The hot water BE and the banaba methanol eluent (BME) stimulated glucose uptake in 3T3-L1 adipocytes with an induction time and a dose-dependent response similar to those of insulin. Furthermore, there were no additive or synergistic effects found between BE and insulin on glucose uptake, and the glucose uptake activity of insulin could be reduced to basal levels by adding increasing amounts of BE. Unlike insulin, BE did not induce adipocyte differentiation in the presence of 3-isobutyl-1-methylxanthine (IBMX) and dexamethasone (DEX). BE inhibited the adipocyte differentiation induced by insulin plus IBMX and DEX (IS-IBMX-DEX) of 3T3-L1 preadipocytes in a dose-dependent manner. The differences in the glucose uptake and differentiation inhibitory activities between untreated cells and those treated with BE were significant (P < 0.01). The inhibitory activity was further demonstrated by drastic reductions of peroxisome proliferator-activated receptor gamma2 (PPARgamma2) mRNA and glucose transporter-4 (GLUT4) protein in cells induced from preadipocytes with IS-IBMX-DEX in the presence of BE. The unique combination of a glucose uptake stimulatory activity, the absence of adipocyte differentiation activity and effective inhibition of adipocyte differentiation induced by IS-IBMX-DEX in 3T3-L1 cells suggest that BE may be useful for prevention and treatment of hyperglycemia and obesity in type II diabetics.
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PMID:An extract of Lagerstroemia speciosa L. has insulin-like glucose uptake-stimulatory and adipocyte differentiation-inhibitory activities in 3T3-L1 cells. 1153 61

Distribution of glucose transporter (GLUT-1) in the microvascular endothelium of scrapie-infected SJL/J hyperglycemic mice showing clinical signs of scrapie, obesity and reduced glucose tolerance was studied in five brain regions: cerebral cortex, hippocampus, thalamus, cerebellum and olfactory bulb. Uninfected normoglycemic SJL/J mice showing normal glucose tolerance were used as a control. Ultrathin sections of brain samples embedded at low temperature in the hydrophilic resin Lowicryl K4M were exposed to anti-GLUT-1 antiserum followed by gold-labeled secondary antibodies. Labeling density was recorded over luminal and abluminal plasma membranes of microvascular endothelial cells. Ultrastructural observations revealed attenuation of the microvascular endothelial lining in numerous vascular profiles from brain samples of diabetic mice. Morphometric analysis revealed significant decreases of the labeling density for GLUT-1 in the microvasculature of the thalamus, cerebellum and, to a lesser degree, the hippocampus of diabetic mice. No significant differences between diabetic and non-diabetic, control mice were observed in the microvessels supplying cerebral cortex and olfactory bulb. These findings suggest that abnormal glucose metabolism, manifested by reduced glucose tolerance and hyperglycemia, leads to impaired transvascular glucose transport in some brain regions but not in others, presumably disturbing the function of those brain regions supplied by the affected blood microvessels.
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PMID:Quantitative immunogold study of glucose transporter (GLUT-1) in five brain regions of scrapie-infected mice showing obesity and reduced glucose tolerance. 1158 53

Our aim was to investigate the effects of one year recombinant human growth hormone (rhGH) therapy on the regulation by insulin of gene expression in muscle and adipose tissue in adults with secondary GH deficiency (GHD). Six GHD subjects without upper-body obesity were submitted to a 3-h euglycemic hyperinsulinemic clamp before and after one year of rhGH therapy. Muscle and abdominal subcutaneous adipose tissue biopsies were taken before and at the end of each clamp. The mRNA levels of insulin receptor, p85 alpha-phosphatidylinositol-3 kinase (p85 alpha PI-3K), insulin dependent glucose transporter (Glut4), hexokinase II, glycogen synthase, lipoprotein lipase (LPL) in muscle and in adipose tissue, hormone sensitive lipase and peroxisome proliferator-activated receptor gamma (PPAR gamma) in adipose tissue were quantified by RT-competitive PCR. One year treatment with rhGH (1.25 IU/day) increased plasma IGF-I concentrations (54+/-7 vs 154+/-11 ng/ml, P<0.01) but did not affect insulin-stimulated glucose disposal rate measured during the hyperinsulinemic clamp (74+/-9 vs 85+/-5 micromol/kg free fat mass/min). Insulin significantly increased p85 alpha PI-3K, hexokinase II and Glut4 mRNA levels in muscle both before and after rhGH treatment. One year of GH therapy increased LPL mRNA levels in muscle (38+/-2 vs 70+/-7 amol/microg total RNA, P<0.05) and in adipose tissue (2490+/-260 vs 4860+/-880 amol/microg total RNA, P<0.05), but did not change the expression of the other mRNAs. We conclude from this study that GH therapy did not alter whole body insulin sensitivity and the response of gene expression to insulin in skeletal muscle of adult GHD patients, but it did increase LPL expression in muscle and adipose tissue. This result could be related to the documented beneficial effect of GH therapy on lipid metabolism.
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PMID:Expression of insulin target genes in skeletal muscle and adipose tissue in adult patients with growth hormone deficiency: effect of one year recombinant human growth hormone therapy. 1169 48

The thiazolidinediones (TZDs) or 'glitazones' are a new class of oral antidiabetic drugs that improve metabolic control in patients with type 2 diabetes through the improvement of insulin sensitivity. TZDs exert their antidiabetic effects through a mechanism that involves activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma), a nuclear receptor. TZD-induced activation of PPAR gamma alters the transcription of several genes involved in glucose and lipid metabolism and energy balance, including those that code for lipoprotein lipase, fatty acid transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase and the GLUT4 glucose transporter. TZDs reduce insulin resistance in adipose tissue, muscle and the liver. However, PPAR gamma is predominantly expressed in adipose tissue. It is possible that the effect of TZDs on insulin resistance in muscle and liver is promoted via endocrine signalling from adipocytes. Potential signalling factors include free fatty acids (FFA) (well-known mediators of insulin resistance linked to obesity) or adipocyte-derived tumour necrosis factor-alpha (TNF-alpha), which is overexpressed in obesity and insulin resistance. Although there are still many unknowns about the mechanism of action of TZDs in type 2 diabetes, it is clear that these agents have the potential to benefit the full 'insulin resistance syndrome' associated with the disease. Therefore, TZDs may also have potential benefits on the secondary complications of type 2 diabetes, such as cardiovascular disease.
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PMID:The mode of action of thiazolidinediones. 1192 33

Human studies suggest that chromium picolinate (CrPic) decreases insulin levels and improves glucose disposal in obese and type 2 diabetic populations. To evaluate whether CrPic may aid in treatment of the insulin resistance syndrome, we assessed its effects in JCR:LA-corpulent rats, a model of this syndrome. Male lean and obese hyperinsulinemic rats were randomly assigned to receive oral CrPic [80 microg/(kg. d); n = 5 or 6, respectively) in water or to control conditions (water, n = 5). After 3 mo, a 120-min intraperitoneal glucose tolerance test (IPGTT) and a 30-min insulin tolerance test were performed. Obese rats administered CrPic had significantly lower fasting insulin levels (1848 +/- 102 vs. 2688 +/- 234 pmol/L; P < 0.001; mean +/- SEM) and significantly improved glucose disappearance (P < 0.001) compared with obese controls. Glucose and insulin areas under the curve for IPGTT were significantly less for obese CrPic-treated rats than in obese controls (P < 0.001). Obese CrPic-treated rats had lower plasma total cholesterol (3.57 +/- 0.28 vs. 4.11 +/- 0.47 mmol/L, P < 0.05) and higher HDL cholesterol levels (1.92 +/- 0.09 vs. 1.37 +/- 0.36 mmol/L, P < 0.01) than obese controls. CrPic did not alter plasma glucose or cholesterol levels in lean rats. Total skeletal muscle glucose transporter (Glut)-4 did not differ among groups; however, CrPic significantly enhanced membrane-associated Glut-4 in obese rats after insulin stimulation. Thus, CrPic supplementation enhances insulin sensitivity and glucose disappearance, and improves lipids in male obese hyperinsulinemic JCR:LA-corpulent rats.
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PMID:Oral chromium picolinate improves carbohydrate and lipid metabolism and enhances skeletal muscle Glut-4 translocation in obese, hyperinsulinemic (JCR-LA corpulent) rats. 1204 18

Genetically (fa/fa) obese Zucker rats represent an established model of impaired glucose tolerance, with profound insulin resistance. Acarbose, an inhibitor of alpha-glucosidases, attenuates postprandial blood glucose peaks, and improves glucose tolerance in these animals. In the present study, we have tested the hypothesis that the effect of acarbose is associated with improved glucose transporter isoform 4 (GLUT4) trafficking in muscle tissue. Acarbose was administered to Zucker rats as a dietary admix (40 mg/100 g diet) for 12 weeks starting at the age of 6 weeks. Serum insulin and leptin were reduced by acarbose from 44 to 19 and 144 to 62 ng/ml, respectively. Glucose tolerance test was performed by i.v. injection of glucose (1 g/kg) and determination of serum glucose up to 60 min. Marked impaired glucose tolerance was observed in obese animals with a profound correction of this defect in acarbose-treated rats. Insulin-regulated translocation of GLUT4 to the plasma membrane in soleus muscle was increased twofold in lean animals, with a totally blunted response in obese rats. Acarbose feeding restored a 1.6-fold effect of insulin on GLUT4 translocation. The exocytotic GLUT4 storage pool in cardiac muscle was completely insulin-insensitive in obese animals, with a largely improved response after acarbose feeding. Activation of Akt, an insulin signaling event upstream of GLUT4, was completely normalized in acarbose-treated rats. In conclusion, we show here that early application of acarbose to obese Zucker rats can prevent the development of impaired glucose tolerance and obesity-associated insulin resistance at the level of the muscle cell, as reflected by an amelioration of defective GLUT4 trafficking in both cardiac and skeletal muscles.
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PMID:Early acarbose treatment ameliorates resistance of insulin-regulated GLUT4 trafficking in obese Zucker rats. 1206 5


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