Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

trans-Resveratrol (t-RVT), a naturally occurring polyphenol found in Polygonum cuspidatum, grape, and red wine, has been reported to have anti-inflammatory, cardioprotective, and cancer chemopreventive properties. However antidiabetic effect of t-RVT has not yet been reported. In this study, we show that t-RVT increases glucose uptake in C2C12 myotubes by activating AMP-activated protein kinase (AMPK), uncovering an antidiabetic potential of t-RVT for the first time. AMPK plays a central role in the regulation of glucose and lipid metabolism, and hence it is considered a novel therapeutic target for metabolic syndrome such as type 2 diabetes. t-RVT significantly induced glucose uptake in C2C12 cells, via AMPK activation, but not a phosphatidylinositol-3 kinase (PI-3 kinase) signal pathway. The induced glucose uptake was attenuated by pretreatment with a pharmacological inhibitor for AMPK, indicating that the effect of t-RVT primarily depends on AMPK activation. However, in the presence of insulin, t-RVT also potentiated the effect of insulin on glucose uptake via AMPK activation, which led to further activation of PI-3 kinase/Akt signal pathway.
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PMID:Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase. 1746 84

Metformin is among the most widely prescribed drugs for the treatment of type 2 diabetes. Organic cation transporter 1 (OCT1) plays a role in the hepatic uptake of metformin, but its role in the therapeutic effects of the drug, which involve activation of AMP-activated protein kinase (AMPK), is unknown. Recent studies have shown that human OCT1 is highly polymorphic. We investigated whether OCT1 plays a role in the action of metformin and whether individuals with OCT1 polymorphisms have reduced response to the drug. In mouse hepatocytes, deletion of Oct1 resulted in a reduction in the effects of metformin on AMPK phosphorylation and gluconeogenesis. In Oct1-deficient mice the glucose-lowering effects of metformin were completely abolished. Seven nonsynonymous polymorphisms of OCT1 that exhibited reduced uptake of metformin were identified. Notably, OCT1-420del (allele frequency of about 20% in white Americans), previously shown to have normal activity for model substrates, had reduced activity for metformin. In clinical studies, the effects of metformin in glucose tolerance tests were significantly lower in individuals carrying reduced function polymorphisms of OCT1. Collectively, the data indicate that OCT1 is important for metformin therapeutic action and that genetic variation in OCT1 may contribute to variation in response to the drug.
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PMID:Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. 1747 55

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is an attractive candidate gene for type 2 diabetes, as genes of the oxidative phosphorylation (OXPHOS) pathway are coordinatively downregulated by reduced expression of PGC-1 alpha in skeletal muscle and adipose tissue of patients with type 2 diabetes. Here we demonstrate that transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) had reduced white adipose tissue (WAT) mass, high basal metabolic rate, improved glucose tolerance, high insulin sensitivity, and enhanced expression of the OXPHOS genes, coordinated by increased levels of PGC-1 alpha and 5'-AMP-activated protein kinase (AMPK) in WAT. As accelerated polyamine flux caused by SSAT overexpression depleted the ATP pool in adipocytes of SSAT mice and N(1),N(11)-diethylnorspermine-treated wild-type fetal fibroblasts, we propose that low ATP levels lead to the induction of AMPK, which in turn activates PGC-1 alpha in WAT of SSAT mice. Our hypothesis is supported by the finding that the phenotype of SSAT mice was reversed when the accelerated polyamine flux was reduced by the inhibition of polyamine biosynthesis in WAT. The involvement of polyamine catabolism in the regulation of energy and glucose metabolism may offer a novel target for drug development for obesity and type 2 diabetes.
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PMID:Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism. 1748 46

The peroxisome proliferator-activated receptor (PPAR)delta has been implicated in the regulation of lipid metabolism in skeletal muscle. Furthermore, activation of PPARdelta has been proposed to improve insulin sensitivity and reduce glucose levels in animal models of type 2 diabetes. We recently demonstrated that the PPARdelta agonist GW501516 activates AMP-activated protein kinase (AMPK) and stimulates glucose uptake in skeletal muscle. However, the underlying mechanism remains to be clearly identified. In this study, we first confirmed that incubation of primary cultured human muscle cells with GW501516 induced AMPK phosphorylation and increased fatty acid transport and oxidation and glucose uptake. Using small interfering RNA, we have demonstrated that PPARdelta expression is required for the effect of GW501516 on the intracellular accumulation of fatty acids. Furthermore, we have shown that the subsequent increase in fatty acid oxidation induced by GW501516 is dependent on both PPARdelta and AMPK. Concomitant with these metabolic changes, we provide evidence that GW501516 increases the expression of key genes involved in lipid metabolism (FABP3, CPT1, and PDK4) by a PPARdelta-dependent mechanism. Finally, we have also demonstrated that the GW501516-mediated increase in glucose uptake requires AMPK but not PPARdelta. In conclusion, the PPARdelta agonist GW501516 promotes changes in lipid/glucose metabolism and gene expression in human skeletal muscle cells by PPARdelta- and AMPK-dependent and -independent mechanisms.
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PMID:Role of AMP kinase and PPARdelta in the regulation of lipid and glucose metabolism in human skeletal muscle. 1750 64

Over the past decade, an epidemic of obesity has developed throughout the Western World. In recent years, significant interest has focused on the role of the AMP-activated protein kinase (AMPK) as a potential therapeutic target for the treatment of obesity and type 2 diabetes and is such the focus of this review. Specifically, the potential role of AMPK in skeletal muscle metabolism as it relates to the insulin sensitizing effects of exercise and the hormones, leptin, adiponectin, ciliary neurotrophic factor and interleukin-6 are discussed. We caution that despite the convincing associations between the activation of AMPK signalling and the restoration of insulin sensitivity, future studies in genetic models of AMPK deficiency or constitutive activation within skeletal muscle are needed to evaluate the quantitative role of AMPK and to validate whether strategies designed to activate skeletal muscle AMPK may be important for regulating whole-body insulin sensitivity.
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PMID:The AMP-activated protein kinase: role in regulation of skeletal muscle metabolism and insulin sensitivity. 1750 87

AMP-activated protein kinase (AMPK) is an energy sensing/signaling protein that, when activated, increases ATP production by stimulating glucose uptake and fatty acid oxidation while at the same time inhibiting ATP = consuming processes such as protein synthesis. Chronic activation of AMPK inhibits expression of lipogenic enzymes in the liver and enhances expression of mitochondrial oxidative enzymes in skeletal muscle. Deficiency of muscle LKB1, the upstream kinase of AMPK, results in greater fluctuation in energy charge during muscle contraction and decreased capacity for exercise at higher work rates. Because AMPK enhances both glucose uptake and fatty acid oxidation in skeletal muscle, it has become a target for prevention and treatment of type 2 diabetes and obesity.
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PMID:Cellular energy sensing and signaling by AMP-activated protein kinase. 1765 79

AMP-activated protein kinase (AMPK) plays a key role in maintaining energy homeostasis. Activation of AMPK in peripheral tissues has been shown to alleviate the symptoms of metabolic diseases, such as type 2 diabetes, and consequently AMPK is a target for treatment of these diseases. Recently, a small molecule activator (A-769662) of AMPK was identified that had beneficial effects on metabolism in ob/ob mice. Here we show that A-769662 activates AMPK both allosterically and by inhibiting dephosphorylation of AMPK on Thr-172, similar to the effects of AMP. A-769662 activates AMPK harboring a mutation in the gamma subunit that abolishes activation by AMP. An AMPK complex lacking the glycogen binding domain of the beta subunit abolishes the allosteric effect of A-769662 but not the allosteric activation by AMP. Moreover, mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of AMPK by A-769662 in cells and in vitro, while only partially reducing activation by AMP. Based on our results we propose a model for activation of AMPK by A-769662. Importantly, this model may provide clues for understanding the mechanism by which AMP leads to activation of AMPK, which in turn may help in the identification of other AMPK activators.
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PMID:Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. 1772 41

Insulin-resistant type 2 diabetic patients have been reported to have impaired skeletal muscle mitochondrial respiratory function. A key question is whether decreased mitochondrial respiration contributes directly to the decreased insulin action. To address this, a model of impaired cellular respiratory function was established by incubating human skeletal muscle cell cultures with the mitochondrial inhibitor sodium azide and examining the effects on insulin action. Incubation of human skeletal muscle cells with 50 and 75 microM azide resulted in 48 +/- 3% and 56 +/- 1% decreases, respectively, in respiration compared with untreated cells mimicking the level of impairment seen in type 2 diabetes. Under conditions of decreased respiratory chain function, insulin-independent (basal) glucose uptake was significantly increased. Basal glucose uptake was 325 +/- 39 pmol/min/mg (mean +/- SE) in untreated cells. This increased to 669 +/- 69 and 823 +/- 83 pmol/min/mg in cells treated with 50 and 75 microM azide, respectively (vs. untreated, both P < 0.0001). Azide treatment was also accompanied by an increase in basal glycogen synthesis and phosphorylation of AMP-activated protein kinase. However, there was no decrease in glucose uptake following insulin exposure, and insulin-stimulated phosphorylation of Akt was normal under these conditions. GLUT1 mRNA expression remained unchanged, whereas GLUT4 mRNA expression increased following azide treatment. In conclusion, under conditions of impaired mitochondrial respiration there was no evidence of impaired insulin signaling or glucose uptake following insulin exposure in this model system.
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PMID:Does impaired mitochondrial function affect insulin signaling and action in cultured human skeletal muscle cells? 1795 36

Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth.
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PMID:Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. 1800 25

Obesity, type 2 diabetes and the metabolic syndrome are disorders of energy balance, which the AMP-activated protein kinase (AMPK) regulates both at the cellular and whole body levels. AMPK switches cells from an anabolic state where nutrients are taken up and stored, to a catabolic state where they are oxidized. Drugs that activate AMPK indirectly (metformin and thiazolidinediones) are now the mainstay of treatment for type 2 diabetes, but more direct AMPK activators may have fewer side effects. However, activating mutations in AMPK can cause heart disease, and it will be important to look for adverse effects in the heart.
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PMID:Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. 1802 88


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