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)

Impairment in the regulation of energy homeostasis and imbalance between energy intake and energy expenditure lead to many metabolic disorders and diseases such as obesity and type 2 diabetes. AMP-activated protein kinase (AMPK) is considered as a "fuel-gauge" in the cell and plays a key role in the regulation of energy metabolism. Activated by an increase in the AMP/ATP ratio, AMPK switches on catabolic pathways such as fatty acid oxidation and switches off anabolic pathways such as lipogenesis or gluconeogenesis. Insulin-sensitizing adipokines (leptin and adiponectin) and anti-diabetic drugs (thiazolidinediones and biguanides) are acting in part through the activation of AMPK. More recent findings indicate that AMPK plays also a major role in the control of whole body energy homeostasis by integrating, at the hypothalamus level, nutrient and hormonal signals that regulate food intake and energy expenditure. AMPK provides therefore a potential target for the treatment of metabolic diseases such as obesity and type II diabetes.
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PMID:[AMPK, an active player in the control of metabolism]. 1714 68

The hexosamine biosynthesis pathway (HBP) serves as a nutrient sensor and has been implicated in the development of type 2 diabetes. We previously demonstrated that fatty acid oxidation was enhanced in transgenic mouse adipocytes, wherein the rate-limiting enzyme of the HBP, glutamine:fructose-6-phosphate amidotransferase (GFA), was overexpressed. To explore the molecular mechanism of the HBP-induced fatty acid oxidation in adipocytes, we studied AMP-activated protein kinase (AMPK), an energy sensor that stimulates fatty acid oxidation by regulating acetyl-CoA carboxylase (ACC) activity. Phosphorylation and activity of AMPK were increased in transgenic fat pads and in 3T3L1 adipocytes treated with glucosamine to stimulate hexosamine flux. Glucosamine also stimulated phosphorylation of ACC and fatty acid oxidation in 3T3L1 adipocytes, and these stimulatory effects were diminished by adenovirus-mediated expression of a dominant negative AMPK in 3T3L1 adipocytes. Conversely, blocking the HBP with a GFA inhibitor reduced AMPK activity, ACC phosphorylation, and fatty acid oxidation. These changes are not explained by alterations in the cellular AMP/ATP ratio. Further demonstrating that AMPK is regulated by the HBP, we found that AMPK was recognized by succinylated wheat germ agglutinin, which specifically binds O-GlcNAc. The levels of AMPK in succinylated wheat germ agglutinin precipitates correlated with hexosamine flux in mouse fat pads and 3T3L1 adipocytes. Moreover, removal of O-GlcNAc by hexosaminidase reduced AMPK activity. We conclude that chronically high hexosamine flux stimulates fatty acid oxidation by activating AMPK in adipocytes, in part through O-linked glycosylation.
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PMID:Chronic hexosamine flux stimulates fatty acid oxidation by activating AMP-activated protein kinase in adipocytes. 1722 72

The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca(2+)-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKbeta. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the alpha subunit being catalytic, the beta subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.
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PMID:AMP-activated protein kinase in metabolic control and insulin signaling. 1730 71

Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation of AMPK is unaffected in lean (BMI approximately 25 kg/m(2)) subjects with type 2 diabetes. However, most type 2 diabetic subjects are obese (BMI >30 kg/m(2)), and exercise stimulation of AMPK is blunted in obese rodents. We examined whether obese type 2 diabetic subjects have impaired exercise stimulation of AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to the putative AMPK targets, AS160 and peroxisome proliferator-activated receptor coactivator (PGC)-1alpha, involved in glucose transport regulation and mitochondrial biogenesis, respectively. Twelve type 2 diabetic, eight obese, and eight lean subjects exercised on a cycle ergometer for 40 min. Muscle biopsies were done before, during, and after exercise. Subjects underwent this protocol on two occasions, at low (50% Vo(2max)) and moderate (70% Vo(2max)) intensities, with a 4-6 week interval. Exercise had no effect on LKB1 activity. Exercise had a time- and intensity-dependent effect to increase AMPK activity and AS160 phosphorylation. Obese and type 2 diabetic subjects had attenuated exercise-stimulated AMPK activity and AS160 phosphorylation. Type 2 diabetic subjects had reduced basal PGC-1 gene expression but normal exercise-induced increases in PGC-1 expression. Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects.
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PMID:Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study. 1732 55

Green tea catechins (GTCs) are polyphenolic flavonoids formerly called vitamin P. GTCs, especially (-)-epigallocatechin-3-gallate (EGCG), lower the incidence of cancers, collagen-induced arthritis, oxidative stress-induced neurodegenerative diseases, and streptozotocin-induced diabetes. Also, inhibition of adipogenesis by green tea and green tea extract has been demonstrated in cell lines, animal models, and humans. The obesity-preventive effects of green tea and its main constituent EGCG are widely supported by results from epidemiological, cell culture, animal, and clinical studies in the last decade. Studies with adipocyte cell lines and animal models have demonstrated that EGCG inhibits extracellular signal-related kinases (ERK), activates AMP-activated protein kinase (AMPK), modulates adipocyte marker proteins, and down-regulates lipogenic enzymes as well as other potential targets. Also, the catechin components of green tea have been shown to possess anti-carcinogenic properties possibly related to their anti-oxidant activity. In addition, it was shown that dietary supplementation with EGCG could potentially contribute to nutritional strategies for the prevention and treatment of type 2 diabetes mellitus. In this review, the biological activities and multiple mechanisms of EGCG in cell lines, animal models, and clinical observations are explained.
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PMID:Proposed mechanisms of (-)-epigallocatechin-3-gallate for anti-obesity. 1736 40

Metabolic disorders, including type 2 diabetes and obesity, represent major health risks in industrialized countries. AMP-activated protein kinase (AMPK) has become the focus of a great deal of attention as a novel therapeutic target for the treatment of metabolic syndromes, because AMPK has been demonstrated to mediate, at least in part, the effects of a number of physiological and pharmacological factors that exert beneficial effects on these disorders. Thus, the identification of a compound that activates the AMPK pathway would contribute significantly to the treatment and management of such syndromes. In service of this goal, we have screened a variety of naturally occurring compounds and have identified one compound, cryptotanshinone, as a novel AMPK pathway activator. Cryptotanshinone was originally isolated from the dried roots of Salvia militorrhiza, an herb that is used extensively in Asian medicine and that is known to exert beneficial effects on the circulatory system. For the first time, in the present study, we have described the potent antidiabetic and antiobesity effects of cryptotanshinone, both in vitro and in vivo. Our findings suggest that the activation of the AMPK pathway might contribute to the development of novel therapeutic approaches for the treatment of metabolic disorders such as type 2 diabetes and obesity.
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PMID:Antidiabetes and antiobesity effect of cryptotanshinone via activation of AMP-activated protein kinase. 1742 5

Over the past two decades increases in obesity, due to high caloric intakes and immobilizing technologies, has led to a surge in type 2 diabetes. In obesity elevated circulating fatty acids set-off a pro-inflammatory cascade that increases the production of tumour necrosis factor-alpha(TNFalpha) from macrophages. Obesity is associated with blunted skeletal muscle fatty acid oxidation, accumulation of bioactive lipids and insulin resistance. The factors contributing to defects in fatty acid metabolism are not understood but new data demonstrates that increased TNFalpha in obesity increases protein phosphatase 2C (PP2C), which in turn suppresses the activity of AMP-activated protein kinase (AMPK), a critical regulator of energy metabolism.(1) These data identify a novel mechanism by which inflammation in obesity is a precursor to defects in skeletal muscle fatty acid oxidation that generates a vicious cycle exacerbating the development of insulin resistance.
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PMID:Inflammation in obesity is the common link between defects in fatty acid metabolism and insulin resistance. 1743 70

Chronic inflammation contributes to vascular insulin resistance and endothelial dysfunction. Systemic infusion of TNF-alpha abrogates insulin's action to enhance skeletal muscle microvascular perfusion. In skeletal muscle TNF-alpha induces insulin resistance via the p38 MAPK pathway. To examine whether p38 MAPK also regulates TNF-alpha-induced vascular insulin resistance, bovine aortic endothelial cells (bAECs) were incubated+/-TNF-alpha (5 ng/ml) for 6 h in the presence or absence of SB203580 (p38 MAPK specific inhibitor, 10 microM) after serum starvation for 10 h. For the last 30 min, cells were treated+/-1 nM insulin, and insulin receptor substrate (IRS)-1, Akt, endothelial nitric oxide synthase (eNOS), p38 MAPK, ERK1/2, c-Jun N-terminal kinase, and AMP-activated protein kinase (AMPK) phosphorylation, and eNOS activity were measured. TNF-alpha increased p38 MAPK phosphorylation, potently stimulated IRS-1 serine phosphorylation, and blunted insulin-stimulated IRS-1 tyrosine and Akt phosphorylation and eNOS activity. TNF-alpha also potently stimulated the phosphorylation of ERK1/2 and AMPK. Treatment with SB203580 decreased p38 MAPK phosphorylation back to the baseline and restored insulin sensitivity of IRS-1 tyrosine and Akt phosphorylation and eNOS activity in TNF-alpha-treated bAECs without affecting TNF-alpha-induced ERK1/2 and AMPK phosphorylation. We conclude that in cultured bAECs, TNF-alpha induces insulin resistance in the phosphatidylinositol 3-kinase/Akt/eNOS pathway via a p38 MAPK-dependent mechanism and enhances ERK1/2 and AMPK phosphorylation independent of the p38 MAPK pathway. This differential modulation of TNF-alpha's actions by p38 MAPK suggests that p38 MAPK plays a key role in TNF-alpha-mediated vascular insulin resistance and may contribute to the generalized endothelial dysfunction seen in type 2 diabetes mellitus and the cardiometabolic syndrome.
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PMID:Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. 1744 86

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


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