Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metformin is one of the most commonly prescribed oral antidiabetic agents worldwide. However, its mechanism of action remains unknown. The Diabetes Prevention Program Research Group studies have shown that metformin administration and lifestyle-intervention (diet and exercise) reduce the incidence of Diabetes Mellitus type 2 (DM2). A possible biochemical connection between both therapies may be the AMP-activated protein kinase (AMPK). This enzyme was originally described as a sensor of cellular energy status, being activated in exercise. On the other hand, several experimental evidences indicate that AMPK may be an important target of metformin action. This paper discusses various ways for AMPK regulation, suggesting a possible mechanism for its activation by metformin that involves the production of reactive nitrogen species. AMPK activation determines a wide variety of physiological effects, including enhanced glucose uptake by skeletal muscle and enhanced lipid catabolism. Thus, it may be a key player not only in the prevention and treatment of DM2, but also in the development of new treatments for obesity and the metabolic syndrome. The finding of AMPK activation by metformin draws attention to this enzyme as an important pharmacological target.
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PMID:[Metformin and AMPK: an old drug and a new enzyme in the context of metabolic syndrome]. 1834 5

Metabolic syndrome accelerates the atherosclerotic process, and the earliest event of which is endothelial dysfunction. Ghrelin, a newly discovered gastric peptide, improves endothelial function and inhibits proatherogenic changes. In particular, low ghrelin concentration has been associated with several features of metabolic syndrome, including obesity, insulin resistance, and high blood pressure. However, the molecular mechanisms underlying ghrelin vascular actions remain largely unclear. Here, we showed that ghrelin activated endothelial nitric oxide (NO) synthase (eNOS) in cultured endothelial cells (ECs) and in intact vessels. Specifically, ghrelin rapidly induced phosphorylation of eNOS on an activation site and production of NO in human umbilical vein ECs and bovine aortic ECs. The eNOS phosphorylation was also observed in mouse aortas ex vivo perfused with ghrelin and in aortic tissues isolated from mice injected with ghrelin. Mechanistically, ghrelin stimulated AMP-activated protein kinase (AMPK) and Akt activation in cultured ECs and intact vessels. Inhibiting AMPK and Akt with their pharmacological inhibitors, small interference RNA and adenoviruses carried dominant-negative mutants, markedly attenuated ghrelin-induced eNOS activation, and NO production. Furthermore, ghrelin receptor/Gq protein/calcium-dependent pathway mediates activation of AMPK, Akt, and eNOS, and calmodulin-dependent kinase kinase is a potential convergent point to regulate Akt and AMPK activation in ghrelin signaling. Importantly, eNOS activation is critical for ghrelin inhibition of vascular inflammation. Together, both in vitro and in vivo data demonstrate a new role of ghrelin signaling for eNOS activation, and highlight the therapeutic potential for ghrelin to correct endothelial dysfunction associated with atherosclerotic vascular diseases and metabolic syndrome.
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PMID:Molecular mechanisms of ghrelin-mediated endothelial nitric oxide synthase activation. 1845 Sep 53

Excess carbohydrate intake leads to fat accumulation and insulin resistance. Glucose and insulin coordinately regulate de novo lipogenesis from glucose in the liver, and insulin activates several transcription factors including SREBP1c and LXR, while those activated by glucose remain unknown. Recently, a carbohydrate response element binding protein (ChREBP), which binds to the carbohydrate response element (ChoRE) in the promoter of rat liver type pyruvate kinase (LPK), has been identified. The target genes of ChREBP are involved in glycolysis, lipogenesis, and gluconeogenesis. Although the regulation of ChREBP remains unknown in detail, the transactivity of ChREBP is partly regulated by a phosphorylation/dephosphorylation mechanism. During fasting, protein kinase A and AMP-activated protein kinase phosphorylate ChREBP and inactivate its transactivity. During feeding, xylulose-5-phosphate in the hexose monophosphate pathway activates protein phosphatase 2A, which dephosphorylates ChREBP and activates its transactivity. ChREBP controls 50% of hepatic lipogenesis by regulating glycolytic and lipogenic gene expression. In ChREBP (-/-) mice, liver triglyceride content is decreased and liver glycogen content is increased compared to wild-type mice. These results indicate that ChREBP can regulate metabolic gene expression to convert excess carbohydrate into triglyceride rather than glycogen. Furthermore, complete inhibition of ChREBP in ob/ob mice reduces the effects of the metabolic syndrome such as obesity, fatty liver, and glucose intolerance. Thus, further clarification of the physiological role of ChREBP may be useful in developing treatments for the metabolic syndrome.
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PMID:ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome. 1849 Aug 33

The metabolic syndrome (MetS) encompasses a constellation of cardio-metabolic abnormalities associated with a high risk of developing type 2 diabetes and cardiovascular disease (CVD), the top killer in the ageing population. Recent studies have demonstrated multiple beneficial effects of moderate wine consumption in the protection against development of the MetS and its related medical complications. The association of moderate wine consumption with lower incidence of the MetS and atherosclerotic heart disease has been repeatedly documented in numerous epidemiological studies on diverse ethnic groups. In addition to the favorable effects of moderate ethanol intake on lipid profiles, polyphenols enriched in red wine possess multiple benefits on the MetS beyond alcohol through their anti-oxidant, anti-inflammatory, vascular-protective and insulin-sensitizing properties. Notable among these red wine polypheolic compounds is resveratrol, a phytoalexin that has recently attracted great attention due to its role in mimicking calorie restriction. This compound can act as a potent activator of the NAD(+)-dependent deacetylases sirtuins to expand the life span and to prevent the deleterious effects of excess intake on insulin resistance and metabolic derangement. In addition, resveratrol exerts its multiple protective effects against the MetS through stimulating AMP-activated protein kinase and promoting mitochondria biogenesis. In this review, we highlight the recent epidemiological and experimental evidences supporting the protective effects of moderate wine intake against the MetS and its associated cardio-metabolic complications, and discuss the molecular mechanisms underlying the multiple beneficial actions of red wine polyphenols with the focus on resveratrol.
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PMID:Moderate wine consumption in the prevention of metabolic syndrome and its related medical complications. 1853 95

In management of metabolic syndrome, the traditional Chinese medicine (TCM) is an excellent representative in alternative and complementary medicines with a complete theory system and substantial herb remedies. In this article, basic principle of TCM is introduced and 25 traditional Chinese herbs are reviewed for their potential activities in the treatment of metabolic syndrome. Three herbs, ginseng, rhizoma coptidis (berberine, the major active compound) and bitter melon, were discussed in detail on their therapeutic potentials. Ginseng extracts made from root, rootlet, berry and leaf of Panax quinquefolium (American ginseng) and Panax ginseng (Asian ginseng), are proved for anti-hyperglycemia, insulin sensitization, islet protection, anti-obesity and anti-oxidation in many model systems. Energy expenditure is enhanced by ginseng through thermogenesis. Ginseng-specific saponins (ginsenosides) are considered as the major bioactive compounds for the metabolic activities of ginseng. Berberine from rhizoma coptidis is an oral hypoglycemic agent. It also has anti-obesity and anti-dyslipidemia activities. The action mechanism is related to inhibition of mitochondrial function, stimulation of glycolysis, activation of AMPK pathway, suppression of adipogenesis and induction of low-density lipoprotein (LDL) receptor expression. Bitter melon or bitter gourd (Momordica charantia) is able to reduce blood glucose and lipids in both normal and diabetic animals. It may also protect beta cells, enhance insulin sensitivity and reduce oxidative stress. Although evidence from animals and humans supports the therapeutic activities of ginseng, berberine and bitter melon, multi-center large-scale clinical trials have not been conducted to evaluate the efficacy and safety of these herbal medicines.
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PMID:Traditional chinese medicine in treatment of metabolic syndrome. 1853 96

Vascular calcification encountered in atherosclerotic lesions is a common consequence of aging. We suggested that apoptosis plays an important role in vascular smooth muscle cells (VSMC) calcification which is dependent on downregulation of the growth arrest-specific gene 6 (Gas6) -mediated survival pathway. Recently, we demonstrated that adiponectin antagonizes the stimulatory effect of TNF-alpha on vascular calcification by restoration of the AMP-activated protein kinase (AMPK) -dependent Gas6-mediated survival pathway. These results provide evidences of the effect of metabolic syndrome on vascular diseases including calcification.
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PMID:[Vascular calcification and anti-aging]. 1859 41

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a major role in maintaining energy homoeostasis. Within individual cells, AMPK is activated by a rise in the AMP/ATP ratio that occurs following a fall in ATP levels. AMPK is also regulated by the adipokines, adiponectin and leptin, hormones that are secreted from adipocytes. AMPK regulates a wide range of metabolic pathways, including fatty acid oxidation, fatty acid synthesis, glycolysis and gluconeogenesis. In peripheral tissues, activation of AMPK leads to responses that are beneficial in counteracting the deleterious effects that arise in the metabolic syndrome. Recent studies have demonstrated that modulation of AMPK activity in the hypothalamus plays a role in feeding. A decrease in hypothalamic AMPK activity is associated with decreased feeding, whereas activation of AMPK leads to increased food intake. Furthermore, signalling pathways occurring in the hypothalamus lead to changes in AMPK activity in peripheral tissues, such as skeletal muscle, via the sympathetic nervous system. AMPK, therefore, provides a mechanism for monitoring changes in energy metabolism within individual cells and at the level of the whole body. Activation of AMPK requires phosphorylation of threonine 172 (Thr-172) within the catalytic subunit. Recent studies have shown that both LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase-beta (CaMKKbeta) play important roles in phosphorylating and activating AMPK. In addition, there is evidence that AMPK can be activated by other upstream kinases, although the physiological significance of this is not clear at present. This review focuses on the role of LKB1 and CaMKKbeta in the regulation of AMPK.
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PMID:The regulation of AMP-activated protein kinase by upstream kinases. 1871

The AMP-activated protein kinase (AMPK) system is a key player in regulating energy balance at both the cellular and whole-body levels, placing it at centre stage in studies of obesity, diabetes and the metabolic syndrome. It is switched on in response to metabolic stresses such as muscle contraction or hypoxia, and modulated by hormones and cytokines affecting whole-body energy balance such as leptin, adiponectin, resistin, ghrelin and cannabinoids. Once activated, it switches on catabolic pathways that generate adenosine triphosphate (ATP), while switching off ATP-consuming anabolic processes. AMPK exists as heterotrimeric complexes comprising a catalytic alpha-subunit and regulatory beta- and gamma-subunits. Binding of AMP to the gamma-subunit, which is antagonized by high ATP, causes activation of the kinase by promoting phosphorylation at threonine (Thr-172) on the alpha-subunit by the upstream kinase LKB1, allowing the system to act as a sensor of cellular energy status. In certain cells, AMPK is activated in response to elevation of cytosolic Ca2+ via phosphorylation of Thr-172 by calmodulin-dependent kinase kinase-beta (CaMKKbeta). Activation of AMPK, either in response to exercise or to pharmacological agents, has considerable potential to reverse the metabolic abnormalities associated with type 2 diabetes and the metabolic syndrome. Two existing classes of antidiabetic drugs, that is, biguanides (for example, metformin) and the thiazolidinediones (for example, rosiglitazone), both act (at least in part) by activation of AMPK. Novel drugs activating AMPK may also have potential for the treatment of obesity.
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PMID:AMPK: a key regulator of energy balance in the single cell and the whole organism. 1871 1

In eukaryotic cells, receptor endocytosis is a key event regulating signaling transduction. Adiponectin receptors belong to a new receptor family that is distinct from G-protein-coupled receptors and has critical roles in the pathogenesis of diabetes and metabolic syndrome. Here, we analyzed the endocytosis of adiponectin and adiponectin receptor 1 (AdipoR1) and found that they are both internalized into transferrin-positive compartments that follow similar traffic routes. Blocking clathrin-mediated endocytosis by expressing Eps15 mutants or depleting K(+) trapped AdipoR1 at the plasma membrane, and K(+) depletion abolished adiponectin internalization, indicating that the endocytosis of AdipoR1 and adiponectin is clathrin-dependent. Depletion of K(+) and overexpression of Eps15 mutants enhance adiponectin-stimulated AMP-activated protein kinase phosphorylation, suggesting that the endocytosis of AdipoR1 might downregulate adiponectin signaling. In addition, AdipoR1 colocalizes with the small GTPase Rab5, and a dominant negative Rab5 abrogates AdipoR1 endocytosis. These data indicate that AdipoR1 is internalized through a clathrin- and Rab5-dependent pathway and that endocytosis may play a role in the regulation of adiponectin signaling.
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PMID:Endocytosis of adiponectin receptor 1 through a clathrin- and Rab5-dependent pathway. 1898 21

Diabetes, one of the major risk factors of metabolic syndrome culminates in the development of Ischemic Heart Disease (IHD). Refined diets that lack micronutrients, mainly trivalent chromium (Cr(3+)) have been identified as the contributor in the rising incidence of diabetes. We investigated the effect of niacin-bound chromium (NBC) during ischemia/reperfusion (IR) injury in streptozotocin induced diabetic rats. Rats were randomized into: Control (Con); Diabetic (Dia) and Diabetic rats fed with NBC (Dia+NBC). After 30 days of treatment, the isolated hearts were subjected to 30 min of global ischemia followed by 2 h of reperfusion. NBC treatment demonstrated significant increase in left ventricular functions and significant reduction in infarct size and cardiomyocyte apoptosis in Dia+NBC compared with Dia. Increased Glut-4 translocation to the lipid raft fractions was also observed in Dia+NBC compared to Dia. Reduced Cav-1 and increased Cav-3 expression along with phosphorylation of Akt, eNOS and AMPK might have resulted in increased Glut-4 translocation in Dia+NBC. Our results indicate that the cardioprotective effect of NBC is mediated by increased activation of AMPK, Akt and eNOS resulting in increased translocation of Glut-4 to the caveolar raft fractions thereby alleviating the effects of IR injury in the diabetic myocardium.
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PMID:Niacin bound chromium treatment induces myocardial Glut-4 translocation and caveolar interaction via Akt, AMPK and eNOS phosphorylation in streptozotocin induced diabetic rats after ischemia-reperfusion injury. 1902 47


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