Novel <scp>d</scp>-Xylose Derivatives Stimulate Muscle Glucose Uptake by Activating AMP-Activated Protein Kinase α

Gruzman, Arie; Shamni, Ofer; Yakir, Moriya Ben; Sandovski, Daphna; Elgart, Anna; Alpert, Evgenia; Cohen, Guy; Hoffman, Amnon; Katzhendler, Yehoshua; Cerasi, Erol; Sasson, Shlomo

doi:10.1021/jm8008713

Cited by 35 publications

(41 citation statements)

References 44 publications

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“…Dozens of molecules that activate AMPK, directly or indirectly, were synthesized or extracted from plants. In the course of our work, we found that the pentose D-xylose augmented the rate of glucose transport in L6 and human myotubes under high glucose conditions by activating AMPK [132]. Because this effect of D-xylose was obtained at very high concentrations (10-20 mM), we synthesized more potent lipophilic derivatives of D-xylose.…”

Section: D-xylose and Lipophilic D-xylose Derivativesmentioning

confidence: 93%

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Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations

Babai²,

2009

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■ AbstractIn view of the epidemic nature of type 2 diabetes and the substantial rate of failure of current oral antidiabetic drugs the quest for new therapeutics is intensive. The adenosine monophosphate-activated protein kinase (AMPK) is an important regulatory protein for cellular energy balance and is considered a master switch of glucose and lipid metabolism in various organs, especially in skeletal muscle and liver. In skeletal muscles, AMPK stimulates glucose transport and fatty acid oxidation. In the liver, it augments fatty acid oxidation and decreases glucose output, cholesterol and triglyceride synthesis. These metabolic effects induced by AMPK are associated with lowering blood glucose levels in hyperglycemic individuals. Two classes of oral antihyperglycemic drugs (biguanidines and thiazolidinediones) have been shown to exert some of their therapeutic effects by directly or indirectly activating AMPK. However, side effects and an acquired resistance to these drugs emphasize the need for the development of novel and efficacious AMPK activators. We have recently discovered a new class of hydrophobic Dxylose derivatives that activates AMPK in skeletal muscles in a non insulin-dependent manner. One of these derivatives (2,4;3,5-dibenzylidene-D-xylose-diethyl-dithioacetal) stimulates the rate of hexose transport in skeletal muscle cells by increasing the abundance of glucose transporter-4 (GLUT-4) in the plasma membrane through activation of AMPK. This compound reduces blood glucose levels in diabetic mice and therefore offers a novel strategy of therapeutic intervention strategy in type 2 diabetes. The present review describes various classes of chemically-related compounds that activate AMPK by direct or indirect interactions and discusses their potential for candidate antihyperglycemic drug development.

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Section: D-xylose and Lipophilic D-xylose Derivativesmentioning

confidence: 93%

“…Representative blot and a summary of n = 3 (* p<0.05) in comparison with the respective controls. Reproduced with permission from [132]. gluconeogenesis in the liver by activating AMPK [98].…”

Section: Metformin and Thiazolidinedionesmentioning

confidence: 99%

Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations

Babai²,

2009

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“…More potent derivatives of D-xylose, such as 2,4;3,5-dibenzylidene-D-xylose-diethyldithioacetal, 2,4-benzylidene-D-xylose-diethyl-dithioacetal, and 2,4-benzylidene-D-xylose-3-O-methyl-diethyl-dithioacetal, were synthesized that showed signifi cant stimulation of glucose uptake in myotubes at concentrations ranging from 5 to 100 M. This effect occurs via AMPK activation through AMPK phosphorylation at Thr-172 and inhibited by the AMPK inhibitor Compound C, suggesting involvement of AMPK activation. Some of these compounds reduced blood glucose levels in the genetically diabetic KKA y mice ( 268 ) and show potential as antihyperglycemic compounds.…”

Section: D-xylose and Lipophilic D-xylose Derivativesmentioning

confidence: 99%

AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases

Srivastava

Pinkosky

Filippov

et al. 2012

Journal of Lipid Research

256

179

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This article is available online at http://www.jlr.org termed as metabolic syndrome (MetS) ( 1 ), characterized by a clustering of major risk factors for developing cardiovascular disease. Obesity, representing derangement in energy balances, is tightly linked with the development of type-2 diabetes through its ability to engender insulin resistance, leading to glucose intolerance and development of type-2 diabetes and dyslipidemia. Thus, insulin resistance The pathophysiology of diabetes and obesity is a very complex process involving many pathways. Deregulation of these pathways gives rise to metabolic abnormalities

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“…Epigallocatechin gallate [71] Stimulates ROS generation, which in turn activates AMPK 65 Genistein [72] 51…”

Section: Ampk Activator and Diabetic Ulcer Animal Studymentioning

confidence: 99%

AMP-activated protein kinase activators in diabetic ulcers: from animal studies to Phase II drugs under investigation

Lin¹,

Chen

Chiu

et al. 2014

Expert Opinion on Investigational Drugs

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Animal studies have demonstrated that AMPK activators are a potential treatment for diabetic ulcers. AMPK activators alleviate tissue inflammation and promote re-epithelialization in diabetic wounds. However, due to the complicated pathological mechanism of diabetic foot ulcers, AMPK activators should be combined with other approaches. The new strategies for combination therapy with AMPK activator may provide a therapeutic advantage for patients with diabetic ulcers.

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Novel d-Xylose Derivatives Stimulate Muscle Glucose Uptake by Activating AMP-Activated Protein Kinase α

Cited by 35 publications

References 44 publications

Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations

Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations

AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases

AMP-activated protein kinase activators in diabetic ulcers: from animal studies to Phase II drugs under investigation

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