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

Abstract

■ 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.

Quercetin But Not Quercitrin Ameliorates Tumor Necrosis Factor-Alpha-Induced Insulin Resistance in C2C12 Skeletal Muscle Cells

“…19) But the enhancement effect by quercetin in our work are weaker (by about 20%, data not shown), it may results from the dose we used (5, 10, 20 µm) is lower than eid et al (100 µm). As the activation of muscle AMPK by exogenous compounds recruits GlUT4 and augments the rate of glucose transport independent of insulin, 27) we suppose that quercetin may also stimulate GLUT4 to promote glucose uptake in C2C12 myotubes, and we have verified it in other works (data not shown). Also, previous studies have demonstrated that quercetin could increase GLUT4 in both ob/ob mice and skeletal muscle myotubes.…”

Chemoproteomic Analysis of Intertissue and Interspecies Isoform Diversity of AMP-activated Protein Kinase (AMPK)

“…The central significance of AMPK as a metabolic regulator makes it an attractive potential target for drug action in diseases of positive malnutrition (5,14,48). Efforts are in hand to evolve prototypical activators into safe and effective drugs (49 -51).…”

Targeting AMPK for Therapeutic Intervention in Type 2 Diabetes

“…Previous work established the essential role of AMPK in the regulation of carbohydrate, protein and lipid metabolism; this made AMPK a key target for the treatment of type 2 diabetes, obesity and metabolic syndrome (Gruzman, Babai & Sasson, 2009;Hardie, 2008b;Steinberg & Kemp, 2009;Viollet et al, 2010;Viollet et al, 2009b). Indeed, in a clinical setting AMPK activity is altered with the anti-diabetic drug metformin and other biguanides.…”

“…Pharmacological drugs have also been critical to define how AMPK mediates metabolic control (see Table 1). These compounds employ a variety of molecular mechanisms that culminate in AMPK activation (Gruzman et al, 2009;Hawley et al, 2010;Mantovani & Roy, 2011). For example, the kinase can be activated by a rise in the AMP/ATP ratio, generation of an AMP mimetic or increase in intracellular Ca 2+ concentrations (Hawley et al, 2010).…”

“…This includes the ability to regulate AMPK (a) in different organs or tissues and (b) in specific subcellular locations. Oral administration of metformin is believed to preferentially alter liver metabolism, whereas TZDs and their derivatives affect adipose tissue, skeletal muscle and probably -cells (Gruzman et al, 2009). One possibility to enhance the tissue-specific action of AMPK will rely on the development of drugs that directly bind to AMPK; indeed such compounds have been described (Hawley et al, 2010).…”