Get Permission
Rev Diabet Stud, 2009, 6(1):13-36 DOI 10.1900/RDS.2009.6.13

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

Arie Gruzman, Gali Babai, Shlomo Sasson

Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel
Address correspondence to: Shlomo Sasson, e-mail:

Manuscript submitted April 10, 2009; resubmitted May 7, 2009; accepted May 9, 2009.

Keywords: diabetes, hyperglycemia, AMP, antihyperglycemic, drug target, energy metabolism, glucose transport, skeletal muscle, D-xylose


In 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 D-xylose 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.

Fulltext: HTML , PDF (453KB)

This article has been cited by other articles:

Molecular mechanisms for anti-aging by natural dietary compounds

Pan MH, Lai CS, Tsai ML, Wu JC, Ho CT

Mol Nutr Food Res 2012. 56(1):88-115

Peptide scaffolds: flexible molecular structures with diverse therapeutic potentials

Deshmukh R, Purohit HJ

Int J Peptide Res Ther 2012. In press

AMPK protects proximal tubular cells from stress-induced apoptosis by an ATP-independent mechanism: potential role of Akt activation

Lieberthal W, Zhang L, Patel VA, Levine JS

Am J Physiol Renal Physiol 2011. 301(6):F1177-F1192

Computer-aided drug design for AMP-activated protein kinase activators

Wang Z, Huo J, Sun L, Wang Y, Jin H, Yu H, Zhang L, Zhou L

Curr Comput Aided Drug Des 2011. 7(3):214-227

Effect of chromium enriched fermentation product of barley and brewer's yeast and its combination with rosiglitazone on experimentally induced hyperglycaemia in mice

Cekic V, Vasovic V, Jakovljevic V, Lalosevic D, Capo I, Mikov M, Sabo A

Srp Arh Celok Lek 2011. 139(9-10):610-618

Antihyperglycaemic activity of 2,4:3,5-dibenzylidene-D-xylose-dithioacetal in diabetic mice

Gruzman A, Elgart A, Viskind O, Billauer H, Dotan S, Cohen G, Mishani E, Hoffman A, Cerasi E, Sasson S

J Cell Mol Med 2011. In press

Nutrigenomics of neuradaptogen amino-acid-therapy and neurometabolic optimizers: overcoming carbohydrate bingeing and overeating through neurometabolic mechanisms

Blum K, Bagchi D, Bowirrat A, Downs BW, Waite RL, Giordano J, Morse S, Madigan M, Downs JM, Braverman ER, Polanin M, Barh D, Fornari F, Simpatico T

Funct Food Health Dis 2011. 9:310-378

Key regulators of mitochondrial biogenesis are increased in kidneys of growth hormone receptor knockout (GHRKO) mice

Gesing A, Bartke A, Wang F, Karbownik-Lewinska M, Masternak MM

Cell Biochem Funct 2011. 29(6):459-467

Targeting the AMP-regulated kinase family to treat diabetes: a research update

Sun G, Rutter GA

Diabetes Manag 2011. 1(3):333-347

Insulin resistance and other metabolic risk factors in the pathogenesis of hepatocellular carcinoma

Siddique A, Kowdley KV

Clin Liver Dis 2011. 15(2):281-296

Curcumin protects hepatic stellate cells against leptin-induced activation in vitro by accumulating intracellular lipids

Tang Y, Chen A

Endocrinology 2010. 151(9):4168-4177

Binding of cordycepin monophosphate to AMP-activated protein kinase and its effect on AMP-activated protein kinase activation

Wang Z, Wang X, Qu K, Zhu P, Guo N, Zhang R, Abliz Z, Yu H, Zhu H

Chem Biol Drug Des 2010. 76(4):340-344

AMP-Activated protein kinase as a target for preconditioning in transplantation medicine

Bouma HR, Ketelaar ME, Yard BA, Ploeg RJ, Henning RH

Transplantation 2010. 90(4):353-358

Does LKB1 Mediate Activation of Hepatic AMP-Protein Kinase (AMPK) and Sirtuin1 (SIRT1) After Roux-en-Y Gastric Bypass in Obese Rats?

Peng Y, Rideout DA, Rakita SS, Gower WR Jr, You M, Murr MM

J Gastrointest Surg 2010. 14(2):221-228

Curcumin activates AMPK and suppresses gluconeogenic gene expression in hepatoma cells

Kim T, Davis J, Zhang AJ, He X, Mathews ST

Biochem Biophys Res Commun 2009. 388(2):377-382