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

Abstract

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.

Figure 1. Metabolic pathways and functions regulated by AMPK

AMPK can be activated directly by three kinases, LKB1, TAK1 and CaMKK. When activated in various tissues and organs different AMPK complexes mediate a variety of cellular and physiological responses by activating cell-specific targets (e.g., enzymes, transcription factors and docking proteins). Major effects of AMPK activations are metabolic (carbohydrate and lipid metabolism), appetite regulation, cell growth and differentiation, vascular function (blood flow) and basic cellular functions (chloride ion transport). Abbreviations: ACC: acetyl-Co-A carboxylase. AS-160: Akt substrate of 160 kDa. CDKIp21and27: cyclin-dependent kinase inhibitors p21 and p27. CFTR: cystic fibrosis transmembrane conductance regulator. ChREBP: carbohydrate responsive element binding protein. CK: creatine kinase. CS: citrate synthase. EF-2-K: elongation factor 2 kinase. eNOS: endothelial nitric oxide synthase. ERK: extracellular signal-regulated kinases. GPAT: glycerol-3-phosphate acyltransferase. GRB2: growth factor receptor-bound protein 2. GS: glycogen synthase. HDAC25: histone deacetylase 25. HSL: hormone sensitive lipase. HMG-CoA reductase: 3-hydroxy-3-methyl-glutaryl-CoA reductase. HNF4-α: hepatocyte nuclear factor 4α. IRS-1: insulin receptor substrate 1. MCD: malonyl-CoA decarboxylase. p38: p38 mitogen-activated protein kinase. PEPCK: phosphoenolpyruvate carboxy kinase. 6-PF-2-Kinase: 6-phosphofructo-2-kinase. PGC-1α: peroxisome proliferator-activated receptor-γ-coactivator-1α. PYK2: proline-rich tyrosine kinase 2. SD: succinate dehydrogenase. SREBP-1: sterol regulatory element binding protein. TORC2: target of rapamycin complex 2.

Figure 2. D-Xylose and Compounds 19, 21 and 24 activate AMPK

A: L6 rat myotube cultures were washed and received fresh medium supplemented with 2% (v/v) FCS, 23.0 mM D-glucose supplemented with 20 mM of D-xylose (D-xyl), 5 μM of Compound 19, 150 μM of Compound 21 or 50 μM of Compound 24. These compounds were present in the medium for 40 min, 12 h, 30 min and 2 h, respectively. Control myotubes received the vehicle (V) only. AICAR (4 mM), 100 nM of insulin (Ins) and 0.25 M of D-sorbitol (S) were present for 1h, 20 min and 30 min, respectively. Whole cell lysates were prepared and Western blot analyses were performed with antibodies against AMPKα and pThr172-AMPKα. B: Human myotubes were treated as described above and taken for Western blot analysis of AMPKα and pThr¹⁷²-AMPKα. Representative blot and a summary of n = 3 (^* p < 0.05) in comparison with the respective controls. Reproduced with permission from [132].

Figure 3. D-Xylose and Compounds 19, 21 and 24 activate AS160

Whole cell content of AS160 and pThr⁶⁴²-AS160 was determined by Western blot analysis in samples that were prepared from L6 myotubes as described in the legend to Figure 1. Representative blot and a summary of n = 3 (^*< p < 0.05) in comparison the respective controls. Reproduced with permission from [132].

Figure 4

Molecular structures of AMPK activators sharing structural similarities to the D-xylose derivatives, Compounds 19, 21 and 24.

Figure 5

Molecular structures of phytoestrogens that interact with AMPK.

Figure 6

Molecular structures of momordicosides representing a class of natural compounds that activate AMPK.

Figure 7

Molecular structures of compounds that have one or two phenol, polyphenol or phenolmethyl ether moieties.

Figure 8

Molecular structure of the thienopyridone derivative A769662 and Compound 202.

Figure 9

Molecular structure of the furanothiazolidine derivative, PT1, a that interacts with the α-subunit of the AMPK complex.

Figure 10

Molecular structures of AMP and structurally related compounds that induce allosterical activation of the AMPK complex.