Table 1. Different AMPK ‘activators’ and their limitations in clinical use.

For further details of AICAR and MF studies, see Tables 2 and 3 respectively. PKC, protein kinase C.

AMPK activator	Possible mechanism(s) of AMPK activation	Activation of other pathways	Limitation(s)
AICAR	(i) Direct activation followed by allosteric modification	(i) Stimulates adiponectin release; (ii) inhibits cytokines such as TNF-α and IL-6	(i) Short half-life; (ii) variable effectiveness; (iii) only intravenous forms available; (iv) may cause bradycardia and significant hypoglycaemia
MF	(i) Indirect activation; (ii) via alteration of the AMP/ATP ratio as a result of inhibition of Complex I in the respiratory chain; (iii) other unknown mechanisms	(i) Anticancer effects via its effects on p53; (ii) up-regulates eNOS and increases NO bioactivity; (iii) enhances fatty acid oxidation, which leads to alleviation of endothelial lipotoxicity	(i) Indirect AMPK activation; (ii) doses and duration of MF required for AMPK activation are not determined; (iii) higher doses of MF result in intolerable gastrointestinal side effects
TZDs	(i) Indirect activation; (ii) via alteration of the AMP/ATP ratio, possibly similar to MF; (iii) via adiponectin	(i) Anti-atherosclerotic and anti-inflammatory effects via adiponectin; (ii) effects on mitochondrial biogenesis; (iii) exerts antioxidative effects by inhibiting PKC via AMPK activation	(i) Indirect inhibition; (ii) risk of developing fluid retention; (iii) risk of developing cardiovascular events is yet to be determined
Statins	(i) Indirect activation; (ii) does not alter the AMP/ATP ratio; (iii) other unknown mechanisms	(i) HMG-CoA reductase inhibition; (ii) activation of AMPK/eNOS/ACC	(i) Doses required for AMPK activation in humans are still to be determined
Compound A-769662	(i) Direct activation	(i) Increased fatty acid oxidation; (ii) decreased plasma and liver triacylglycerol levels; (iii) inhibits fatty acid synthesis	(i) Poor oral bioavailability; (ii) data on long-term AMPK activation are awaited