From the Guidelines
Metformin activates AMP-activated protein kinase (AMPK), a key mechanism behind its therapeutic effects. This activation is believed to improve cellular metabolic performance, independent of blood glucose levels, as suggested by the UK Prospective Diabetes Study Group's findings that metformin-treated patients had better clinical outcomes than those on insulin therapy, despite similar improvements in blood glucose levels 1. The activation of AMPK by metformin is thought to occur through the inhibition of complex I of the mitochondrial respiratory chain, leading to a decrease in ATP production and an increase in the AMP:ATP ratio, which in turn triggers AMPK activation.
Some of the key effects of AMPK activation by metformin include:
- Reduction of hepatic glucose production
- Increase in peripheral glucose uptake in skeletal muscle
- Improvement in insulin sensitivity
- Potential benefits for cardiovascular health
- Anti-cancer properties
- Possible anti-aging effects
As noted in the study published in Reviews in Endocrine and Metabolic Disorders, metformin is considered a metabolic modulator that can improve cellular metabolism in a blood glucose-independent way 1. This means that the actual blood glucose value does not reveal the heterogeneity in actual cellular metabolism, and metformin's effects on AMPK activation can lead to beneficial metabolic effects beyond just glucose control. The activation of AMPK by metformin is a crucial mechanism by which it exerts its therapeutic effects, and this is supported by the findings of the study, which highlights the importance of metformin as a metabolic promoter that can improve clinical outcomes in patients with type 2 diabetes 1.
From the Research
Effect of Metformin on AMPK
- Metformin activates AMP-activated protein kinase (AMPK) in hepatocytes, resulting in reduced acetyl-CoA carboxylase (ACC) activity, induced fatty acid oxidation, and suppressed expression of lipogenic enzymes 2.
- The activation of AMPK by metformin is required for its inhibitory effect on glucose production by hepatocytes 2.
- Metformin stimulates glucose uptake in isolated rat skeletal muscles coincident with AMPK activation 2.
- The mechanism of metformin's activation of AMPK is different from that of the existing AMPK-activating agent, 5-aminoimidazole-4-carboxamide (AICA) riboside, and is not a consequence of depletion of cellular energy charge 3.
- Metformin increases AMPK activity in skeletal muscle of subjects with type 2 diabetes, associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity 4.
- AMPK activation by metformin may be an important target of metformin action, determining a wide variety of physiological effects, including enhanced glucose uptake by skeletal muscle and enhanced lipid catabolism 5.
- Low-dose metformin targets the lysosomal AMPK pathway through PEN2, inhibiting the lysosomal proton pump v-ATPase and activating AMPK without effects on cellular AMP levels 6.
Key Findings
- Metformin's activation of AMPK is a key mechanism for its glucose-lowering effects 2, 4.
- AMPK activation by metformin is associated with improved glucose disposal and muscle glycogen concentrations in subjects with type 2 diabetes 4.
- The finding of AMPK activation by metformin draws attention to this enzyme as an important pharmacological target for the treatment of metabolic disorders 5.