The mechanisms of action of metformin

By G. Rena, D. Hardie, E. Pearson. Diabetologia, 2017

2,013 citations recorded by the source corpus.

Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration. Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving the lysosome. In the last 10 years, we have moved from a simple picture, that metformin improves glycaemia by acting on the liver via AMPK activation, to a much more complex picture reflecting its multiple modes of action. More work is required to truly understand how this drug works in its target population: individuals with type 2 diabetes.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/70925d1af1358fd113f54765e29603a957b5074b

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In Endocrinology, Diabetes and Metabolism

1. Rhian M. Touyz
2. A. Chait
3. Laura J. den Hartigh

In Molecular Biology

1. Rhian M. Touyz
2. A. Chait
3. Laura J. den Hartigh

In Surgery

1. A. Chait
2. Laura J. den Hartigh

Citations in the corpus

• Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease (2020, background): “Metformin has been proposed to lower blood glucose levels through suppression of gluconeogenesis in the liver, activation of AMPactivated protein kinase (AMPK), inhibition of themitochondrial respiratory chain (complex 1), and by unknown mechanisms in the gut (555, 556).”
• Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms (2017, background): “Among the many proposed mechanisms of action of metformin is activation of AMPK: This is now thought to be a secondary effect of inhibition of the mitochondrial respiratory chain.(96) Such effects of metformin may act directly (ie, independent of blood glucose lowering) on other tissues, including v”
• Insulin Resistance: From Mechanisms to Therapeutic Strategies (2021, background): “Metformin, the most commonly prescribed drug for diabetes, may also increase insulin sensitivity in peripheral tissues during fasting by reducing HGP, which is considered to be mediated by the promotion of mitochondrial activity or the inhibition of glucagon signaling through AMPK activation [160,16”