Action of metformin
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Mechanisms of Action of Metformin
Introduction to Metformin and Its Clinical Use
Metformin is a widely-used first-line therapy for type 2 diabetes (T2D) due to its robust glucose-lowering effects, well-established safety profile, and relatively low cost 2. Despite its extensive use, the precise mechanisms by which metformin exerts its effects remain complex and not fully understood 12.
Inhibition of Hepatic Gluconeogenesis
One of the primary mechanisms by which metformin lowers blood glucose levels is through the inhibition of hepatic gluconeogenesis. This process involves the suppression of glucose production in the liver, which is a significant contributor to hyperglycemia in T2D patients 247. Metformin achieves this by altering cellular redox balance and inhibiting mitochondrial complex I, which affects cAMP and protein kinase A signaling in response to glucagon 7.
Role of AMP-Activated Protein Kinase (AMPK)
Metformin's action is often associated with the activation of AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis. Activation of AMPK by metformin leads to reduced hepatic glucose production, increased fatty acid oxidation, and improved insulin sensitivity 159. However, recent studies suggest that AMPK activation may not account for all of metformin's effects, highlighting the importance of AMPK-independent pathways 68.
AMPK-Independent Mechanisms
In addition to AMPK-dependent pathways, metformin also exerts its effects through AMPK-independent mechanisms. These include the inhibition of mitochondrial glycerophosphate dehydrogenase and alterations in lysosomal function 18. These pathways contribute to the drug's ability to lower blood glucose levels and improve metabolic health.
Impact on Gut Microbiota
Recent research has highlighted the role of the gut microbiota in mediating some of metformin's therapeutic effects. Metformin has been shown to alter the composition of the gut microbiome, which in turn improves glucose tolerance and insulin sensitivity 35. This gut-mediated mechanism adds another layer of complexity to the drug's action.
Effects on Glucose Utilization
Metformin also enhances glucose uptake and utilization in peripheral tissues such as skeletal muscle and adipocytes. This effect is particularly pronounced in diabetic individuals, suggesting an enhanced action of the drug in hyperglycemic states 9. The drug increases glucose transport across cell membranes, which is independent of and additive to insulin action 9.
Conclusion
Metformin's glucose-lowering effects are mediated through a combination of mechanisms, including the inhibition of hepatic gluconeogenesis, activation of AMPK, AMPK-independent pathways, and alterations in gut microbiota. These multifaceted actions make metformin a highly effective treatment for type 2 diabetes, although further research is needed to fully elucidate its mechanisms and optimize its use in clinical practice.
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The mechanisms of action of metformin
Metformin improves glucose metabolism and diabetes-related complications through multiple mechanisms, including reducing hepatic glucose production and a key role for the gut.
Rigorous Journal
Highly CitedCellular and Molecular Mechanisms of Metformin Action
Metformin's glucose-lowering effect in type 2 diabetes patients is mainly mediated through inhibition of hepatic gluconeogenesis, with a redox-dependent mechanism of action being proposed.
Literature ReviewHighly CitedMetformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug
Metformin alters the gut microbiome in individuals with treatment-naive type 2 diabetes, contributing to its therapeutic effects and improving glucose tolerance.
RCT
Very Rigorous JournalHighly CitedMechanism of Metformin Action in Non-Insulin-Dependent Diabetes
Metformin significantly lowers oral glucose tolerance curve in noninsulin-dependent diabetes patients, primarily due to a fall in basal glucose concentration and an increase in hepatic insulin sensitivity.
RCTHighly CitedMetabolic Action of Metformin
Metformin effectively suppresses hepatic glucose production, improves insulin sensitivity, and alters gut microbiota composition, maintaining intestinal barrier integrity, and reducing inflammation in type 2 diabetes patients.
Metformin: from mechanisms of action to therapies.
Metformin's mechanism of action centers on energy metabolism, with potential relevance to cardiovascular diseases and cancer, and its AMPK-dependent and -independent mechanisms influence its effectiveness.
Very Rigorous JournalHighly CitedMetformin—mode of action and clinical implications for diabetes and cancer
Metformin lowers glucose levels by inhibiting hepatic gluconeogenesis and may influence tumorigenesis through systemic reduction of insulin levels and energetic stress.
Highly CitedMolecular mechanism of action of metformin: old or new insights?
Recent research challenges the notion that AMPK mediates metformin's anti-hyperglycemic action, highlighting AMPK-independent effects and potential new targets for second-generation diabetes drugs.
Rigorous JournalHighly CitedCellular Mechanism of Action of Metformin
Metformin's hypoglycemic effect is primarily due to its insulin-independent action on glucose transport across the cell membrane in skeletal muscle.
Highly CitedRole of AMP-activated protein kinase in mechanism of metformin action.
Metformin's beneficial effects on lipids and glucose metabolism are due to activation of AMP-activated protein kinase, which reduces lipogenic enzyme expression and inhibits glucose production in hepatocytes.
Non-RCT
Animal StudyHighly Cited