Metformin metabolism
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Metformin Metabolism: Mechanisms and Effects
Introduction to Metformin Metabolism
Metformin, a widely used biguanide derivative, is primarily prescribed for the treatment of type 2 diabetes mellitus (T2DM) due to its ability to influence various metabolic pathways. This article synthesizes the current understanding of metformin's metabolic actions, focusing on its effects on glucose and lipid metabolism, insulin sensitivity, and gut microbiota.
Mechanisms of Action: Hepatic Glucose Production
AMPK-Dependent and Independent Pathways
Metformin's primary mechanism involves the suppression of hepatic glucose production. This suppression occurs through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. AMPK activation leads to the inhibition of gluconeogenesis, while AMPK-independent mechanisms involve the inhibition of mitochondrial glycerophosphate dehydrogenase and possibly lysosomal pathways 1610.
Mitochondrial Respiration
At therapeutic doses, metformin enhances cellular respiration in the liver, whereas supra-therapeutic doses can suppress mitochondrial respiration in intestinal epithelial cells. This dual action underscores the complexity of metformin's effects on cellular energy metabolism 16.
Effects on Glucose and Lactate Metabolism
Hepatic Glucose Production and Gluconeogenesis
Metformin significantly reduces fasting plasma glucose levels by decreasing hepatic glucose production. This reduction is primarily due to the inhibition of hepatic glycogenolysis and gluconeogenesis from lactate. However, metformin does not significantly enhance total body glucose disposal during insulin stimulation 37.
Lactate Metabolism
Metformin increases lactate production in the intestine, which is then utilized by hepatocytes to produce glucose, creating a futile intestine-liver cycle. Despite this, metformin does not alter the rate of lactate turnover or gluconeogenesis from lactate in either basal or insulin-stimulated states 23.
Impact on Lipid Metabolism and Insulin Sensitivity
Lipid Secretion and Oxidation
Metformin decreases the secretion of lipids from intestinal epithelial cells and enhances the oxidation of fatty acids in adipose tissue and muscles. This contributes to improved lipid profiles and reduced plasma triglyceride levels in patients 13.
Insulin Sensitivity
Metformin improves systemic insulin sensitivity by reducing blood lipopolysaccharides, which in turn lowers low-grade inflammation and increases oxidative phosphorylation in liver and adipose tissues. These effects collectively enhance glucose utilization in extrahepatic tissues 28.
Role of Gut Microbiota
Alteration of Gut Microbiota Composition
Metformin treatment leads to significant changes in the gut microbiota, particularly increasing the abundance of beneficial bacteria such as Akkermansia muciniphila. These changes are associated with improved markers of metabolic disorders, including reduced serum glucose levels and body weight 19.
Gut-Liver Axis
The interaction between metformin and gut microbiota also influences the gut-liver axis, contributing to the drug's overall metabolic effects. This includes the maintenance of intestinal barrier integrity and alleviation of low-grade inflammation, which further supports improved insulin sensitivity 19.
Conclusion
Metformin exerts its metabolic effects through a multifaceted mechanism involving the suppression of hepatic glucose production, modulation of lipid metabolism, enhancement of insulin sensitivity, and alteration of gut microbiota composition. These combined actions make metformin a cornerstone in the management of type 2 diabetes and other metabolic disorders. Further research is needed to fully elucidate the complex molecular pathways influenced by metformin, particularly at different dosages and treatment durations.
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Most relevant research papers on this topic
Metabolic 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 and Systemic Metabolism.
Metformin improves blood sugar levels and insulin sensitivity by suppressing hepatic glucose production and altering intestinal metabolism.
Highly CitedMetabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus.
Metformin effectively lowers plasma glucose levels in noninsulin-dependent diabetes mellitus patients, but its effect on hepatic glucose production and lactate metabolism remains unclear.
RCTHighly CitedMetformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults
Metformin has metabolic and nonmetabolic effects linked to aging in older adults, potentially influencing the development of biomarkers for these effects.
RCTHighly CitedMetformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7–9 years of age
Metformin or insulin for gestational diabetes during pregnancy resulted in similar offspring body fat and metabolic measures at 7-9 years, with metformin-exposed children being larger at 9 years.
RCT
Large Human Trial
Rigorous JournalHighly CitedThe 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 JournalHighly CitedMetabolic effects of metformin in non-insulin-dependent diabetes mellitus.
Metformin reduces hepatic glucose output and induces weight loss in obese patients with non-insulin-dependent diabetes mellitus by inhibiting gluconeogenesis.
Non-RCTHighly CitedAdipokines as a therapeutic target by metformin to improve metabolic function: A systematic review of randomized controlled trials.
Metformin improves metabolic function in individuals with metabolic syndrome by promoting weight loss, reducing inflammation, and promoting adiponectin upregulation and suppressing leptin and resistin.
Systematic ReviewRigorous JournalEffect of Metformin on Metabolic Improvement and Gut Microbiota
Metformin treatment improves metabolic markers and influences gut microbiota composition, influencing metabolic pathways in mice on a high-fat-diet.
Non-RCT
Animal StudyHighly 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 Cited