What are the pathways involved in the mechanism of action of metformin?

Mechanism of Action of Metformin: Molecular Pathways

Metformin primarily works through activation of AMP-activated protein kinase (AMPK) pathway, inhibition of hepatic gluconeogenesis, and modulation of intestinal glucose absorption, which collectively improve insulin sensitivity and reduce hyperglycemia without stimulating insulin secretion. 1

Primary Molecular Pathways

• Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization 1
• The drug activates AMPK through inhibition of mitochondrial respiration, which serves as a cellular energy sensor that regulates catabolic processes 2
• Metformin inhibits feeding-induced hepatic mTORC1 signaling through AMPK activation, which is a key regulatory element controlling metabolic processes in cells 2
• With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease 1

Hepatic Mechanisms

• In the liver, metformin reduces glucose production through:
  • Inhibition of gluconeogenesis via AMPK-dependent suppression of gluconeogenic enzymes 3
  • Alteration of cellular redox balance, affecting substrate-selective inhibition of hepatic gluconeogenesis at clinically relevant concentrations (50-100 μM) 4
  • Interruption of mitochondrial oxidative processes in the liver 5
  • Inhibition of mitochondrial complex I, resulting in defective cAMP and protein kinase A signaling in response to glucagon 6

Intestinal and Peripheral Tissue Effects

• Metformin decreases intestinal absorption of glucose, contributing to its glucose-lowering effect 1
• The drug improves insulin sensitivity in peripheral tissues by:
  • Correcting abnormalities of intracellular calcium metabolism in insulin-sensitive tissues (liver, skeletal muscle, and adipocytes) 5
  • Modulating lipid metabolism through AMPK activation, which confers insulin sensitivity 6
  • Increasing peripheral glucose uptake and utilization 1

Emerging Pathways and Effects

• Metformin impacts gut microbiome composition, particularly increasing Akkermansia muciniphila, which may contribute to its therapeutic efficacy 7
• The drug induces expression of GDF15 (Growth Differentiation Factor 15) in the kidneys, which results in increased circulating GDF15 levels, reduced food intake, and weight loss 2
• GDF15 upregulation in individuals with T2D who receive metformin corresponds with reduction in body mass 2
• Metformin may influence tumor development both indirectly through systemic reduction of insulin levels and directly via induction of energetic stress 6

Pharmacokinetic Considerations

• Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) 1
• The absolute bioavailability of metformin is approximately 50-60% under fasting conditions 1
• Renal clearance is approximately 3.5 times greater than creatinine clearance, indicating tubular secretion as the major route of elimination 1
• At usual clinical doses, steady state plasma concentrations are reached within 24-48 hours and are generally <1 μg/mL 1

Clinical Implications of Mechanism

• Metformin rarely causes hypoglycemia when used as monotherapy because it does not stimulate insulin secretion 8
• The drug is weight neutral or may cause slight weight loss, likely due to its effects on GDF15 and reduced food intake 8, 2
• Metformin is considered a "metabolic promoter" that improves cellular metabolism in a blood glucose-independent way 8
• The drug's mechanism explains its applications beyond diabetes, such as in polycystic ovary syndrome (PCOS) due to its ability to normalize ovulatory abnormalities 8

Dosage Considerations and Mechanism

• Metformin's effects vary depending on the doses used and duration of treatment, with clear differences between acute and chronic administration 3
• Higher concentrations (>1 mM) that are not clinically achievable may activate different pathways than therapeutic concentrations (50-100 μM) 4
• The complex and multiple modes of action of metformin explain its broad therapeutic effects beyond glucose control 3