What is the mechanism of action of metformin (biguanide) in treating type 2 diabetes?

Mechanism of Action of Metformin in Type 2 Diabetes

Metformin primarily works by decreasing hepatic glucose production, improving peripheral insulin sensitivity, and decreasing intestinal glucose absorption, without directly stimulating insulin secretion. 1

Primary Mechanisms of Action

Hepatic Effects

• Decreases hepatic glucose output by:
  • Suppressing gluconeogenesis (conversion of non-carbohydrate substrates to glucose) 2
  • Inhibiting glycogenolysis (breakdown of glycogen to glucose) 2
  • Non-competitively inhibiting mitochondrial glycerophosphate dehydrogenase, which alters the hepatocellular redox state 3

Peripheral Effects

• Improves insulin sensitivity in peripheral tissues, particularly muscle 1
• Enhances glucose uptake and utilization in muscle tissue 4
• Activates adenosine monophosphate-activated protein kinase (AMPK), which functions as a metabolic sensor to improve cellular metabolic performance 4

Intestinal Effects

• Decreases intestinal absorption of glucose 1
• May increase glucose utilization in the intestines 5

Metabolic Consequences

• Unlike sulfonylureas, metformin does not:

  • Stimulate insulin secretion
  • Cause hypoglycemia when used alone
  • Promote weight gain 4

• Metformin treatment results in:

  • Reduced fasting plasma glucose levels (approximately 1.5 mmol/L reduction) 5
  • Decreased HbA1c by approximately 1-1.5 percentage points 4
  • Weight stability or modest weight loss 4
  • Improved lipid profiles (decreased LDL cholesterol and triglycerides) 4

Recent Research Insights

Recent studies have challenged the traditional understanding of metformin's mechanism:

• A 2019 study found that metformin actually increased endogenous glucose production by approximately 30% in both individuals with recent-onset type 2 diabetes and non-diabetic controls, while simultaneously increasing glucose disposal rate 5

• This suggests that metformin's glucose-lowering effects may be more complex than previously thought, with potential mechanisms beyond hepatic glucose production inhibition 5

Clinical Implications

• Metformin is effective as monotherapy or in combination with other antihyperglycemic agents 6
• It has beneficial cardiovascular effects beyond glucose control, as demonstrated in clinical trials 4
• Metformin can be considered a metabolic promoter that improves cellular metabolism in ways that are not fully reflected by blood glucose values alone 4

Common Pitfalls and Caveats

• Gastrointestinal side effects are common but can be minimized by:

  • Starting with a low dose (500 mg daily)
  • Gradually increasing by 500 mg every 1-2 weeks
  • Taking with meals 6

• Lactic acidosis is an extremely rare but potentially fatal complication:

  • Risk is minimal when contraindications are respected
  • Avoid in patients with significant renal dysfunction (eGFR < 45 mL/min/1.73m²) 4
  • Temporarily discontinue during acute illness with dehydration or hypoxemia 1

• Long-term use may cause vitamin B12 deficiency, which should be monitored 4

• Metformin should be temporarily discontinued when administering iodinated contrast agents for radiological procedures 4