What is the effect of Metformin (biguanide) on insulin resistance?

Effect of Metformin on Insulin Resistance

Metformin improves insulin resistance primarily by decreasing hepatic glucose production and enhancing peripheral insulin sensitivity, making it an effective first-line treatment for type 2 diabetes. 1

Mechanism of Action on Insulin Resistance

Metformin addresses insulin resistance through multiple pathways:

1. Hepatic Effects:

   • Decreases hepatic glucose production 1, 2
   • Suppresses gluconeogenesis and glycogenolysis 2
   • Reduces hepatic extraction of certain substrates (e.g., lactate) 3
   • Opposes the effects of glucagon 3

2. Peripheral Effects:

   • Enhances insulin-stimulated glucose uptake into skeletal muscle 3
   • Increases movement of insulin-sensitive glucose transporters into cell membranes 3
   • Improves functional properties of insulin- and glucose-sensitive transporters 3
   • Increases glycogen synthase activity and glycogen storage 3

3. Molecular Mechanisms:

   • Activates insulin receptor tyrosine kinase activity 3
   • Enhances post-receptor insulin signaling pathways 3
   • Works through both AMPK-dependent and AMPK-independent pathways 2

Clinical Impact on Insulin Resistance

Metformin's effects on insulin resistance translate to significant clinical benefits:

• Reduces HbA1c by approximately 1.0% to 1.5% versus placebo 4
• Improves glycemic control without causing hypoglycemia when used as monotherapy 4
• Remains weight neutral or may promote modest weight loss, unlike insulin secretagogues 4
• Decreases fasting plasma insulin concentrations rather than increasing them 5
• Reduces cardiovascular events and mortality, particularly in overweight patients with type 2 diabetes 4, 5

Beyond Glycemic Control

Metformin's effects on insulin resistance extend to additional metabolic benefits:

• Improves lipid profiles 6
• Reduces hepatic steatosis and suppresses liver inflammation 2
• Enhances endothelial function 6
• Improves hemostasis and oxidative stress 6
• Facilitates fat redistribution 6

Dosing Considerations for Optimal Effect on Insulin Resistance

• Initial dose typically starts low (500 mg once or twice daily) and is gradually increased to minimize gastrointestinal side effects 4
• Extended-release formulations can improve tolerability while maintaining efficacy 4
• Maximum effective dose is typically 2000-2500 mg/day 4

Safety Considerations

• Contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) 4
• Should be used with caution in patients with liver dysfunction, severe infection, or hypoxia 4
• Risk of lactic acidosis is very rare but should be considered in high-risk patients 4
• Long-term use may be associated with vitamin B12 deficiency, requiring periodic monitoring 4

Clinical Application

Metformin remains a cornerstone therapy for insulin resistance in type 2 diabetes due to its:

• Efficacy in improving insulin sensitivity
• Favorable safety profile
• Low cost and wide availability
• Cardiovascular benefits
• Neutral effect on weight

While newer agents like SGLT-2 inhibitors and GLP-1 receptor agonists have emerged with additional cardiorenal benefits 4, 7, metformin's direct effects on insulin resistance make it a valuable component of diabetes management, either as monotherapy or in combination with these newer agents.