How Metformin Works in Type 2 Diabetes
Metformin lowers blood glucose primarily by decreasing hepatic glucose production and increasing peripheral insulin sensitivity, without stimulating insulin secretion or causing hypoglycemia. 1, 2
Primary Mechanisms of Action
Hepatic Effects (Liver)
- Metformin suppresses hepatic gluconeogenesis (the liver's production of new glucose), which is the dominant mechanism for its glucose-lowering effect 1, 2
- This occurs through inhibition of mitochondrial glycerophosphate dehydrogenase, which alters the hepatocellular redox state and reduces conversion of lactate and glycerol to glucose 3
- Metformin also reduces hepatic extraction of gluconeogenic substrates like lactate and opposes the effects of glucagon 4
- It decreases glycogenolysis (breakdown of stored glycogen) and reduces activity of hepatic glucose-6-phosphatase 4
Peripheral Tissue Effects (Muscle and Fat)
- Metformin increases peripheral insulin sensitivity, enhancing insulin-stimulated glucose uptake into skeletal muscle 1, 2, 4
- This involves increased movement of insulin-sensitive glucose transporters (GLUT4) to the cell membrane 4
- Metformin increases glycogen synthase activity and glycogen storage in muscle tissue 4
- It improves insulin receptor tyrosine kinase activity, which activates post-receptor insulin signaling pathways 4
Intestinal Effects
- Metformin decreases intestinal absorption of glucose 2, 5
- It may increase glucose turnover in the splanchnic bed (intestinal circulation) 4
Key Clinical Characteristics
What Makes Metformin Unique
- Insulin secretion remains unchanged—metformin does not stimulate the pancreas to produce more insulin 2
- Does not cause hypoglycemia when used as monotherapy because it does not increase insulin levels 1, 5
- Weight neutral or causes modest weight loss, unlike sulfonylureas which cause weight gain 1, 6
- Fasting insulin levels and day-long plasma insulin response may actually decrease with metformin therapy 2
Additional Metabolic Benefits
- Reduces LDL cholesterol and triglycerides, improving cardiovascular risk profile 6
- Suppresses fatty acid oxidation, which reduces energy supply for gluconeogenesis and helps balance the glucose-fatty acid (Randle) cycle 4
- In the landmark UKPDS trial, metformin reduced diabetes-related outcomes by 32%, myocardial infarction by 39%, and all-cause mortality by 36% compared to conventional therapy 1
Clinical Efficacy
- Metformin typically reduces HbA1c by 1.0-1.5% compared to placebo 6
- The absolute bioavailability is approximately 50-60% under fasting conditions 2
- Steady-state plasma concentrations are reached within 24-48 hours 2
- Metformin is not metabolized in the liver and is excreted unchanged in the urine 2
Important Caveats
When Metformin Cannot Work
- Metformin requires the presence of insulin to exert its clinical effects—it cannot substitute for insulin 4
- In patients with severe insulin deficiency (like type 1 diabetes), metformin has limited utility 4
Safety Considerations
- Metformin carries a small risk of lactic acidosis and must be used with caution in patients with chronic kidney disease 1
- It is contraindicated when eGFR is <30 mL/min/1.73 m² 1
- Should be temporarily discontinued before procedures, during hospitalizations, and when acute illness may compromise renal or liver function 1
- Long-term use may cause vitamin B12 deficiency, requiring periodic monitoring 1, 6