Metformin is the only approved oral agent for youth with type 2 diabetes (T2DM), but its mechanism of action remains controversial. Recent data suggests a primary role for the entero-insular pathway instead of the gluconeogenic pathway, but there is no data in youth, in whom metformin efficacy is only 50%.


Our objectives were to: (1) compare gut hormone concentrations, glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP) and peptide-YY (PYY) and (2) compare basal rates of glucose production and glycerol turnover in 19 youth with T2DM not on metformin to 10 healthy age and BMI-matched controls, and (3) determine the change in gut hormones and basal rates of gluconeogenesis (GNG) before and after 3 months of metformin therapy in 9 youth with T2DM. Intact GLP-1, total GIP and PYY were measured at 0 and 2-hr during a 75g 2-hr OGTT and glucose production (6,62H2glucose), basal GNG (2H20), and whole body lipolysis (2H5 glycerol) were measured after an overnight fast.


Compared to controls, youth with T2DM before metformin therapy had higher fat mass, HbA1c and fasting and 2-hr glucose levels and lower fasting GLP-1 (P<0.05). After 3 months of metformin therapy, HbA1c decreased, fasting GLP-1 and fasting and 2-hr PYY increased but there was no change in BMI (42±9 vs. 41±8 kg/m2), GNG (1.82±0.34 vs. 1.78±0.32 mg/kgLBM/min) or glucose production (2.76±0.69 vs 2.73±0.41 mg/kgFFM/min) (P>0.1). Post-metformin GLP-1 and PYY was comparable to levels in controls (P>0.1). There was no difference in GIP between youth with and without T2DM and no change after short-term metformin therapy.


Overall, improved glycemic control with short-term metformin therapy in youth was associated with increased GLP-1 and PYY concentrations independent of changes in BMI and GNG supporting an entero-insular mechanistic pathway.