Metformin improves blood glucose by increasing incretins independent of changes in gluconeogenesis in youth with type 2 diabetes

Aims/hypothesis Metformin is the only approved oral agent for youth with type 2 diabetes but its mechanism of action remains controversial. Recent data in adults suggest a primary role for the enteroinsular pathway, but there are no data in youth, in whom metformin efficacy is only similar to 50%. Our objectives were to compare incretin concentrations and rates of glucose production and gluconeogenesis in youth with type 2 diabetes before and after short-term metformin therapy compared with peers with normal glucose tolerance (NGT). Methods This is a case-control observational study in youth with type 2 diabetes who were not on metformin (n = 18) compared with youth with NGT (n = 10) who were evaluated with a 2 day protocol. A 75 g OGTT was administered to measure intact glucagon-like 1 peptide (iGLP-1), gastric inhibitory polypeptide (GIP) and peptide YY (PYY). Insulinogenic index (IGI) and whole-body insulin sensitivity were calculated using glucose and insulin levels from the OGTT. Basal rates of gluconeogenesis ((H2O)-H-2), glucose production ([6,6-H-2(2)]glucose) and whole-body lipolysis ([H-2(5)]glycerol) were measured after an overnight fast on study day 2. Youth with type 2 diabetes (n = 9) were subsequently evaluated with an identical 2 day protocol after 3 months on the metformin study. Results Compared with individuals with NGT, those with type 2 diabetes had higher fasting (7.8 +/- 2.5 vs 5.1 +/- 0.3 mmol/l, mean +/- SDp = 0.002) and 2 h glucose concentrations (13.8 +/- 4.5 vs 5.9 +/- 0.9 mmol/l,p = 0.001), higher rates of absolute gluconeogenesis (10.0 +/- 1.7 vs 7.2 +/- 1.1 mu mol [kg fat-free mass (FFM)](-1) min(-1),p < 0.001) and whole-body lipolysis (5.2 +/- 0.9 vs 4.0 +/- 1.4 mu mol kg(FFM)(-1) min(-1),p < 0.01), but lower fasting iGLP-1 concentrations (0.5 +/- 0.5 vs 1.3 +/- 0.7 pmol/l,p < 0.01). Metformin decreased 2 h glucose (pre metformin 11.4 +/- 2.8 vs post metformin 9.9 +/- 1.9 mmol/l,p = 0.04) and was associated with similar to 20-50% increase in IGI (median [25th-75th percentile] pre 1.39 [0.89-1.47] vs post 1.43 [0.88-2.70],p = 0.04), fasting iGLP-1 (pre 0.3 +/- 0.2 vs post 1.0 +/- 0.7 pmol/l,p = 0.02), 2 h iGLP (pre 0.4 +/- 0.2 vs post 1.2 +/- 0.9 pmol/l,p = 0.06), fasting PYY (pre 6.3 +/- 2.2 vs post 10.5 +/- 4.3 pmol/l,p < 0.01) and 2 h PYY (pre 6.6 +/- 2.9 vs post 9.0 +/- 4.0 pmol/l,p < 0.01). There was no change in BMI, insulin sensitivity or GIP concentrations pre vs post metformin. There were no differences pre vs post metformin in rates of glucose production (15.0 +/- 3.9 vs 14.9 +/- 2.2 mu mol kg(FFM)(-1) min(-1),p = 0.84), absolute gluconeogenesis (9.9 +/- 1.8 vs 9.7 +/- 1.7 mu mol kg(FFM)(-1) min(-1),p = 0.76) or whole-body lipolysis (5.0 +/- 0.7 vs 5.3 +/- 1.3 mu mol kg(FFM)(-1) min(-1),p = 0.20). Post metformin iGLP-1 and PYY concentrations in youth with type 2 diabetes were comparable to levels in youth with NGT. Conclusions/interpretation Overall, the improved postprandial blood glucose levels and increase in incretins observed in the absence of changes in insulin sensitivity and gluconeogenesis, support an enteroinsular mechanistic pathway in youth with type 2 diabetes treated with short-term metformin.