Metformin and exercise effects on postprandial insulin sensitivity and glucose kinetics in pre-diabetic and diabetic adults

The potential interaction between metformin and exercise on glucose-lowering effects remains controversial. We studied the separated and combined effects of metformin and/or exercise on fasting and postprandial insulin sensitivity in individuals with pre-diabetes and type 2 diabetes (T2D). Eight T2D adults (60 +/- 4 yr) with overweight/obesity (32 +/- 4 kg<middle dot>m(-2)) under chronic metformin treatment (9 +/- 6 yr; 1281 +/- 524 mg<middle dot>day(-1)) underwent four trials; 1) taking their habitual metformin treatment (MET), 2) substituting during 96 h their metformin medication by placebo (PLAC), 3) placebo combined with 50 min bout of high-intensity interval exercise (PLAC + EX), and 4) metformin combined with exercise (MET + EX). Plasma glucose kinetics using stable isotopes (6,6-H-2(2) and [U-C-13] glucose), and glucose oxidation by indirect calorimetry, were assessed at rest, during exercise, and in a subsequent oral glucose tolerance test (OGTT). Postprandial glucose and insulin concentrations were analyzed as mean and incremental area under the curve (iAUC), and insulin sensitivity was calculated (i.e., MATSUDA(index) and OGIS(index)). During OGTT, metformin reduced glucose iAUC (i.e., MET and MET + EX lower than PLAC and PLAC + EX, respectively; P = 0.023). MET + EX increased MATSUDA(index) above PLAC (4.8 +/- 1.4 vs. 3.3 +/- 1.0, respectively; P = 0.018) and OGIS(index) above PLAC (358 +/- 52 vs. 306 +/- 46 mL<middle dot>min(-1)<middle dot>m(-2), respectively; P = 0.006). Metformin decreased the plasma appearance of the ingested glucose (R-a OGTT; MET vs. PLAC, -3.5; 95% CI -0.1 to -6.8 mu mol<middle dot>kg(-1)<middle dot>min(-1); P = 0.043). Metformin combined with exercise potentiates insulin sensitivity during an OGTT in individuals with pre-diabetes and type 2 diabetes. Metformin's blood glucose-lowering effect seems mediated by decreased oral glucose entering the circulation (gut-liver effect) an effect partially blunted after exercise.