Despite the known glucose-lowering effects of metformin, more recent clinical interest lies in its potential as a weight loss drug. Herein, we discuss the potential mechanisms by which metformin decreases appetite and opposes unfavorable fat storage in peripheral tissues. Many individuals struggle to maintain clinically relevant weight loss from lifestyle and bariatric surgery interventions. Long-term follow-up from the Diabetes Prevention Program demonstrates that metformin produces durable weight loss, and decreased food intake by metformin is the primary weight loss mechanism. Although the effect of metformin on appetite is likely to be multifactorial, changes in hypothalamic physiology, including leptin and insulin sensitivity, have been documented. In addition, novel work in obesity highlights the gastrointestinal physiology and circadian rhythm changes by metformin as not only affecting food intake, but also the regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue. Metformin induces modest weight loss in overweight and obese individuals at risk for diabetes. A more detailed understanding of how metformin induces weight loss will likely lead to optimal co-prescription of lifestyle modification with pharmacology for the treatment of obesity independent of diabetes.

OBJECTIVE: Physical activity or metformin enhances insulin sensitivity and opposes the progression from prediabetes to type 2 diabetes. The combination may be more effective because each treatment stimulates AMP-activated protein kinase activity in skeletal muscle. We evaluated the effects of exercise training plus metformin on insulin sensitivity in men and women with prediabetes, compared with each treatment alone. RESEARCH DESIGN AND METHODS: For 12 weeks, men and women with prediabetes were assigned to the following groups: placebo (P), 2,000 mg/day metformin (M), exercise training with placebo (EP), or exercise training with metformin (EM) (n = 8 per group). Before and after the intervention, insulin sensitivity was measured by euglycemic hyperinsulinemic (80 mU/m2/min) clamp enriched with [6,6-2H]glucose. Changes due to intervention were compared across groups by repeated-measures ANOVA. RESULTS: All three interventions increased insulin sensitivity (P < 0.05) relative to the control group. The mean rise was 25–30% higher after EP than after either EM or M, but this difference was not significant. CONCLUSIONS: Insulin sensitivity was considerably higher after 12 weeks of exercise training and/or metformin in men and women with prediabetes. Subtle differences among condition means suggest that adding metformin blunted the full effect of exercise training.

• Habitual aerobic exercise helps manage blood glucose. • Resistance exercise benefits insulin sensitivity in those with type 2 diabetes. • Movement throughout the day by breaking up sitting time benefits blood glucose and insulin. • Physical activity after meals reduces blood glucose. • Performing exercise later in the day can benefit glycemic control and insulin sensitivity.

Results from the Diabetes Prevention Program highlight the effectiveness of metformin or regular physical activity in the prevention of type 2 diabetes. Independently, metformin and exercise increase insulin sensitivity, but they have not been studied in combination. To assess the combined effects, insulin-resistant subjects ( n = 9) matched for weight, body fat, and aerobic fitness were studied before any treatment (B), after 2–3 wk of 2,000 mg/day metformin (MET), and after metformin plus 40 min of exercise at 65% V̇o_2peak (MET + Ex). A second group ( n = 7) was studied at baseline and after an identical bout of exercise with no metformin (Ex). Biopsies of the vastus lateralis were taken at B, after MET, immediately after MET + Ex ( group 1), or immediately after Ex ( group 2). Insulin sensitivity was assessed 4 h postexercise with a euglycemic hyperinsulinemic (40 mU·m²·min⁻¹) clamp enriched with [6,6-²H]glucose. Insulin sensitivity was 54% higher after Ex ( P < 0.01), but there was no change with Met + Ex. Skeletal muscle AMPKα2 activity was elevated threefold ( P < 0.01) after Ex, but there was no increase with MET + Ex. These findings suggest that the combination of short-term metformin treatment and an acute bout of exercise does not enhance insulin sensitivity, and the addition of metformin may attenuate the well-documented effects of exercise alone.

Background: Increased dietary whole-grain intake may protect against cardiovascular disease (CVD).Objective: The objective was to evaluate the effica

Although some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic β-cell function is unknown. Thirty-five older obese adults with prediabetes underwent a progressive 12-wk supervised exercise intervention (5 days/wk for 60 min at ∼85% HR_max). Insulin and C-peptide responses to an OGTT were used to define the first- and second-phase disposition index (DI; β-cell function = glucose-stimulated insulin secretion × clamp-derived insulin sensitivity). Maximum oxygen consumption (V̇o_2max) and body composition (dual-energy X-ray absorptiometry and computed tomography) were also measured before and after the intervention. Exercise dose was computed using V̇o₂/heart-rate derived linear regression equations. Subjects expended 474.5 ± 8.8 kcal/session (2,372.5 ± 44.1 kcal/wk) during the intervention and lost ∼8% body weight. Exercise increased first- and second-phase DI ( P < 0.05), and these changes in DI were linearly related to exercise dose (DI_{first phase}: r = 0.54, P < 0.001; DI_{second phase}: r = 0.56, P = 0.0005). Enhanced DI was also associated with increased V̇o_2max (DI_{first phase}: r = 0.36, P = 0.04; DI_{second phase}: r = 0.41, P < 0.02) but not lower body fat (DI_{first phase}: r = −0.21, P = 0.25; DI_{second phase}: r = −0.30, P = 0.10) after training. Low baseline DI predicted an increase in DI after the intervention (DI_{first phase}: r = −0.37; DI_{second phase}: r = −0.41, each P < 0.04). Thus, exercise training plus weight loss increased pancreatic β-cell function in a linear dose-response manner in adults with prediabetes. Our data suggest that higher exercise doses (i.e., >2,000 kcal/wk) are necessary to enhance β-cell function in adults with poor insulin secretion capacity.