Contrary to our original hypothesis, adding metformin did not accentuate the effects of exercise training on whole-body insulin sensitivity in this group of men and women with prediabetes. Consistent with our prior study of acute exercise (18
), the addition of metformin may have blunted the response to exercise training alone. In prior studies, combining lifestyle modification with metformin has had inconsistent effects. Atabek and Pirgon (11
) reported that lifestyle modification plus metformin reduced BMI, fasting hyperinsulinemia, and 2-h plasma insulin concentrations in obese adolescents compared with lifestyle modification alone. Love-Osborne et al. (12
) demonstrated that lifestyle modification plus metformin resulted in more weight loss than lifestyle modification alone, and the weight loss was correlated with lower 2-h blood glucose concentrations. In the Indian Diabetes Prevention Program (IDPP), 500 mg/day of metformin, lifestyle modification, and a combination of the two had equivalent effects to improve insulin sensitivity and reduce the progression from prediabetes to type 2 diabetes (16
). The inconsistency in the literature may be related to the outcomes used. In the four studies (including ours) that report no additive effects of metformin and exercise, insulin sensitivity is a key outcome. In the studies that do suggest additive effects, weight loss and a response to an oral glucose tolerance test are the key outcomes. Differences in the outcomes between the studies are also likely related to the effects of metformin and exercise on different tissues. Insulin sensitivity is primarily a measure of skeletal muscle glucose uptake, whereas glucose tolerance also reflects contributions from hepatic glucose output.
There are several potential explanations for the lack of additive effects when metformin and exercise were combined in this study. Metformin is a mild inhibitor of Complex I in the mitochondrial electron transport chain (21
) and, thus, it is possible that metformin constrains the cellular adaptations to training. Although we cannot address mitochondrial adaptations to training in this study, there were no statistical differences in Vo2peak
after training with or without metformin.
We previously found that short-term metformin treatment blunted the upregulation of AMPK and insulin sensitivity after one bout of moderate-intensity exercise (18
). If habitual treatment with metformin does not enhance stimulation of AMPK by training, we would expect few additive effects (22
). Direct measurements of AMPK activity will be required to test this hypothesis. Gain of FFM may raise insulin sensitivity, although this observation is not universal (5
). Metformin increased FFM in adolescent girls treated during puberty (23
), but in the current study, FFM was unaffected by metformin and slightly higher after training alone. Scaling insulin-mediated glucose uptake to FFM did not alter the results, implying that differences between conditions were not attributable to small variations in FFM.
On the basis of results from the DPP and other studies (24
), there is a strong relationship between weight loss and greater insulin sensitivity. In the current study, EM and M resulted in 4 kg of weight loss, whereas EP had no effect. Despite the differences in total weight loss, however, both EM and EP lost similar quantities of body fat and “central” fat as estimated from dual-energy X-ray absorptiometry. There is a clear relationship between reduced body fat, especially central visceral fat, and greater insulin sensitivity (25
). Equivalent losses of body fat may partly explain why both EM and EP had impressive rises to insulin sensitivity despite no weight loss in the EP group. In our prior study, the addition of metformin to a single bout of exercise raised the plasma concentrations of NEFA, which could have blunted insulin sensitivity (18
). In the current study, however, adding metformin to training did not raise NEFA concentrations during the clamp (data not shown), although they were higher in the fasted state. It is possible that elevated fasting NEFA concentrations may be related to the blunted rise in insulin sensitivity when metformin was combined with training.
Although not statistically significant (P
≤ 0.50), the 25–30% blunting effect of adding metformin to training versus M or EP () has potential clinical relevance and is worth considering. Inclusion of subjects with different subtypes of prediabetes may have increased interindividual variability and obscured a true difference between conditions (1
). Like the individuals in the DPP, we included men and women with prediabetes who had IGT, with or without IFG concentrations. The response to all three interventions was accentuated in the individuals with fasting hyperglycemia (i.e., those with IFG plus IGT compared with those who had IGT only) (Supplementary Fig. 1
). On the basis of these results and similar outcomes in larger studies (J.M. Hagberg, personal communication), it would be fruitful to study the effects of exercise and/or metformin in the different subgroups of prediabetes to better understand the effects of fasting hyperglycemia.
In summary, exercise training increased insulin sensitivity in individuals with prediabetes. Adding metformin to training did not accentuate improvements in insulin sensitivity, and it may have blunted the full effects of training. The results we observed were independent of weight loss and not explainable by any difference in the effects of training on cardiorespiratory fitness in the presence of metformin. Although acute bouts of exercise can increase insulin sensitivity for up to 48 h, the time-course effects of the combined treatment remain unclear. Despite the lack of additive effects on insulin sensitivity, combining metformin with training, as described in the recent American Diabetes Association clinical recommendations (9
), may still be a potentially useful strategy to prevent the transition from prediabetes to diabetes. Further work is required to understand the utility of combining metformin with training in regard to its impact on insulin sensitivity and other aspects of cardiometabolic health.