In the 1960s and 1970s several studies had investigated the effect of metformin on exercise performance because of concerns over lactic acidosis (see reference 13
for a detailed review). Although the combination of metformin and exercise was perceived as safe, interest in this area has reemerged in recent years (4
). The current study is unique in that it focused on continuous exercise at several submaximal intensities that are relevant to activity patterns of people with type 2 diabetes and that we examined the interaction between exercise and metformin on the glycemic and hormonal responses to a subsequent meal.
We found that metformin increased lipid oxidation as evidenced by a lower RER during all three submaximal intensities of exercise. According to nonprotein RER tables, this would correspond to an increased lipid oxidation from 16 to 26% of total energy expenditure when walking at 3.5 km/h. Increased lipid oxidation is considered a normal adaption to exercise training. However, metformin increased submaximal HR and lactate concentrations, which are opposite to the direction of changes expected with regular exercise training. In the current study, HR was increased by a mean of 6 bpm. Interestingly, Sharoff et al. (4
) also found an increased HR of about 8 and 5 bpm during exercise at 65 and 85% of Vo2peak
, respectively; however, in their study the increase in HR did not reach statistical significance. In our study, a higher rating of perceived exertion in the metformin condition was also observed, although participants were all able to complete the exercise bouts. Taken together, this suggests that metformin has the potential to lower some patients’ selected exercise intensity since perceived exertion and HR are common feedback modalities and are frequently used to prescribe exercise intensities.
Although statistical significance was not reached, peak and mean torque for knee extension were lower in the metformin condition. Lower mean torque may have been expected based on the reduced muscle ATP concentrations observed by week 4 of metformin treatment in the study by Musi et al. (16
Maximal metformin concentrations are typically reached 120–240 min after a dose. In the current study, we observed greater plasma metformin concentrations 25 min before exercise and 20 min after exercise compared with samples taken at the same times on the rest day (150 and 225 min postdose). The reasons for these higher concentrations are unknown but may have been caused by the anticipatory and stress responses to exercise, which are known to increase HR and blood pressure while redistributing blood flow to tissues such as skeletal muscle (17
). Hence, the alteration in blood flow may have caused a transient decrease in the distribution of drug to certain tissues, including the liver. Indeed, this may have contributed to the reduced hypoglycemic effect of metformin after exercise even though plasma concentrations were higher at some time points. A reduced renal blood flow could increase plasma concentrations of drugs such as metformin, which are primarily eliminated by the kidneys (18
). This may have also contributed to some of the higher concentrations measured in the exercise group, although only a more complete assessment of plasma metformin concentrations and urinary recovery could answer this question. A limitation of the current study is that the three blood samples taken immediately after each aerobic exercise bout were not taken at the corresponding times on the nonexercise days.
Although some previous studies had suggested that the effects of exercise and metformin on insulin sensitivity (4
) or on the risk of diabetes (3
) are not additive, our results suggest that in some conditions the combination may in fact be less effective at lowering the glycemic response to a meal than metformin alone. The reasons for this are not clear, but may be related to the strong counterregulatory response when the two were combined. In our study, the glucagon concentrations peaked immediately before lunch and were highest in the combined metformin and exercise condition. In support of the notion that glucose production may have been increased by the higher glucagon concentrations, Sharoff et al. (4
) showed that hepatic glucose production was increased 2 h after exercise with metformin, unchanged by metformin alone, and decreased by exercise alone (4
). Important differences between our study and Sharoff et al. (4
) are that in the latter study participants were nondiabetic and 2 to 3 weeks of metformin use did not appear to alter insulin sensitivity or resting glucose concentration. Nonetheless, taken together these studies provide interesting insight on glucose homeostasis after metformin and exercise.
The lack of improvement in postmeal (lunch) plasma glucose concentrations on the exercise days should not discourage the use of exercise as a treatment modality. Rather, this study emphasizes that it may be important to further consider the timing of exercise and meals to obtain optimal glycemic benefits. For example, others have shown that exercising in the fasting state (a condition that also leads to pronounced counterregulatory responses) was much less effective at lowering plasma glucose than was exercising after a meal (19
Furthermore, it is important to remember that the exercise protocol in the current study ended with 5 min of exercise at an intensity above ventilatory threshold. Similarly, in the study by Sharoff et al. (4
), the exercise protocol ended with 10 min at 85% of Vo2peak
. High intensity exercise (i.e., above ventilatory threshold) in the postabsorptive state is known to cause an increase in counterregulatory hormones and glucose in type 2 diabetes (21
). However, high intensity exercise performed 45 min after the beginning of breakfast led to a decreased glycemic response to a meal that was provided 2.5 h after exercise (22
). It would be of interest to examine if interactions between metformin and exercise on glucose homeostasis would be as pronounced after lower intensity exercise.
Type 2 diabetes is characterized not only by insulin deficiency but also by hyperglucagonemia (23
). We are aware of nonexercise studies that have suggested that metformin may increase glucagon concentrations, but the increases were not statistically significant (24
). In the nonrandomized exercise studies by Cunha et al. (14
), glucagon concentrations were significantly higher in the participants with type 2 diabetes taking metformin compared with those taking glibenclamide or those with normal glucose tolerance. Although speculative, the glucose-lowering benefits of metformin could be further enhanced by strategies that could help minimize the exercise-induced increased glucagon levels such as exercising after a meal.
In conclusion, our study reports several novel findings regarding the concomitant use of metformin and exercise, specifically: 1) increased HR during exercise with metformin, 2) higher plasma metformin concentrations with exercise, and 3) nonadditive effects of metformin and exercise on the glycemic response to feeding. In our opinion, the magnitudes of these effects were small but have the potential to reduce the effectiveness of this therapeutic combination in diabetes treatment. Additional research could help optimize the concurrent use of these important and widely prescribed treatment modalities for diabetes.