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Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk

Malin, Steven K.1,2; Braun, Barry3

Exercise and Sport Sciences Reviews: January 2016 - Volume 44 - Issue 1 - p 4–11
doi: 10.1249/JES.0000000000000070
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Combining metformin with exercise has been proposed to improve glucose homeostasis. However, we primarily discuss evidence suggesting that metformin and other pharmacological agents/dietary supplements (e.g., statins, resveratol, or antioxidants) may in fact oppose exercise-induced benefits on insulin sensitivity and cardiometabolic health. We explore the novel hypothesis that attenuation of oxidative stress from exercise by these exogenous compounds blunts metabolic adaptation.

Combining metformin (as well as statins and antioxidants) with exercise may not add and even attenuate exercise-induced adaptations for glucose homeostasis.

1Department of Kinesiology and 2Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA; and 3Department of Health and Exercise Science, Colorado State University, Fort Collins, CO

Address for correspondence: Steven K. Malin, Ph.D., Department of Kinesiology, 225A Memorial Gymnasium, University of Virginia, Charlottesville, VA (E-mail: skm6n@virginia.edu).

Accepted for publication: October 15, 2015.

Associate Editor: John P. Kirwan, Ph.D., FACSM

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INTRODUCTION

Approximately 29 million individuals in the United States have type 2 diabetes, and it is projected that nearly 366 million men and women worldwide will have diabetes by 2030 (7). In addition, nearly 86 million people in the United States have prediabetes, which places them at high risk to develop type 2 diabetes. This is problematic because individuals with type 2 diabetes and prediabetes are at greatly elevated risk for cardiovascular disease (CVD). The primary causes of type 2 diabetes are an area of intense research, but insulin resistance is considered to be a central defect that impairs glucose homeostasis. Insulin resistance results in hyperinsulinemia that, if not lowered, then across time the beta cells of the pancreas become “exhausted” and unable to compensate for the prevailing degree of multiorgan insulin resistance resulting in severe hyperglycemia. Thus, targeting insulin resistance for prevention and management of type 2 diabetes has become a major public health effort. The first-line therapy for improving glycemic control and cardiometabolic health includes exercise and dietary change. Despite randomized clinical trials showing the efficacy of exercise and diet therapy to prevent the progression from prediabetes to type 2 diabetes (13,30), long-term adherence to exercise remains low and individuals often require pharmacological therapy to maintain normoglycemia. Recently, the American Diabetes Association (ADA) recommended that, in addition to lifestyle modification, individuals with prediabetes should be considered for metformin, an antidiabetes medication, to lower blood glucose concentrations. The assumption underlying this combined recommended therapy is that actions of metformin will add to the effects of physical activity, and this combined treatment will be more effective than either intervention alone.

Metformin (i.e., 1,1-dimethyl-biguanide) is the most widely used prescription drug to treat hyperglycemia in men and women with type 2 diabetes (26,33). In fact, metformin is the first-line oral antidiabetic medication recommended by the ADA, and individuals with prediabetes and at least one CVD risk factor (e.g., hypertension, elevated triacylglycerol, low high-density lipoprotein (HDL), fasting hyperglycemia, etc.) also are encouraged to be treated with metformin (31). In addition, metformin has been extensively studied for cancer prevention/treatment, suggesting that metformin is a highly complex drug with multiple health effects (29). To that end, many of these same individuals at risk for diabetes are prescribed statins and/or take dietary supplements including resveratrol and antioxidants to reduce blood lipids and bolster cardiometabolic health. The mechanisms by which exercise lowers type 2 diabetes risk involve increasing insulin sensitivity and lowering circulating lipids (e.g., triacylglycerol, low-density lipoproteins, etc.), blood pressure, and inflammation (e.g., C-reactive protein (CRP)). Metformin, statins, resveratrol, and antioxidant treatment also can increase insulin sensitivity and/or improve CVD risk factor profiles. However, the interaction these compounds have with exercise-induced adaptations has received little attention. From a cellular perspective, one of the chief factors believed to promote metabolic adaptation to exercise is the generation of reactive oxygen species (ROS). Given that recent work suggests that exogenous compounds, including metformin and antioxidants, reduce ROS generation, we explore the novel hypothesis that agents such as metformin attenuate metabolic adaptation pertaining to insulin sensitivity through an oxidative stress-related mechanism. Thus, the present article dicusses the most recent evidence describing whether combining metformin with exercise has additive, opposing, or no benefit for glucose regulation and CVD risk reduction.

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DOES METFORMIN HAVE ADDITIVE EFFECTS ON EXERCISE-INDUCED INCREASES IN INSULIN SENSITIVITY?

Several laboratories have shown that exercise enhances insulin sensitivity in individuals across the glucose tolerance continuum, and the increase in skeletal muscle glucose disposal often is used as a primary mechanism to explain reductions in postprandial blood glucose after exercise training (14). In contrast, metformin primarily lowers blood glucose by decreasing hepatic glucose production (25,26,33), with mixed evidence for metformin to improve peripheral insulin sensitivity (15,32). In addition, metformin and exercise each independently increase 5-adenosine monophosphate kinase (AMPK), which is one of the several mechanisms for insulin-stimulated glucose uptake (32,33). Collectively, these observations lead our group to hypothesize that combining metformin with exercise would have additive effects on insulin sensitivity.

We initially determined the effect of combining exercise with metformin on whole-body insulin sensitivity in overweight, sedentary, insulin-resistant individuals after a single bout of exercise (32). Metformin or placebo was provided to all participants for 2 to 3 weeks at 2000 mg d−1, after which individuals exercised for 30 min at 65% V˙O2peak and 10 min at 85% V˙O2peak. Insulin sensitivity was measured approximately 4 h after exercise using the hyperinsulinemic-euglycemic clamp. Compared with baseline, exercise alone enhanced peripheral insulin sensitivity by 54%, whereas metformin abolished the exercise-induced rise in insulin sensitivity (Fig. 1). Because both exercise and metformin activate AMPK (32,33), we assessed the individual and combined effects of these treatments on AMPK in vastus lateralis skeletal muscle. Consistent with the blunted insulin sensitivity results, metformin attenuated the effects of exercise on skeletal muscle AMPK activation, suggesting that metformin opposes the exercise-induced action of cellular mediators regulating insulin sensitivity and blood glucose. In addition, work by Boulé et al. (3) tested the effect of metformin on the acute metabolic response to submaximal aerobic exercise on the treadmill (ranging from ∼33%, 67%, and 79% of V˙O2peak during 3- to 15-min bouts) and resistance exercise (i.e., leg extension and flexion) during a standardized meal in 10 subjects with type 2 diabetes and suggested that metformin attenuated reductions in postprandial blood glucose concentrations. Taken together, these studies suggest that metformin opposes some of the beneficial effects of acute exercise on insulin sensitivity in both nondiabetic and type 2 diabetic individuals.

Figure 1

Figure 1

From a clinical perspective, repeated bouts of exercise (i.e., lifestyle change) are recommended by major health organizations such as the ADA and American College of Sports Medicine to reduce type 2 diabetes risk. Thus, we designed a prospective, double-blind, randomized, controlled trial to examine the long-term effects of combining exercise training and metformin on insulin sensitivity in men and women with prediabetes to clarify the interaction of these two “medications” (21). For 12 wk, individuals with prediabetes were assigned to one of four groups: placebo, metformin, exercise training plus placebo, or exercise training plus metformin. All individuals received either metformin at 2000 mg d−1 or a placebo, whereas half of the individuals participated in a progressive aerobic and resistance training program at 70% of their individual heart rate peak and 1-repetition max, respectively. Insulin sensitivity was assessed 28 to 30 h after exercise via the hyperinsulinemic-euglycemic clamp with glucose isotope tracers to isolate the effects of metformin on skeletal muscle versus hepatic insulin sensitivity. Although all treatments reduced fasting plasma insulin and maintained hepatic glucose production, suggesting improved hepatic insulin sensitivity, metformin and exercise training alone increased skeletal muscle insulin sensitivity by approximately 55% and 90% compared with baseline, respectively, and this effect was independent of baseline levels (P < 0.05). In contrast, metformin attenuated the effect of training on skeletal muscle insulin sensitivity by approximately 30% (Fig. 2), suggesting that metformin mitigates the glucose-regulatory effects of exercise after both single and repeated bouts of exercise (2,21,32). However, despite this smaller insulin sensitivity improvement after the combination of exercise and metformin treatment, it is worth recognizing that blood glucose does not rise (21,32). A possible explanation for this observation is that metformin results in distinct adaptations within the pancreatic beta cells after exercise to protect glucose homeostasis by increasing insulin secretion capacity. Indeed, short-term administration of metformin for 28 days has been reported to increase postprandial glucagon-like polypeptide-1 (GLP-1) to a standardized meal (∼56% carbohydrate, 30% fat, and 14% protein) after exercise compared with exercise alone in people with type 2 diabetes (9). Although the interaction of metformin and exercise on pancreatic beta-cell function has not been investigated systematically in humans, changes in GLP-1 after metformin treatment with exercise suggest that pancreatic insulin secretion may play a role in maintaining circulating glucose. Nonetheless, combining lifestyle modification with metformin has had mixed results on blood glucose and insulin sensitivity. Love-Osborne et al. (17) 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. However, in the Indian Diabetes Prevention Program, 500 mg d−1 of metformin, lifestyle modification, and a combination therapy had equivalent effects in improving insulin sensitivity and reducing the progression from prediabetes to type 2 diabetes (30). In addition, the Diabetes Aerobic and Resistance Exercise (DARE) trial demonstrated that patients with type 2 diabetes taking metformin plus lifestyle modification had comparable reductions in HbA1c to lifestyle modification only, and there were no differences in weight loss between groups (3). An important distinction from the DARE trial in comparison with the majority of other clinical trials presented herein is that people with type 2 diabetes were already prescribed metformin and were diagnosed as having diabetes for approximately 3 yr or longer (mean ± SD, 3.6 ± 3.7 vs 6.3±4.4), thereby raising questions about the efficacy of metformin plus exercise interaction with disease duration on glycemic control. Together, the inconsistency in the literature may be related to the outcomes used. In the studies (including ours) that report no additive effects of metformin and exercise, insulin sensitivity or HbA1c was a key outcome. Yet, in the studies that do suggest additive effects, weight loss and responses to an oral glucose tolerance test are the key outcomes. Therefore, with the exception of potentially greater weight loss (∼3 kg) after metformin plus exercise compared with exercise alone, there seems to be no additive effect of metformin to improve insulin sensitivity or HbA1c. In fact, rigorously controlled trials suggest that metformin may dampen the beneficial effects of exercise on glucose regulation.

Figure 2

Figure 2

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DOES COMBINING METFORMIN WITH EXERCISE HAVE ADDITIVE EFFECTS ON CVD RISK REDUCTION?

Numerous studies have demonstrated that insulin resistance is linked to CVD risk factors, including hypertension, low-grade inflammation, and dyslipidemia. Exercise lowers CVD risk in part by lowering blood pressure, triacylglycerols (TAG), and inflammation (14). Metformin not only is used to treat type 2 diabetes but also is suggested to lower CVD risk (33). However, there is limited evidence from randomized controlled trials investigating whether metformin alters the cardioprotective effects of exercise. Based on our observations of insulin resistance after the combined treatment (21), we examined the effects of metformin on exercise-induced changes in CVD risk factors (i.e., blood pressure, inflammation, and blood lipids) (23). After 12 weeks, metformin or exercise training alone lowered systolic blood pressure and high-sensitivity CRP (hs-CRP) by approximately 7% to 8% and 20% to 25%, respectively, in men and women with prediabetes. The combined treatment, however, blunted the reductions in systolic blood pressure and hs-CRP. Our findings are in line with others reporting that combining metformin with lifestyle modification (i.e., low-fat diet/increase physical activity) has little to no further improvement in blood pressure (8). Interestingly, our findings also were confirmed in obese insulin-resistant adolescents whereby the addition of metformin to lifestyle modification blunted reductions not only in CRP levels but also circulating fibrinogen (24). These observations have strong clinical implications for using the combination of metformin and exercise because blunted improvement in blood pressure and/or inflammation may relate to opposing the reversal of metabolic syndrome (Fig. 3). Although a recent report by Jenkins et al. (12) suggested that the combined treatment of metformin (300 mg kg−1 d−1) and exercise (20 m min−1 on 15% incline 5 d wk−1) for about 12 wk lowered HbA1c and circulating leptin and raised interleukin-10 concentrations to a greater extent than exercise training alone in obese insulin-resistant animals, suggesting an improved adipose-derived inflammatory profile, there are no published data to date in humans assessing the effect of metformin plus exercise on hormones secreted from adipose tissue that relate to insulin sensitivity or glycemic control. Thus, further investigation is warranted to determine if the altered blood pressure and/or inflammation after the combined treatment has clinical ramifications for CVD incidence across time. Moreover, work also is required for elucidating the cardiovascular mechanism(s) (e.g., flow-mediated dilation or angiogenesis) by which metformin alters the benefits of exercise to lower CVD risk in people at risk for type 2 diabetes.

Figure 3

Figure 3

Reducing lipotoxicity is considered important for preventing and/or reversing type 2 diabetes and CVD risk. Elevated TAG and low HDL have been implicated as potential mechanisms for insulin resistance because this lipid milieu favors the accumulation of ectopic lipids (intramuscular TAG and hepatic steatosis) that impair insulin signaling and glucose homeostasis (14). Prior work in overweight insulin-resistant adolescents has reported that combining metformin with lifestyle modification reduced TAG concentrations more than lifestyle modification alone (8), although others report no additive effects of the combined treatment on blood lipids in adults with prediabetes (1). Consistent with this latter report, we show that exercise training with metformin had similar effects on lowering TAG and raising HDL compared with either treatment alone (23). However, elevated and/or blunted reductions in nonesterified fatty acids (NEFA) concentrations have been observed after metformin plus exercise treatment in multiple studies during rest, exercise, or insulin-stimulated conditions compared with exercise alone (2,20,21,32), and these altered NEFA levels have been associated with the attenuated improvement in insulin sensitivity after the combination of metformin and exercise (21,32). Interestingly, recent work done in obese adolescents demonstrates that intrahepatic fat accumulation was lowered more after a diet and exercise program than when combined with metformin (24). This observation is consistent with the hypothesis that elevated NEFA flux from adipose tissue to the liver via the portal vein is a primary mechanism for increasing hepatic lipid content. It remains unclear how metformin exactly blunts reductions in hepatic fat content after exercise, but this observation is consistent with elevated circulating NEFA levels. Taken together, these data suggest that adipose-derived metabolism may play a role in cardiometabolic health after the combined treatment of metformin and exercise.

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DOES FITNESS OR FUEL SELECTION AFTER METFORMIN AND EXERCISE IMPACT INSULIN SENSITIVITY?

It is well accepted that physical fitness is related to reduced CVD mortality, and in longitudinal studies of nondiabetic men, it has been shown that high aerobic fitness confers protection against developing type 2 diabetes, even when adjusting for age and family diabetes history (34). It is not surprising then that major health organizations recommend physical activity as a first-line therapy in the prevention of type 2 diabetes because exercise enhances both the delivery and utilization of oxygen to raise cardiorespiratory fitness (i.e., V˙O2peak). Increases in V˙O2peak-related metabolic adaptations (e.g., mitochondrial biogenesis, oxidative enzymes) are associated strongly with increased sensitivity to insulin, and this is consistent with literature linking mitochondrial density and fat utilization to insulin action (14). But whether metformin affects in vivo oxygen utilization in humans has received little attention. Consequently, we investigated the short-term effects of metformin administration on cardiorespiratory fitness in a group of recreationally active men and women (4). The results suggested that 7 to 10 d of metformin treatment at 2000 mg d−1 significantly reduced V˙O2peak, heart rate peak, and exercise duration. Because metformin has been reported to partially inhibit Complex 1 of the mitochondrial electron transport system (5), metformin may constrain V˙O2peak by altering mitochondrial oxidative capacity. The implication of this finding is important because reducing aerobic fitness would cause an individual to exercise at a higher percentage of their V˙O2peak when performing a task at the same absolute workload as previously prescribed metformin. This effect on exercise intensity not only would increase the perception of effort (and possibly decrease long-term exercise adherence) but also would shift fuel reliance away from fat and minimize exercise-induced benefits for insulin sensitivity (14). However, it is important to recognize that not all work supports the notion that metformin decreases V˙O2peak, and some have shown metformin to increase exercise tolerance in patients with coronary artery disease (11). This suggests that some groups who are characterized by alterations in vascular function may benefit from the addition of metformin to exercise interventions, although the impact of metformin on peak oxygen consumption in relation to glycemic control and CVD risk reduction remains an area of needed research.

To determine whether metformin alters submaximal exercise metabolism, we conducted a study in healthy overweight men and women to investigate if metformin raised perception of effort and decreased fat utilization during exercise (18). Consistent with reduced cardiorespiratory fitness by metformin in our prior work, metformin raised perceptions of effort (via the Borg Scale) and blood lactate levels during exercise at intensities ranging from approximately 40% to 80% V˙O2peak. However, metformin actually increased fat oxidation during submaximal exercise (18). The reason for this rise in submaximal fat utilization during exercise is unknown, but it may relate to constraints in blood glucose availability by lowering hepatic gluconeogenesis through decreased lactate clearance and/or activation of AMPK that regulates entry of fat into the mitochondria. Although more work is needed to understand how metformin mechanistically impacts fuel selection during short-term metformin administration, recent work in type 2 diabetic men and women confirmed our increased fat oxidation findings during submaximal exercise across a range of low-, moderate-, and high-intensity exercise (2). The physiologic relevance of this increased fat utilization after metformin plus acute exercise remains unclear (2,18) because no direct relationship was observed with improved glycemic control. Nevertheless, it is worth mentioning that the intensity at which individuals exercise while prescribed metformin may impact fuel selection. Recent work has shown that metformin increased total carbohydrate oxidation during high-intensity interval exercise in insulin-resistant adults when compared with exercise alone (27). This finding was correlated directly with surrogate measures of insulin sensitivity using an intravenous glucose tolerance test, suggesting for the first time that metformin may potentiate the exercise effect. Although these data are to be interpreted with caution because substrate utilization was determined during discontinuous high-intensity interval exercise (i.e., 4 min at 70% and 4 min at 90% HRmax), and it is not possible to determine whether this rise in carbohydrate oxidation was derived from blood glucose and/or muscle glycogen; the findings of Ortega et al. (27) suggest that exercise intensity may interact with metformin to influence insulin-stimulated glucose disappearance when compared with prior work on moderate-intensity exercise (2,18). Taken together, although the collective literature suggests that metformin may at least acutely impact oxygen consumption and/or fuel utilization, the long-term consequence of altered cardiorespiratory fitness or fat oxidation in relation to improvements in insulin sensitivity require further research.

We investigated the effect of metformin on V˙O2peak and fuel metabolism after a 10-wk exercise intervention in obese adults with prediabetes (20). As expected, exercise training alone significantly enhanced V˙O2peak, and metformin blunted the rise in V˙O2peak by approximately 50% when compared with exercise alone in adults with prediabetes. This reduced cardiorespiratory fitness improvement after the combined treatment resulted in people exercising at a slightly higher percentage of their posttraining V˙O2peak (EM, ∼55 vs EP, 51% V˙O2peak; P < 0.05) (20), which is consistent with new work highlighting that only exercise training raised the anaerobic threshold in insulin-resistant adults (6). Strengthening the position that blunted increases in V˙O2peak may influence glycemic control, we observed strong associations between reduced gains in cardiorespiratory fitness and smaller increases in both fat utilization during submaximal exercise and peripheral insulin sensitivity after exercise training (20). Consistent with these whole-body oxygen/fuel utilization data in humans, metformin has had no additive effect on hepatic markers of oxidative capacity/mitochondrial content (i.e., citrate synthase and β-HAD activities) in Otsuka Long-Evans Tokushima Fatty rats and, in fact, attenuated the improvement in liver diacylglycerol content and measures of de novo lipogenesis when dosed with metformin plus exercise (16). It is worth acknowledging, however, that not all groups report blunted physical fitness when lifestyle modification is performed in a background of metformin (3), and recent work in animals from the same group (16) suggests that the combined therapy of metformin plus exercise may induce greater improvements in HbA1c than either monotherapy alone (12). The inconsistency of metformin to lower cardiorespiratory fitness and alter fuel selection in the literature is unclear, but it may be related to the population (animal vs human adolescents or prediabetes or type 2 diabetes), metformin treatment time frame (7 to 10 d, 10 wk or habitual use), order in which metformin or exercise is provided (metformin for 10 wk then exercise for 10 more weeks vs vice versa), or the intervention itself (4–6,20). Nevertheless, the majority of data from our group and others suggest that metformin constrains/promotes maladaptations in aerobic fitness, which may relate to attenuated improvements in cardiometabolic health. Mechanistic studies are needed after metformin and exercise treatment to investigate mitochondrial biogenesis and/or blood flow to better understand how these coprescribed therapies work to improve chronic disease management.

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POSSIBLE MECHANISMS AND COMPARATIVE INTERACTIONS OF STATINS AND ANTIOXIDANTS WITH METFORMIN ON EXERCISE METABOLISM

Recent work suggests that metformin is not the only exogenous compound that may impede metabolic adaptations to exercise. Statins often are prescribed to reduce CVD risk by lowering blood lipids. However, statins have been implicated in skeletal muscle myopathy and mitochondrial dysfunction, suggesting a possible deleterious interaction with exercise. Mikus et al. (25) recently evaluated the effects of statins (40 mg d−1) during aerobic exercise training (at 60% to 75% of HR reserve) in overweight/obese adults at risk for metabolic syndrome and found that V˙O2peak increased by 10% with exercise training alone but only 1.5% with the combination therapy. These differential responses in fitness were paralleled by attenuated citrate synthase activity in skeletal muscle, suggesting that statins may in fact blunt exercise responses to lower CVD risk. Interestingly, the detrimental effects of pharmacology with exercise also seem to extend to dietary supplements, including resveratrol, vitamin C, and vitamin E. Traditionally, these dietary antioxidants have been viewed as an ergogenic aid to improve sports performance, muscle recovery, and metabolic health by reducing the adverse effects of ROS on impairing insulin signaling and vascular function. Although some data report no altered effect of the antioxidants vitamin C or E on exercise-induced adaptations (35), several studies highlight that resveratrol or vitamin C or E blunts exercise adaptations to exercise, including but not limited to insulin sensitivity, blood pressure, flow-mediated dilation, angiogenesis, cardiorespiratory fitness, and mitochondrial biogenesis (10,28). Together, these dietary supplement studies provide support to the current view that ROS generation actually may serve as an important cellular signaling mechanism to promote metabolic adaptation to exercise. As a result, the collective evidence in the literature highlights a need to rethink the coprescription of two independent doses of exercise and exogenous compounds.

There is little argument that exercise, pharmacological agents, or antioxidants alone confer beneficial effects on cellular processes for insulin sensitivity and CVD risk reduction. However, the concern observed in much of the aforementioned literature investigating the combined therapy of exercise with these exogenous compounds may lie in the logic that prescribing two seemingly “good” therapies in tandem should yield optimal adaptation. It now seems clear that the mechanism by which these therapies act to improve health independently actually when combined counteract some signaling processes that lead to beneficial adaptation. Interestingly, as with antioxidants, metformin also has been shown to reduce ROS generation, suggesting that oxidative stress may be the common thread between explaining how some pharmaceutical drugs and dietary antioxidant supplements blunt exercise-stimulated adaptation. Subsequently, our working hypothesis is that muscle contraction-induced ROS generation is an important mediator of metabolic adaptation related to insulin action after exercise, and metformin likely opposes ROS signaling to some extent and attenuates cellular signals important for mitochondrial biogenesis (e.g., PGC-1α), nitric oxide-mediated blood flow (e.g., endothelial function), and glucose uptake (GLUT-4 protein) that contribute to insulin sensitivity (Fig. 4). Concomitantly, this model also acknowledges the possibility that unknown cellular mechanisms linked to excessive energetic stress from muscle contraction and exogenous compounds may exist such that these “medications” may lead to overtaxation of bioenergetic pathways that result in maladaptation. Future studies should consider incorporating the concept of hormesis, a biological dose-response phenomenon, into exercise trials with exogenous compounds to better understand the interaction of exercise intensity, diet, and pharmacology (i.e., drug or diet supplement) on metabolic health responses.

Figure 4

Figure 4

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CLINICAL IMPLICATIONS AND CONCLUSIONS

Our collective work suggests that adding two metabolically beneficial treatments do not necessarily equate to additive health, and tailoring exercise prescription for optimal metabolic disease prevention/treatment remains to be identified (Table). A practical question from this work is should clinicians coprescribe metformin (or statins/antioxidants) with exercise to treat their patients or is exercise treatment alone sufficient to lower diabetes risk? The answer to this question is complicated. Certainly, our findings, as well as those from other groups, suggest that metformin blunts the effects of exercise at improving insulin sensitivity, metabolic syndrome prevalence, and inflammation. Although these findings are concerning, it is important to recognize that metformin seems to have distinct effects on multiple tissues (e.g., skeletal muscle, adipose, vasculature, and liver) and the degree of benefit will vary depending on what tissue or outcome is of interest. In addition, questions remain as to what dose of metformin (or other agents) should be combined with exercise to maximize health. Systemic studies determining the benefit of different drug doses with exercise prescription would enable more precise treatment plans that favor glycemic control. Nevertheless, based on current findings from the literature, exercise alone seems to be the ideal “drug” to be prescribed as a first-line therapy for reducing type 2 diabetes risk in insulin-resistant individuals. We also recognize that exercise training may not improve blood glucose and/or insulin sensitivity to the same extent in all individuals (19), and pharmacological agents, such as metformin, should be considered in addition to exercise for the promotion of weight loss, which may across time contribute to improved cardiometabolic health (22). In fact, it remains possible that prescribing multiple pharmacological agents (e.g., metformin and GLP-1 agonists) in combination with exercise may exert unique effects on glucose metabolism compared with monotherapy plus exercise alone. However, if our metformin findings of blunted insulin sensitivity, blood pressure, and/or inflammation are replicated in the “real world” following exercise and are truly independent of weight loss, then individuals treated with peak doses of metformin plus exercise may be at higher risk of developing type 2 diabetes or cardiovascular abnormalities compared with those treated with exercise alone. Thus, there is a strong need for large randomized clinical trials to determine the optimal dose of combining exogenous compound with lifestyle modification to define best practices for CVD and type 2 diabetes risk reduction.

TABLE C

TABLE C

The authors thank Carrie G. Sharoff, Ph.D., Todd A. Hagobian, Ph.D., Stuart R. Chipkin, M.D., Brooke R. Stephens, Ph.D., Rebecca E. Hasson, Ph.D., Kirsten Granados, M.S., Richard Viskochil, M.S., Jennifer Rivero, M.S., and Robert Gerber, M.S., for outstanding support. We extend our appreciation to all the dedicated participants and undergraduate research assistants for their help. B. Braun receives consultant fees and research funding from Pfizer, Inc. This research was supported by NIH 5R56 DK081038 (B. Braun), ADA 7-04-JF-10 (B. Braun), and an ACSM Doctoral Student Foundation Grant S17100000000113 (S.K. Malin).

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Keywords:

obesity; prediabetes; type 2 diabetes; insulin resistance; metabolic syndrome; lifestyle modification

© 2016 American College of Sports Medicine