Metformin is the most prescribed blood sugar (glucose)-lowering medication for patients diagnosed with type 2 diabetes mellitus (T2DM). Metformin stimulates glucose uptake in skeletal muscle similar to the effects of exercise, though, some studies report that metformin may decrease exercise capacity.

The main question this study looks to answer is:

• Does metformin alter exercise capacity?

Participants will:

• Complete 5 exercise tests on a stationary bike.
• Undergo a body composition test.
• Take metformin and placebo.
• Complete food and symptom logs.

The researchers hypothesize that:

• Metformin will reduce aerobic capacity.

Metformin, a potent biguanide, is the most prescribed glucose-lowering medication for patients newly diagnosed with type 2 diabetes mellitus (T2DM). Metformin has purported utility for various conditions such as aging, autoimmune conditions, and cancer, however, the primary use of metformin is for blood glucose reduction via decreased glucose production in the liver (increased glycogenesis, decreased glycogenolysis and gluconeogenesis), reduced glucose absorption in the gut, and enhanced insulin-independent skeletal muscle glucose uptake. The effect of metformin within skeletal muscle is the focus of this study.

The mechanism for improved metformin-mediated skeletal muscle glucose uptake involves the inhibition of complex 1 (NADH:ubiquinone oxidoreductase) in the mitochondrial electron transport chain (ETC). This leads to a reduced cellular energy charge, marked by a reduced ATP concentration and increased ratios of ADP:ATP and AMP:ATP. This energetic imbalance initiates phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK), which in turn induces glucose transporter (GLUT4) translocation to the cell membrane and upregulates insulin-independent glucose uptake by skeletal muscle fibers. This cellular energy imbalance and subsequent AMPK signaling cascade is similar to stress elicited by exercise. However, during exercise, the energy imbalance is created by increased ATP utilization from skeletal muscle contraction rather than incomplete glucose metabolism (less ATP per glucose) and an increased reliance on glycolysis.

Exercise training is considered the gold standard approach to enhanced cardiorespiratory fitness and peripheral insulin sensitivity across the lifespan. Metformin also benefits glycemic control and reduces cardiovascular risk. Although the evidence is not conclusive, metformin has been shown to potentially decrease exercise capacity in healthy subjects and those with metabolic syndrome. Importantly, due to the increased reliance on anaerobic metabolism, metformin may reduce the lactate threshold (LT) and lactate turn point (LTP), which are strong predictors of perception of effort, submaximal fitness, and endurance performance. Given cardiorespiratory fitness, strength, glucose control, and insulin sensitivity are predictors of disease, disability, and all-cause mortality, it is important to determine the effects of metformin on cardiorespiratory fitness and physical function.

While these mechanisms of metformin in skeletal muscle are compelling for glucose regulation, there is significant variation in the literature on the effects of metformin on exercise capacity, largely due to differences in dosing (e.g., ~50-500 mg/kg) and exercise intervention design (e.g., acute vs. short-term or chronic exercise and/or submaximal vs. maximal exercise intensity). A recent meta-analysis by found that because previous studies have predominantly used exercise intensities well below VO2max, metformin does not appear to affect maximal oxygen uptake in healthy volunteers; metformin may only alter exercise capacity at high or near-maximal work rates. Thus, there is a lack of data on the effects of metformin on lactate threshold, blood lactate clearance, and exercise-induced fatigue.

Data from this study will provide valuable insight into the effects of metformin compared to placebo on exercise capacity at near-maximal work rates in young, healthy adults. While some studies have examined metformin's impact on exercise performance, these tend to be studies where exercise intensity was well below maximal effort, in highly trained cyclists, or in clinical populations (e.g., individuals with T2DM). Importantly, the results from this study may lead healthy individuals to adjust exercise protocols to accommodate for the decline in performance along with an increased perceived exertion that may accompany metformin consumption. Moreover, this study may fill the gap in literature on a slightly longer timeline for metformin ingestion effects on exercise capacity compared to acute consumption, which may have a more profound impact on cardiorespiratory fitness and capacity over time.

Inclusion Criteria:

• 18-30 years old
• Metformin-naïve
• BMI < 30 kg/m2
• Recreationally active (≥ 3 days/week of exercise)
• Females must be premenopausal and report normal menstrual cycles
• Willingness and ability to comply with scheduled visits and study procedures.

Exclusion Criteria:

• History of cardiometabolic disease, such as type 1 or type 2 diabetes
• Smoking (must have quit at least 6 mos prior)
• Use of medication that significantly alters glucose regulation (e.g., metformin, insulin, GLP-1 receptor agonists, SGLT-2 inhibitors, biguanides)
• Severe liver or kidney disease, or medications to treat liver or kidney disease
• Pregnant, breastfeeding, or plans to become pregnant during study period

Double-blind