Summary:
Metformin is widely prescribed as a first-line medication for elevated blood glucose and is known to reduce the risk of cardiovascular disease. In the United States, over 30 million adults have diabetes, and metformin remains one of the most commonly used treatments. Despite its benefits, evidence suggests that metformin may interfere with some exercise-induced metabolic adaptations. However, it is unclear whether these effects depend on exercise intensity. This study is a double-blind, placebo-controlled randomized trial, which tested the hypothesis that metformin reduces exercise-induced improvements in vascular insulin sensitivity in an intensity-dependent manner among adults at risk for metabolic syndrome. Participants were randomly assigned to one of four groups for 16 weeks: low-intensity exercise with placebo (22 participants), low-intensity exercise with metformin (21 participants), high-intensity exercise with placebo (24 participants), or high-intensity exercise with metformin (24 participants). Exercise was performed five days per week at prescribed intensities. Vascular insulin sensitivity was assessed before and after the intervention, along with inflammatory markers, aerobic fitness, and body composition. Exercise training with placebo at both low and high intensity improved aerobic fitness, whereas these improvements were not observed in participants taking metformin. Reductions in body fat occurred in both high-intensity groups regardless of metformin use. Metformin blunted exercise-induced improvements in vascular insulin sensitivity compared with placebo and attenuated training-related reductions in fasting glucose and inflammatory markers. These findings indicate that metformin reduces some of the beneficial vascular, metabolic, and inflammatory adaptations to exercise. In the context of widespread metformin use among adults with or at risk for diabetes, these results highlight the importance of considering how metformin may interact with exercise-based interventions.
Abstract:
Context: Metformin is the first-line pharmacotherapy for treating hyperglycemia, and it lowers cardiovascular disease risk. Prior work suggests that metformin can, however, interfere with metabolic adaptations to exercise. To date, no work has tested if metformin (Met) alters exercise training mediated vascular insulin sensitivity, and whether this is exercise intensity dependent.
Objective: This work aimed to test the hypothesis that Met blunts vascular insulin sensitivity in an intensity-based manner among adults at risk for metabolic syndrome.
Methods: In a double-blind, placebo-controlled trial, participants were randomly assigned to low-intensity exercise plus placebo (∼55% VO2max 5d/wk, LoEx + PL, n = 22) or metformin (2000 mg/d, LoEx + Met, n = 21) and high-intensity exercise plus placebo (∼85% VO2max 5d/wk, HiEx + PL, n = 24) or metformin (HiEx + Met, n = 24) for 16 weeks. A 120-minute euglycemic-hyperinsulinemic clamp (40 mU/m2/min, 90 mg/dL) was conducted pre and post treatment to assess macrovascular insulin sensitivity via brachial artery flow-mediated dilation (%FMD, conduit artery) as well as microvascular insulin sensitivity using contrast-enhanced ultrasound (eg, microvascular blood volume [MBV, perfusion] and microvascular blood flow [MBF]). Fasting and clamp-derived glucose, insulin, inflammatory measures (eg, endothelin-1 [ET-1], tumor necrosis factor α [TNF-α], soluble receptor for advanced glycation end products [sRAGE]), and nitric oxide (nitrite/nitrate) were assessed. Aerobic fitness (maximal oxygen consumption [VO2max]) and body composition (dual-energy x-ray absorptiometry [DXA]) were also analyzed.
Results: LoEx + PL and HiEx + PL increased VO2max (both P < .05), while there was no change after LoEx + Met or HiEx + Met. Body fat was reduced following HiEx + PL and HiEx + Met only (both P < .05). Met blunted the increase in insulin-stimulated FMDallometric and MBF seen with LoEx + PL and HiEx + PL (P < .05). Met also attenuated the reductions in fasting glucose, ET-1, and TNF-α compared with LoEx + PL and HiEx + PL (P < .05).
Conclusion: Met blunts exercise training-mediated increases in vascular insulin sensitivity at the levels of conduit arteries and capillaries, in parallel with altered inflammation and glycemic benefits.
Article Publication Date: 07/10/2025
DOI: 10.1210/clinem/dgaf551
