Metformin Blunts Vascular Insulin Sensitivity After Exercise Training in Adults at Risk for Metabolic Syndrome

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.