Abstract
5´AMP–activated protein kinase (AMPK) is a mediator of a healthy metabolic phenotype in skeletal muscle. Metformin may exacerbate the energy disturbances observed during exercise leading to enhanced AMPK activation, and these disturbances may provoke early muscular fatigue. We studied acute (1 day) and short‐term (4 days) effects of metformin treatment on AMPK and its downstream signaling network, in healthy human skeletal muscle and adipose tissue at rest and during exercise, by applying a randomized blinded crossover study design in 10 lean men. Muscle and fat biopsies were obtained before and after the treatment period at rest and after a single bout of exercise. Metformin treat ment elicited peak plasma and muscle metformin concentrations of 31 μM and 11 μM, respectively. Neither of the treatments affected AMPK activity in skeletal muscle and adipose at rest or during exercise. In contrast, whole‐body stress during exercise was elevated as indicated by increased plasma lactate and adrenaline concentrations as well as increased heart rate and rate of perceived exertion. Also whole‐body insulin sensitivity was enhanced by 4 days metformin treatment, that is reduced fasting plasma insulin and HOMA‐IR. In conclusion, acute and short‐term metformin treatment does not affect energy homeostasis and AMPK activation at rest or during exercise in skeletal muscle and adipose tissue of healthy subjects. However, metformin treatment is accompanied by slightly enhanced perceived exertion and whole‐body stress which may provoke a lesser desire for physical activity in the metformin‐treated patients.
Highlights
Metformin is the most prevalent drug for treatment of type II diabetic patients and other patient groups with decreased insulin sensitivity (Boyle, Salt, & McKay, 2010)
Whole-body stress during exercise was elevated as indicated by increased plasma lactate and adrenaline concentrations as well as increased heart rate and rate of perceived exertion
In the present study we investigated whether acute (A-MES) or short-term metformin treatment (ST-MES) per se activates AMPK in skeletal muscle and abdominal subcutaneous adipose tissue, and whether metformin treatment potentiates AMPK activation during exercise
Summary
Metformin is the most prevalent drug for treatment of type II diabetic patients and other patient groups with decreased insulin sensitivity (Boyle, Salt, & McKay, 2010). Watt et al reported increased AMPK activity after 90 min cycle ergometer exercise whereas our laboratory did not observe AMPK activation after 40 min one-legged knee extensor exercise with superimposed arm cranking to increase sympatho-adrenal activity (Kristensen et al, 2007) Whereas both long-term metformin treatment and acute exercise per se have been verified as AMPK activators in skeletal muscle and adipose tissue, the acute effect of metformin treatment on AMPK activation in human skeletal muscle and adipose tissue at rest and during exercise has not been described. We hypothesized that acute metformin treatment increases AMPK activity and signaling in human skeletal muscle and adipose tissue. This hypothesis we used 1 or 4 days metformin/placebo treatment of healthy subjects in combination with an acute bout of one-legged knee extensor exercise
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