Amino acid-induced impairment of glucose oxidation by isolated rat muscle: mechanism of action

Aims: High concentrations of amino acids have been reported to impair tissue insulin sensitivity in vitro and in vivo. This has been attributed to activation of the so-called mTOR/p70S6K-pathway, but here we present evidence that amino acids directly modulate glucose oxidation of skeletal muscle via a different mechanism of action.

Methods: Strips of isolated rat soleus muscle were incubated for 2h with a mixture of amino acids (Aminoplasmal®) or with individual amino acids added to the incubation medium. Rates of glucose oxidation and glycogen synthesis were measured during the 2nd hour with or without concomitant insulin stimulation (10 nmol/l). All results are given as % change vs. an intraindividual control.

Results: Addition of mixed amino acids to the incubation medium dose-dependently impaired the oxidation of glucose into CO₂ in isolated rat skeletal muscle (total concentration of amino acids raised by 5, 10, and 20 mmol/l: -16±3%, -25±7%, and -44±4%, respectively; p<0.02 each). This was obviously due to specific inhibition of the oxidative pathway rather than to insulin desensitisation, (i) because glucose flux into alternative intracellular pathways remained unaffected (glycogen synthesis: +1±6%, -5±6%, and -9±8%; ns each) or was even increased (lactate production: +14±5%, +17±4%, and +20±6%; p<0.01 each), and (ii) because the inhibition of glucose oxidation persisted without concomitant insulin stimulation (for 20 mmol/l mixed amino acids: -50±7%; p<0.001). Furthermore, the ability to impair glucose oxidation was restricted to individual amino acids known to be metabolised in skeletal muscle (amino acids metabolised in muscle, 4 mmol/l each: leucine, -39±5%, p<0.001; isoleucine, -29±9%, p=0.02; glycine, -20±5%, p=0.01; amino acids not metabolised in muscle, 4 mmol/l each: methionine, +17±9%, ns; arginine, +5±9%, ns; threonine, -9±5%, ns).

Conclusion: Our results suggest that amino acids impair glucose metabolism of skeletal muscle by competition for mitochondrial oxidation rather than by insulin desensitisation via the mTOR/p70S6K-pathway.