Whether changes in substrate and insulin levels that occur during peritoneal dialysis (PD) have effects on muscle protein dynamics was evaluated by studying muscle protein synthesis (PS), breakdown (PB), and net protein balance (NB) by the forearm perfusion method associated with the kinetics of 3H-phenylalanine in acute, crossover studies in which PD patients served as their own controls. Studies were performed (1) in the basal state and during PD with dialysates that contained dextrose alone in different concentrations (protocol 1: eight patients), (2) during PD with dialysates that contained dextrose alone or dextrose and amino acids (AA) (protocol 2: five patients), and (3) in time controls (five patients). PD with dextrose alone induced (1) a two- to threefold increase in insulin, as well as a 20 to 25% decrease in AA, mainly BCAA, levels; (2) an insulin-related decline (-18%) in forearm PB (P<0.002); (3) a 20% decrease in muscle PS (P<0.04), which was related to arterial BCAA and K+ (P<0.02 to 0.05); (4) a persistent negative NB; and (5) a decrease in the efficiency of muscle protein turnover, expressed as the ratio NB/PB. PD with dextrose+AA versus PD with dextrose induced (1) similarly high insulin levels but with a significant increase in total arterial AA (+30 to 110%), mainly valine; (2) a reduced release of AA from muscle (P<0.05); and (3) a decrease in the negative NB observed during PD with dextrose, owing to an increase (approximately 20%) in muscle PS, without any further effect on muscle PB. This study indicates that in PD patients in the fasting state, the moderate hyperinsulinemia that occurs during PD with dextrose alone causes an antiproteolytic action that is obscured by a parallel decrease in AA availability for PS. Conversely, the combined use of dextrose and AA results in a cumulative effect, because of the suppression of endogenous muscle PB (induced by insulin) and the stimulation of muscle PS (induced by AA availability). The hypothesis, therefore, is that in patients who are treated with PD, when fasting or when nutrient intake is reduced, muscle mass could be maintained better by the combined use of dextrose and AA.