Insulin is anabolic in human skeletal muscle but our knowledge of the dose-response relationships between its availability and protein turnover is poor. We set out to remedy this in studies of 8 healthy men (20.4 ±1.2 y, BMI 23.8 ± 2.6 kg/m2) in whom we measured leg amino acid balance, and rates of appearance and disappearance of D5-phenylalanine (Phe) from arterio-venous concentrations and enrichments of Phe, as indices of leg protein breakdown and synthesis. We made measurements before and during a hyperinsulinaemic-euglycaemic clamp (octreotide (30 ng/kg/min), glucagon (15 ng /kg/h) and 20 % glucose) during mixed amino acid infusion (18 g/h, Glamin?). Leg protein metabolism was measured in the post-absorptive (PA) state and during 3 h of infusion of insulin aimed to achieve plasma concentrations of ~5, ~30, ~80 and ~180 mU/l. In the PA state, leg protein balance was negative, with protein breakdown exceeding synthesis. Infusion of amino acids during insulin availability at a fasting level (~5 mU/l) doubled protein synthesis (P<0.001) with no effect on breakdown, so protein balance became positive. However a modest increase in insulin availability (to a target value of ~15 mU/l) suppressed protein breakdown by ~50% (P<0.001). Thereafter, further increases oin insulin to concentrations higher than those seen post-prandially (i.e. ~ 105 mU/l) caused no further increase in protein balance, or decreases in breakdown. Leg protein synthesis tended to be lower at all insulin concentrations above the fasting value, possibly due to suppression of protein breakdown limiting intracellular availability of amino acids despite the exogenous amino acid supply. The results suggest (i) that no rise in insulin availability is necessary for amino acids to stimulate leg (probably muscle) protein synthesis, and (ii) that the extent of the insulin suppression of leg (muscle) protein breakdown is almost maximal with modest rises of insulin availability – less than seen during normal feeding. Apparently, switching from a net catabolic to a net anabolic state (as on feeding) may be achieved by amino acid-stimulated increases of protein synthesis alone, without any increase in insulin availability. However small increases in insulin, while not further stimulating protein synthesis, markedly suppress protein breakdown to an extent not increased by further increases in insulin availability.