Insulin-induced glucose disposal is impaired in Type 2 diabetes mellitus (T2DM). To determine whether insulin-induced suppression of protein breakdown also is impaired, we measured leucine flux (an index of protein breakdown) in diabetic and nondiabetic subjects during a hyperinsulinemic euglycemic clamp. To avoid the confounding effects of a difference in baseline glucose, glucose concentration in the diabetic subjects was normalized by means of an overnight insulin infusion. Despite higher plasma insulin levels (33.5+/-0.05 vs 132+/-2.7 pmol/l, p<01) diabetic subjects had similar amino acid concentrations and leucine flux (96.9+/-5.8 vs 93.4+/-3.7 micromol/kg/h) as nondiabetic subjects. Infusion of insulin (0.5 mU/kg/min) increased insulin levels (p<0.01) to identical levels in both groups (218+/-16 vs 222+/-19), but the glucose infusion required to maintain euglycemia was higher (p<0.01) in nondiabetic than in diabetic subjects, indicating insulin resistance to glucose disposal in the diabetic subjects. In contrast, leucine flux (81.3+/-4.8 vs 81.6+/-3.4 micromol/kg/h) reached identical levels in both groups. The individual and total amino acid levels also were comparable in both groups. We conclude that suppression of whole body protein turnover in response to an acute increase in insulin is normal in people with T2DM. However, chronic adaptation to high insulin levels occurs, thereby enabling protein breakdown and amino acid concentration to remain within the normal range in people with T2DM.