The dietary protein requirements of patients with insulin-dependent diabetes mellitus (IDDM) are unknown. We studied the metabolic adaptation of IDDM patients with early nephropathy to therapeutic, low-protein diets. Six patients were studied at baseline and following 1 and 12 weeks of consuming 0.6 g/kg-1 ideal body weight.day-1 protein. Outcome variables included quadriceps muscle strength, body composition, nitrogen balance, and estimates of whole body protein turnover using an infusion of L-[1-13C]leucine. All subjects experienced decreased muscle strength (6.6% decline in maximal torque, P = 0.05) and increased body fatness (11% increase in fat mass, P = 0.03) with no change in total body weight. This was accompanied by an initial 40% decrease in the rate of whole-body leucine oxidation after 1 week of dietary restriction which returned almost to baseline rates by 12 weeks (P less than 0.001, 1 week vs. 12 weeks). Nitrogen balance remained negative throughout the period of protein restriction. We conclude that IDDM subjects with early nephropathy experience protein undernutrition during the first 3 months of the dietary protein restriction currently recommended for the treatment of nephropathy. This may result, in part, from an inability to conserve essential amino acids from oxidative loss over the time period of the study.