Insulin-dependent diabetes mellitus (IDDM) is characterized by a metabolic and hormonal disarray that may be more evident during exercise. However, the metabolic response to exercise of different intensities has not been evaluated in IDDM. We therefore used stable isotope techniques and indirect calorimetry to quantify substrate kinetics and oxidation during 30 min of exercise at 45 and 75% of maximal oxygen uptake (Vo2max) in seven men with IDDM (D group) infused with insulin at a constant basal rate. Normal control subjects (C group) matched for age, weight, and Vo2max were also studied. During moderate exercise, glucose uptake (Rd) was lower in the D than in the C group (15.3 ± 1.0 vs. 20.8 ± 1.6 μmol · min−1 · kg−1; P < 0.05). Carbohydrate oxidation also tended to be lower in the D group (71.0 ± 7.2 vs. 87.5 ± 10.6 μmol · min−1 · kg−1; P = 0.08). The D group relied on fat oxidation to a greater extent than did the C group (16.9 ± 1.1 vs. 10.4 ± 1.6 μmol · min−1 · kg−1; P < 0.05). The enhanced fat oxidation was not due to increased lipolysis because no differences occurred in glycerol release (Ra) or in plasma free fatty acid Ra or concentration, and the source of the extra lipid appeared to be intramuscular fat stores. These differences in substrate metabolism were not evident during exercise at 75% of Vo2max. The lower glucose uptake and oxidation in the diabetic subjects during moderate, but not intense, exercise suggest that glucose metabolism is regulated differently depending on exercise intensity. During moderate exercise, glucose uptake into muscle seems to be limiting, and the higher intramuscular triglyceride oxidation observed in IDDM might be a compensatory adaptation needed to maintain energy supply.