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Impairments in metabolic flexibility (MF) and substrate handling are associated with metabolic syndrome. However, it is unknown whether metabolic inflexibility causes insulin resistance. We therefore measured MF and substrate handling before and after 8 weeks of overfeeding in initially healthy adults as a model of the early stages of insulin resistance.Twenty-nine healthy men (27 ± 5 years old; body mass index 25.5 ± 2.3 kg m-2) were overfed by 40% above baseline energy requirements for 8 weeks and gained 7.6 ± 2.1 kg of weight. Before and after overfeeding, energy expenditure, substrate oxidation and MF were measured in two ways: (a) during 1 day of eucaloric feeding in a whole-room indirect calorimeter and (b) during a two-step hyperinsulinemic-euglycemic clamp.Eight weeks of overfeeding decreased insulin sensitivity at low and high doses of insulin (P = 0.001 and P = 0.06, respectively). This was accompanied by decreases in the respiratory quotient (RQ) while sleeping (from 0.877 ± 0.020 to 0.864 ± 0.026; P = 0.05) and at low insulin levels during the clamp (from 0.927 ± 0.047 to 0.907 ± 0.032; P = 0.01). Overfeeding did not affect MF as measured during a clamp (P≥0.17), but it tended to increase 24-h MF (awake RQ - sleep RQ) as measured by chamber by 0.010 ± 0.028 (P = 0.08). In terms of substrate oxidation, overfeeding increased protein oxidation by 13 ± 23 g day-1 (P = 0.003) and tended to increase fat oxidation by 6 ± 16 g day-1 (P = 0.07) but did not affect carbohydrate oxidation (P = 0.64). Individuals with greater metabolic adaptation to overfeeding had higher carbohydrate oxidation rates (r = 0.66, P = 8×10-5) but not fat oxidation rates (P = 0.09).The early stages of insulin resistance are accompanied by modest declines in the RQs during sleep and during a clamp, with no changes in fasting RQ or signs of metabolic inflexibility. Our data therefore suggest that metabolic inflexibility does not cause insulin resistance.