OBJECTIVE To study the effects of a very low calorie diet (VLCD) on glucose and lipid metabolism in obese subjects, in particular, the effects on insulin sensitivity and the activities of the key enzymes of glucose disposal, glycogen synthase (GS) and the pyruvate dehydrogenase complex (PDHC). METHODS Clinical dietary intervention study (1.67 MJ (400 kcal)/day) until weight loss of > 10%. METHODS 11 (seven male, four female) non-diabetic, obese subjects (age: 27-62 y; BMI: 40.5 +/- 1.4 kg/m2). METHODS Whole body glucose disposal (by euglycemic hyperinsulinemic clamp), respiratory quotient (RQ), resting energy expenditure (REE), glucose and lipid oxidation (by indirect calorimetry), insulin-stimulated PDHC and GS activity (in muscle biopsies) both before and immediately after VLCD (i.e. while still in a hypocaloric state), serum hormone and metabolite levels throughout the dietary period. RESULTS Weight loss was accompanied by reduced insulin and elevated NEFA levels, improved insulin sensitivity due to increased nonoxidative glycolysis with no increase in PDHC or GS activities. The rate of weight loss was inversely related to the initial RQ. PDHCa was strongly age-related. CONCLUSIONS A low RQ may be used as a predictor of the efficacy of VLCD treatment and that while VLCD improves nonoxidative glycolytic flux, changes in oxidative glucose disposal and muscle glucose storage are prevented by high NEFA availability during this catabolic phase of dietary intervention.