The mechanism of the blood glucose-lowering effect of a 2-day very low calorie diet (VLCD; 1890 kJ/d) in combination with the cessation of all blood glucose-lowering agents was studied in 12 (7 women, 5 men) obese (body mass index, 36.3 +/- 1.0 kg/m 2 [mean +/- SEM]) type 2 diabetic patients (age, 55 +/- 4 years; HbA 1c , 7.3% +/- 0.4%) undergoing insulin therapy. Endogenous glucose production (EGP) and whole body glucose disposal (6,6 2 H 2 -glucose), lipolysis ( 2 H 5 -glycerol), and substrate oxidation (indirect calorimetry) rates were measured before and after the intervention in basal and hyperinsulinemic conditions. After 2 days of a VLCD and discontinuation of all blood glucose-lowering therapies, fasting plasma glucose levels did not increase (11.3 +/- 1.3 vs 10.3 +/- 1.0 mmol/L). Basal EGP significantly declined (14.2 +/- 1.0 to 11.9 +/- 0.7 mu mol/kg per minute; P = .009). Basal metabolic clearance rate of glucose and rate of basal lipolysis did not change. During hyperinsulinemia, EGP (5.5 +/- 0.8 to 5.2 +/- 0.5 mu mol/kg per minute), whole body glucose disposal (12.1 +/- 0.7 to 11.3 +/- 1.0 mu mol/kg per minute), the metabolic clearance rate of glucose, and the rate of lipolysis did not change after the 2-day intervention. Cessation of blood glucose-lowering therapy in combination with a 2-day VLCD does not lead to hyperglycemia and is associated with a reduction in basal EGP. Insulin-stimulated whole body glucose disposal did not improve, nor did insulin suppressibility of EGP and lipolysis.