OBJECTIVE: In health, the rise in glucose after lunch is less if breakfast is eaten. We evaluated the second-meal effect in type 2 diabetes. RESEARCH DESIGN AND METHODS: Metabolic changes after lunch in eight obese type 2 diabetic subjects were compared on 3 days: breakfast eaten, no breakfast, and no breakfast but intravenous arginine 1 h before lunch. RESULTS: Despite comparable insulin levels, the rise in plasma glucose after lunch was considerably less if breakfast had been eaten (0.68 +/- 1.49 vs. 12.32 +/- 1.73 vs. 7.88 +/- 1.03 mmol x h(-1) x l(-1); P < 0.0001). Arginine administration almost halved the lunch rise in plasma glucose (12.32 +/- 1.73 vs. 7.88 +/- 1.03 mmol x h(-1) x l(-1)). The plasma free fatty acid concentration at lunchtime directly related to plasma glucose rise after lunch (r = 0.67, P = 0.0005). CONCLUSIONS: The second-meal effect is preserved in type 2 diabetes. Premeal administration of a nonglucose insulin secretagogue results in halving the postprandial glucose rise and has therapeutic potential.