AbstractLipid and protein ingested before carbohydrate reduce postprandial hyperglycemia. We tested feasibility, safety and clinical efficacy of manipulating the sequence of nutrient ingestion in patients with type 2 diabetes (T2D). After a 4-week run-in, 17 T2D patients were randomized to either a control diet (CD) or to an experimental diet (ED) allowing the consumption of high-carbohydrate foods only after high-protein and high-fat foods at each main meal (lunch+dinner). Both diets were accurately followed and neutral on arterial blood pressure, plasma lipids and indices of hepatic and kidney function. After 8 weeks, in spite of a similar reduction of body weight (ED −1.9 95% confidence interval (−3.4/−0.4)kg, P<0.03; CD −2.0 (−3.6/−0.5)kg, P<0.02) and waist circumference (ED −2.9 (−4.3/−1.5)cm, P<0.002; CD −3.3 (−5.9/−0.7)cm, P<0.02), the ED only was associated with significant reductions of HbA1c (−0.3 (−0.50/−0.02)%, P<0.04), fasting plasma glucose (−1.0 (−1.8/−0.3)mmol l⁻¹, P<0.01), postprandial glucose excursions (lunch −1.8 (−3.2/−0.4)mmol l⁻¹, P<0.01; dinner: −1.0 (−1.9/−0.1)mmol l⁻¹, P<0.04) and other indices of glucose variability (s.d.: −0.5 (−0.7/−0.2)mmol l⁻¹, P<0.02; Coefficient of variation: −6.6 (−10.4/−2.7)%, P<0.02). When compared with the CD, the ED was associated with lower post-lunch glucose excursions (P<0.02) and lower glucose coefficients of variation (P<0.05). Manipulating the sequence of nutrient ingestion might reveal a rapid, feasible, economic and safe strategy for optimizing glucose control in T2D.