This study compared classical and model-based beta-cell responses during an oral glucose tolerance test (OGTT) and a meal tolerance test (MTT) in a population-based cohort. Individuals with normal glucose metabolism (NGM, n=161), impaired glucose metabolism (IGM, n=19) and type 2 diabetes mellitus (DM, n=20) underwent a 75 g-OGTT and an MTT (75 g carbohydrates, 50 g fat, 24 g proteins). Classical estimates of beta-cell function (insulinogenic index and the ratio of areas under insulin and glucose curves) were calculated. Mathematical modelling was used to determine beta-cell glucose sensitivity, rate sensitivity and potentiation. Insulin sensitivity was characterized by three surrogate estimates. Both classical and model-based estimates of beta-cell function were higher during MTT than during OGTT (P<0.05). Regarding the model-based parameters, especially beta-cell sensitivity was increased following MTT as compared with OGTT (P<0.05). Both during OGTT and MTT, across most parameters describing beta-cell function, the largest reduction in beta-cell response occurred between IGM and DM, while the largest reduction in insulin sensitivity occurred between NGM and IGM. We conclude that beta-cell response is stronger after a mixed meal than after an OGTT with equal carbohydrate quantity, both for classical and model-based parameters. The higher response was mostly explained by higher beta-cell sensitivity during the meal.