Modeling analysis of glucose, insulin, and C-peptide following a meal has been proposed as a means to estimate insulin sensitivity (S i ) and ␤-cell function from a single test. We compared the model-derived meal indexes with analogous indexes obtained from an intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp (HGC) in 17 nondiabetic subjects (14 men, 3 women, aged 50 ؎ 2 years [mean ؎ SE], BMI 25.0 ؎ 0.7 kg/m 2 ). S i estimated from the meal was correlated with S i estimated from the IVGTT and the HGC (r ‫؍‬ 0.59 and 0.76, respectively; P < 0.01 for both) but was ϳ2.3 and 1.4 times higher (P < 0.05 for both). The meal-derived estimate of the ␤-cell's response to a steady-state change in glucose (static secretion index) was correlated with the HGC second-phase insulin response (r ‫؍‬ 0.69; P ‫؍‬ 0.002), but the estimated rate-of-change component (dynamic secretion index) was not correlated with first-phase insulin release from either the HGC or IVGTT. Indexes of ␤-cell function obtained from the meal were significantly higher than those obtained from the HGC. In conclusion, insulin sensitivity and ␤-cell indexes derived from a meal are not analogous to those from the clamp or IVGTT. Further work is needed before these indexes can be routinely used in clinical and epidemiological studies. Diabetes 53:1201-1207, 2004 E stablishing a single test that assesses insulin secretion and insulin sensitivity under normal physiologic conditions is potentially of great value for both epidemiological and clinical studies. To this end, a minimal model estimate of insulin sensitivity based on a meal tolerance test has recently been developed by Caumo et al. (1), and several groups (2-10) have proposed model-based methods for assessing ␤-cell function from arbitrary glucose excursions. The meal-derived estimate of insulin sensitivity [S i(MEAL) ] has been shown to correlate with that obtained from an intravenous glucose tolerance test (IVGTT) [S i(IVGTT) ] (1), but none of the model-based indexes of ␤-cell function have been rigorously compared with estimates of first-and second-phase insulin release obtained from standard tests such as the IVGTT (11-13) or hyperglycemic clamp (HGC) (14 -16).To more fully assess whether indexes of insulin sensitivity and ␤-cell function can both be obtained from a meal test, we measured plasma glucose, insulin, and C-peptide concentrations over a 24-h period. On separate days, an IVGTT and HGC were performed. The IVGTT was used to assess insulin sensitivity [S i(IVGTT) ] and first-phase insulin release [⌽ 1(IVGTT) ]. The HGC was used to assess first-[⌽ 1(HGC) ] and second-phase insulin release [⌽ 2(HGC) ] and to obtain an additional estimate of insulin sensitivity [S i(HGC) ]. These estimates were then compared with analogous estimates of S i and ␤-cell function obtained from the breakfast meal. The role of potentiation in enhancing ␤-cell secretion throughout the day was evaluated by comparing the secretion indexes obtained from breakfast with those obtained from lunch and di...