The intravenous glucose tolerance test (IVGTT) single-compartment minimal model (1CMM) method has recently been shown to overestimate glucose effectiveness and underestimate insulin sensitivity. Undermodeling, i.e., use of single- instead of two-compartment description of glucose kinetics, has been advocated to explain these limitations. We describe a new two-compartment minimal model (2CMM) into which we incorporate certain available knowledge on glucose kinetics. 2CMM is numerically identified using a Bayesian approach. Twenty-two standard IVGTT (0.30 g/kg) in normal humans were analyzed. In six subjects, the clamp-based index of insulin sensitivity (ScI) was also measured. 2CMM glucose effectiveness (S2G) and insulin sensitivity (S2I) were, respectively, 60% lower (P < 0.0001) and 35% higher (P < 0.0001) than the corresponding 1CMM S1G and S1I indexes: 2.81 +/- 0.29 (SE) vs. S1G = 4.27 +/- 0.33 ml. min(-1). kg(-1) and S2I = 11.67 +/- 1.71 vs. S1I = 8.68 +/- 1.62 10(2) ml. min(-1). kg(-1) per microU/ml. S2I was not different from ScI = 12.61 +/- 2.13 10(2) ml. min(-1). kg(-1) per microU/ml (nonsignificant), whereas S1I was 60% lower (P < 0.02). In conclusion, a new 2CMM has been presented that improves the accuracy of glucose effectiveness and insulin sensitivity estimates of the classic 1CMM from a standard IVGTT in normal humans.