A model-based method was developed to quantify pancreatic beta-cell responsiveness during a meal tolerance test (MTT). C peptide secretion was related in a linear fashion to glucose concentration, whereas the standard population model was used to derive transfer rate constants of the two compartmental model of C peptide kinetics. Two indexes of pancreatic beta-cell responsiveness were defined: 1) postprandial sensitivity M(I) (ability of postprandial glucose to stimulate beta-cell), and 2) basal sensitivity M0 (ability of fasting glucose to stimulate beta-cell). The method was evaluated using plasma glucose and C peptide measured over 180 min with a 10- to 30-min sampling interval during a MTT (75 g carbohydrates; 500 Cal) performed in 16 normal subjects (7 men and 9 women; age, 50 +/- 10 yr; body mass index, 29.2 +/- 3.6 kg/m2; fasting plasma glucose, 5.1 +/- 0.5 mmol/L; mean +/- SD) and 16 body mass index-matched subjects with newly diagnosed noninsulin-dependent diabetes mellitus (NIDDM; 15 men and 1 woman; age, 50 +/- 9 yr; body mass index, 29.3 +/- 3.7 kg/m2; fasting plasma glucose, 12.6 +/- 3.2 mmol/L). M(I) and M0 indexes were estimated with very good precision (coefficient of variation, < 15%). Subjects with NIDDM demonstrated lower postprandial sensitivity M(I) (17.7 +/- 11.4 vs. 90.0 +/- 43.3 x 10(-9)/min; NIDDM vs. normal, P < 0.001) and basal sensitivity M0 (5.4 +/- 2.2 vs. 10.3 +/- 4.9 x 10(-9)/min; P < 0.005). Deconvolution analysis documented that the relationship between C peptide secretion and glucose concentration is approximately linear during MTT in both normal subjects (plasma glucose range, 5-8 mmol/L) and subjects with NIDDM (12-17 mmol/L). We conclude that pancreatic responsiveness during glucose stimulation (M(I)) and under basal conditions (M0) can be obtained from this novel method during MTT in healthy and disease states.