['It is commonly thought that hyperglycaemia results from insufficient compensation of insulin secretion for insulin resistance. To verify this hypothesis, we assessed beta cell function and insulin sensitivity (IS) in a large cohort of volunteers with normal glucose tolerance (NGT) or impaired glucose regulation (IGR), i.e. impaired glucose tolerance or impaired fasting glucose.', 'In men and women with NGT (n=1,123) or IGR(n=156) (age 44 +/- 8 years, BMI 25+/-4 kg/m2, mean +/- SD)we measured: (1) IS by clamp; (2) insulin secretion rates(ISR) and beta cell glucose sensitivity (=slope of the insulin secretion/plasma glucose dose-response) by C-peptide deconvolution and OGTT modelling; and (3) acute insulin response to intravenous glucose.', 'After controlling for centre, sex, age and BMI, fasting and total ISR were inversely related to IS in both groups,whereas beta cell glucose sensitivity was not. Acute insulin response was reciprocally related to IS in both groups, but the relationships were incompatible with inadequate compensation and significance was lost after controlling for fasting ISR. InIGR vs NGT, IS was impaired (92 [75] vs 133 [86] micromol min(-1)[kg fat-free mass](-1) [nmol/l](-1), median [interquartile range],p<0.0001) as was beta cell glucose sensitivity (69 [46] vs 119[83] pmol min(-1) m(-2) [nmol/l](-1), p<0.0001), whereas fasting and total ISR were increased (35% and 25%, respectively, p<0.0001). In fully adjusted models, beta cell glucose sensitivity was the strongest determinant of OGTT glucose levels.'] Is impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance the dominant defect in glucose intolerance?