The relationship between the insulin sensitivity index (SI) and the acute insulin response to glucose (AIRg) has been shown to be hyperbolic for indices derived from an intravenous glucose tolerance test. Based on this relationship, the disposition index (SI x AIRg) provides a measure of β-cell function and has been shown to be significantly lower in subjects at risk for diabetes (DM). We postulated that a similar hyperbolic relationship exists between measures of insulin sensitivity and insulin release derived from an oral glucose tolerance test (OGTT). 653 (276M/ 377F) first-degree relatives with no known history of DM underwent an OGTT. Of these, 242 were classified as being normal glucose tolerant (NGT), 292 as impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT) and 119 as DM. Insulin sensitivity was determined as 1/HOMA-IR and insulin release as the ratio of the incremental changes from 0-30 minutes in insulin and glucose (ΔI30/ΔG30). By regression analysis, the relationship between 1/HOMA-IR and ΔI30/ΔG30 was hyperbolic in all three groups. This was demonstrated with a linear fit between ln(1/HOMA-IR) and ln(ΔI30/ΔG30) having a slope not significantly different from -1 (mean±SD; NGT: slope = -1.12±0.08, r2 = 0.42; IFG/IGT: slope = -1.05±0.09, r2 =0.33; and DM: slope =-1.3±0.96, r2 =0.02). The curve fit for subjects with IFG/IGT fell below and to the left of NGT consistent with β-cell dysfunction. That for subjects with DM was below and to the left of that for IFG/IGT. When 1/HOMA-IR*ΔI30/ΔG30 was calculated to provide a measure of the adjusted insulin response, it was significantly lower in the IFG/IGT and DM groups (NGT:15.9±0.7 mM-2; IFG/IGT 8.5±0.4; DM 4.0±0.5; p≤0.001 for comparisons between each group). Based on the finding of this hyperbolic relationship, this adjusted insulin response (1/HOMA-IR*ΔI30/ΔG30) may be a useful tool to estimate β-cell function in large population studies based on an OGTT.