Contribution of Insulin-Stimulated Glucose Uptake and Basal Hepatic Insulin Sensitivity to Surrogate Measures of Insulin Sensitivity

Abstract

OBJECTIVE—The goal of this study was to evaluate the performance of surrogate measures of insulin sensitivity and insulin secretion. RESEARCH DESIGN AND METHODS—The homeostasis model assessment (HOMA) of insulin resistance (IR) and the insulin sensitivity index (Si) from oral glucose tolerance test (OGTT) were compared with the M value from a hyperinsulinemic-euglycemic clamp in 467 subjects with various degrees of glucose tolerance. Endogenous glucose production (EGP) and hepatic insulin sensitivity were determined in a subset (n = 143). Insulin secretion was estimated as the HOMA β-cell index and as the insulinogenic index from the first 30 min of the OGTT (I/G30) and compared with the first-phase insulin response (FPIR) to an intravenous glucose tolerance test (n = 218). RESULTS—The M value correlated with the HOMA-IR (r = −0.591, P < 0.0001) and the Si (r = 0.533, P < 0.0001) indexes in the total study group. HOMA-IR correlated with basal EGP in the total study group (r = 0.378, P < 0.0005) and in subjects with diabetes (r = 0.330, P = 0.01). However, neither HOMA-IR nor Si correlated significantly with the M value in subjects with impaired fasting glucose (IFG) (r = −0.108, P = 0.5; r = 0.01, P = 0.9) or IFG/impaired glucose tolerance (IGT) (r = −0.167, P = 0.4; r = 0.09, P = 0.6). The HOMA-IR correlated with hepatic insulin sensitivity in the whole study group (r = −0.395, P < 0.005) as well as in the IFG/IGT subgroup (r = −0.634, P = 0.002) and in the diabetic subgroup (r = −0.348, P = 0.008). In subjects with IFG/IGT, hepatic insulin sensitivity was the most important determinant of HOMA-IR, explaining 40% of its variation. The HOMA β-cell index showed a weak correlation with FPIR in the whole study group (r = 0.294, P = 0.001) but not in the subgroups. In contrast, the I/G30 correlated with FPIR in the whole study group (r = 0.472, P < 0.0005) and in the IFG/IGT subgroup (r = 0.493, P < 0.005). CONCLUSIONS—HOMA-IR is dependent upon both peripheral and hepatic insulin sensitivity, the contribution of which differs between subjects with normal and elevated fasting glucose concentrations. These discrepancies develop as a consequence of a nonparallel deterioration of the variables included in the equations with worsening of glucose tolerance.