Modeling Hepatic Insulin Sensitivity during a Meal: Validation against the Euglycemic-Hyperinsulinemic Clamp.

We have recently proposed a model describing the suppression of endogenous glucose production (EGP) during a meal. It assumes that EGP suppression depends on glucose concentration and its rate of change, and on delayed insulin action. Hepatic insulin sensitivity (S(I)(Lmeal)) can be derived from EGP model parameters. This model was shown to adequately describe EGP profiles measured with multiple tracer techniques; however S(I)(Lmeal) has never been directly compared with its euglycemic-hyperinsulinemic clamp counterpart (S(I)(Lclamp)). To do so, 62 subjects with different degree of glucose tolerance underwent a triple tracer mixed meal. 57 subjects also underwent a labelled ([3-(3)H]-glucose) euglycemic-hyperinsulinemic clamp. From the triple tracer meal data, virtually model-independent estimates of EGP were obtained using the tracer-to-tracee clamp technique and the EGP model was identified in each subject. Model fit was satisfactory and S(I)(Lmeal) was estimated with good precision. Correlation between S(I)(Lclamp) and S(I)(Lmeal) was good (r=0.72, p<0.001), however, S(I)(Lmeal) was lower than S(I)(Lclamp) (4.60±0.64 vs. 8.73±1.07 10(-4) dl/kg/min per μU/ml, p<0.01). This difference may be due to both different ranges of insulin explored during the two tests (ΔI(clamp)=15.60±1.61 vs. ΔI(meal)= 83.37±10.71 μU/ml) as well as steady vs. nonsteady state glucose and insulin profiles. In conclusion, the new EGP model provides an estimate of hepatic insulin sensitivity during a meal that is in good agreement with that derived in the same individuals with a hyperinsulinemic clamp. When used in conjunction with the minimal model, the approach potentially enables estimation of hepatic insulin sensitivity from a single tracer labeled meal or OGTT.