Application of modified Watanabe's approach for reconstruction of insulin secretion rate during OGTT under non-constant fraction of hepatic insulin extraction

In this study, insulin and C-peptide concentration are used to assess the rate of insulin production. First, the data of insulin and C-peptide concentrations during OGTT are generated from an extended combined model (Watanabe et al., 1998). Two different patterns of the fraction of hepatic insulin extraction in the extended combined model are utilized to generate the data of insulin and Cpeptide concentrations. On the one hand, the fraction is assumed constant. On the other hand, a non-constant fraction is used. Watanabe's approach (Watanabe et al., 1998) designed from the extended combined model, assuming constant fractional hepatic extraction, is then used to quantify the rate of insulin production from insulin and C-peptide concentrations generated from the extended combined model with both patterns of fraction of hepatic extraction. It is found that the Watanabe's approach is appropriate for the estimation of the kinetic parameters and the rate of insulin production in the extended combined model only when fractional hepatic extraction is constant. However, Watanabe's approach cannot be relied upon for accurate estimation when the fractional hepatic extraction is not constant. Since there is clinical evidence that the fractional hepatic extraction is not constant during OGTT, the modification of Watanabe's approach is necessary to accommodate variations in the fractional hepatic extraction. The modified approach proposed in this work is able to provide the accurate estimate of the rate of insulin production from the data generated by the extended combined model in the situation where the fractional hepatic extraction is not constant