A Population Kinetic Analysis of Prehepatic Insulin Secretion

Introduction

Quantitative estimation of pancreatic insulin release is necessary for the understanding of the pathogenesis of type 2 diabetes (T2D), which is characterized by a progressive loss of beta-cell function.1 However, direct measurement of insulin secretion rate (ISR) from beta-cells in a human is not feasible because of the need for prehepatic blood sampling. The plasma insulin concentration is accessible in vivo, but that only provides information about the posthepatic insulin delivery because insulin released from the beta-cells is partly extracted by the liver before entering the circulation.2 However, the ISR can be quantified indirectly using plasma C-peptide (CP) data based on the fact that CP and insulin are secreted at an equal molar ratio.3 The deconvolution technique4–(6) can reconstruct ISR from the time course of CP and its disposition kinetics. The required CP kinetics can be acquired in a separate experiment in the same subjects4 or, alternatively, by using parameter values from population analysis.7 Another choice is the “combined model”8–(10) that combines insulin and CP data in a single experiment analysis. The advantage of the combined model approach is the combined use of insulin and CP kinetics and does not require a prior knowledge of the CP kinetic parameter. However, the combined model does not accurately estimate the second-phase of insulin secretion11 and does not evaluate the effect of glucose on insulin secretion. The minimal model of insulin secretion12–(14) can quantify both the ISR and the glucose effect on ISR. However, the minimal model describes insulin and CP kinetics separately and does capture the insulin concentration profiles well under oral glucose load.12

Abstract

Keywords

insulin secretion, insulin extraction, oral glucose tolerance test, insulin modeling, glucose tolerance, population analysis