Population pharmacokinetic/pharmacodynamic modeling of insulin kinetics

The development of type 2 diabetes over time involves defects in insulin action and insulin secretion. Defects in insulin action alone can be compensated with appropriate hyperinsulinemia. However, the progressive loss of pancreatic beta-cell function leads eventually to the development of persistent hyperglycemia that characterizes type 2 diabetes. Insulin secretion patterns reflect two phases when beta-cells are exposed to acute and sustained glucose stimulation. Through the study and understanding of the roles of these two phases in the regulation of glucose homeostasis, it is clear that insulin must not only be secreted in sufficient amounts, but also at the right time. In type 2 diabetes, the timing and magnitude of insulin secretion are altered, and an abnormal first-phase release initiates before the onset of the disease. Only a few pharmacokinetic/pharmacodynamic (PK/PD) models have considered the biphasic nature of insulin secretion. This study is aimed at describing the biphasic dynamics of insulin secretion through developing a PK/PD model based on current knowledge of the cellular mechanism of biphasic insulin secretion.

The objectives of this work are to 1) evaluate the insulin-glucose kinetics using nonparametric analysis, 2) develop a physiologically based mechanistic PK/PD model to dynamically describe the biphasic insulin secretion, 3) evaluate the impact of ethnicity on insulin secretion kinetics following an intravenous glucose administration using population analysis and 4) extend the proposed model to oral glucose administration and utilize the co-secretion kinetics of insulin and C-peptide in a population PK/PD analysis of the prehepatic insulin secretion. Population analysis was done using a nonlinear mixed-effects model combined with the proposed PK/PD model to estimate population parameters and their variations between- and within-subjects and the covariates' effects on model parameters. The proposed model describes biphasic insulin behavior, accounts for first-phase insulin secretion, and also applies to oral glucose administration for estimating prehepatic insulin secretion in vivo and in liver extraction. This is done by an analysis that simultaneously uses plasma insulin and C-peptide concentrations. A significant higher first-phase insulin secretion was identified in healthy youths of African-American compared to Caucasians. The analysis showed no significant differences in the clearance of insulin from the plasma and the liver extraction of insulin between subjects with various levels of glucose tolerance. Obesity leads to a higher insulin production rate and lower elimination rate from the plasma than normal weight subjects. Also, type 2 diabetes and impaired glucose tolerance were found to reduce insulin production rate and resulted in a delayed insulin secretion from the beta-cells.