TY - JOUR

T1 - An Extended Minimal Model of OGTT

T2 - estimation of α- and β-cell dysfunction, insulin resistance, and the incretin effect

AU - Subramanian, Vijaya

AU - Bagger, Jonatan I

AU - Harihar, Vinayak

AU - Holst, Jens J.

AU - Knop, Filip K.

AU - Vilsbøll, Tina

PY - 2024

Y1 - 2024

N2 - Loss of insulin sensitivity, alpha- and beta-cell dysfunction, and impairment in incretin effect have all been implicated in the pathophysiology of type 2 diabetes (T2D). Parsimonious mathematical models are useful in quantifying parameters related to the pathophysiology of T2D. Here we extend the minimum model developed to describe the glucose-insulin-glucagon dynamics in the intravenous glucose infusion (IIGI) experiment to the oral glucose tolerance test (OGTT). The extended model describes glucose and hormone dynamics in OGTT including the contribution of the incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), to insulin secretion. A new function describing glucose arrival from the gut is introduced. The model is fitted to OGTT data from 8 patients with T2D and 8 weight-matched control subjects (CS) without diabetes to obtain parameters related to insulin sensitivity, beta- and alpha-cell function. The parameters, i.e., measures of insulin sensitivity, a 1, suppression of glucagon secretion, k 1, magnitude of glucagon secretion, g 2, and incretin-dependent insulin secretion, g 3, were found to be significantly different between CS and T2D with p values < .002, < .017, < .009, < .004, respectively. A new rubric for estimating the incretin effect directly from modeling the OGTT is presented. The average incretin effect correlated well with the experimentally determined incretin effect with a Spearman Rank test correlation coefficient of .67 (p < .012). The average incretin effect was found to be significantly different between CS and T2D (p <.032). The developed model is shown to be effective in quantifying the factors relevant to T2D pathophysiology.

AB - Loss of insulin sensitivity, alpha- and beta-cell dysfunction, and impairment in incretin effect have all been implicated in the pathophysiology of type 2 diabetes (T2D). Parsimonious mathematical models are useful in quantifying parameters related to the pathophysiology of T2D. Here we extend the minimum model developed to describe the glucose-insulin-glucagon dynamics in the intravenous glucose infusion (IIGI) experiment to the oral glucose tolerance test (OGTT). The extended model describes glucose and hormone dynamics in OGTT including the contribution of the incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), to insulin secretion. A new function describing glucose arrival from the gut is introduced. The model is fitted to OGTT data from 8 patients with T2D and 8 weight-matched control subjects (CS) without diabetes to obtain parameters related to insulin sensitivity, beta- and alpha-cell function. The parameters, i.e., measures of insulin sensitivity, a 1, suppression of glucagon secretion, k 1, magnitude of glucagon secretion, g 2, and incretin-dependent insulin secretion, g 3, were found to be significantly different between CS and T2D with p values < .002, < .017, < .009, < .004, respectively. A new rubric for estimating the incretin effect directly from modeling the OGTT is presented. The average incretin effect correlated well with the experimentally determined incretin effect with a Spearman Rank test correlation coefficient of .67 (p < .012). The average incretin effect was found to be significantly different between CS and T2D (p <.032). The developed model is shown to be effective in quantifying the factors relevant to T2D pathophysiology.

U2 - 10.1152/ajpendo.00278.2023

DO - 10.1152/ajpendo.00278.2023

M3 - Journal article

C2 - 38088864

VL - 326

SP - E182-E205

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

SN - 0193-1849

IS - 2

ER -