A Physiologically‐Based Quantitative Systems Pharmacology Model of the Incretin Hormones GLP‐1 and GIP and the DPP4 Inhibitor Sitagliptin

Abstract

Incretin hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) play a major role in regulation of postprandial glucose and the development of type 2 diabetes mellitus. The incretins are rapidly metabolized, primarily by the enzyme dipeptidyl‐peptidase 4 (DPP4), and the neutral endopeptidase (NEP), although the exact metabolization pathways are unknown. We developed a physiologically‐based (PB) quantitative systems pharmacology model of GLP‐1 and GIP and their metabolites that describes the secretion of the incretins in response to intraduodenal glucose infusions and their degradation by DPP4 and NEP. The model describes the observed data and suggests that NEP significantly contributes to the metabolization of GLP‐1, and the traditional assays for the total GLP‐1 and GIP forms measure yet unknown entities produced by NEP. We further extended the model with a PB pharmacokinetics/pharmacodynamics model of the DPP4 inhibitor sitagliptin that allows predictions of the effects of this medication class on incretin concentrations.

Recent applications of quantitative systems pharmacology and machine learning models across diseases

“…According to this model, dapagliflozin is more beneficial to patients with more inadequate glycemic control by insulin [ 77 ]. Another model (#28) focuses on several protagonists in glucose levels after food consumption [ 78 ]. The incretin hormones, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) catalyzed by enzyme dipeptidyl-peptidase 4 (DPP4), and the neutral endopeptidase (NEP) stimulate insulin release to lower glucose.…”

“…By modeling GLP-1 and GIP dynamics, and PK/PD of DPP4 inhibitors, model #28 showed that inhibition of DPP4 occurs in a dose-dependent manner. Still, the highest dose of DDP4 inhibitor stimulated a high GLP-1 secretion, suggesting the triggering of alternative pathways upon DPP4 inhibition [ 78 ].…”

Study on Optimal Extraction and Hypoglycemic Effect of Quercetin

“…GLP-1 has been identifed as an incretin hormone produced by L cells in the intestine and neurons in the nucleus of the solitary tract (NTS) of the brainstem; together with GLP-1 receptor (GLP-1R), this hormone enhances glycemic control [18][19][20]. DPP-IV activity is associated with the Glp-1 level in plasma [21,22] because native GLP-1 undergoes swift degradation by enzyme dipeptidyl peptidase-IV (DPP-IV) [23]. Stable GLP-1 mimetics and DPP-IV inhibitor drugs have been introduced into clinical practice to treat obesity and T2DM [24].…”