Semimechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes

Abstract

The integrated glucose-insulin (IGI) model is a previously published semimechanistic model that describes plasma glucose and insulin concentrations after glucose challenges. The aim of this work was to use knowledge of physiology to improve the IGI model's description of glucose absorption and gastric emptying after tests with varying glucose doses. The developed model's performance was compared to empirical models. To develop our model, data from oral and intravenous glucose challenges in patients with type 2 diabetes and healthy control subjects were used together with present knowledge of small intestinal transit time, glucose inhibition of gastric emptying, and saturable absorption of glucose over the epithelium to improve the description of gastric emptying and glucose absorption in the IGI model. Duodenal glucose was found to inhibit gastric emptying. The performance of the saturable glucose absorption was superior to linear absorption regardless of the gastric emptying model applied. The semiphysiological model developed performed better than previously published empirical models and allows better understanding of the mechanisms underlying glucose absorption. In conclusion, our new model provides a better description and improves the understanding of dynamic glucose tests involving oral glucose.

Modelling gastric emptying: A pharmacokinetic model simultaneously describing distribution of losartan and its active metabolite EXP‐3174

“…A variety of approaches has been proposed in the literature aiming to describe GE within the context of pharmacokinetics. In most cases, GE has been modelled by first‐order rate constants and lag times coupled with different modulating mathematical equations accounting for gastric motor activity, while gastric emptying's relation to caloric density and meal volume has also been taken into consideration …”

“…In most cases, GE has been modelled by first-order rate constants and lag times coupled with different modulating mathematical equations accounting for gastric motor activity, while gastric emptying's relation to caloric density and meal volume has also been taken into consideration. 6,[26][27][28][29][30][31] In this analysis, an appropriate approach to mathematically describe the multiple peaks noted in losartan's and its metabolite's profiles due to GE was sought. DDEs, which practically express the derivative of an equation with a lag time, can mathematically account for delays noted in plasma appearance of the drug as well as for plasma oscillations.…”

Toward Better Understanding of Insulin Therapy by Translation of a PK‐PD Model to Visualize Insulin and Glucose Action Profiles

“…10 The bioavailability parameter for insulin glargine, the k a of regular insulin, and the CL/F for regular insulin showed a relationship with the administered dose amount. 10 A published IGI systems pharmacology model (supplementary equations 1-13) [11][12][13][14][15][16] was used to characterize the blood glucose response following subcutaneous insulin administration ( Figure 1). The key components of the glucose and insulin feedback system are briefly summarized in this section.…”

“…The model has a baseline secretion of insulin, representing pancreatic release of insulin, and clearance of insulin from a central insulin compartment (CL I ), representing insulin elimination from the plasma. [11][12][13][14][15][16] The endogenous pancreatic secretion of insulin is stimulated by elevated glucose amounts and has a nighttime decrease of insulin secretion. 14 First-order rate constants between the central compartments and the effect compartments were used to capture the delays in the effects of glucose and insulin.…”

“…Expanding on a previous analysis that established a pharmacokinetic (PK) model to describe typical profiles of insulin concentration over time following subcutaneous administration of various insulin formulations, 10 the goal of the current analysis was to link the PK model for subcutaneous insulins to an integrated glucose-insulin (IGI) systems pharmacology model. [11][12][13][14][15][16] Although several pharmacology models describing the feedback relationship between insulin and glucose have been developed over the years, 17 the selected glucose-insulin model for this work had a structure that was amenable to joining with the subcutaneous insulin PK model, enabled prospective simulations, and allowed for consideration of population variability. The subsequent linked pharmacokineticpharmacodynamic (PK-PD) model was then used to simulate insulin concentrations and associated blood glucose response following some commonly prescribed insulin-dosing regimens.…”