Semi‐physiological model of postprandial triglyceride response in lean, obese and very obese individuals after a high‐fat meal

Leohr, Jennifer; Heathman, Michael; Kjellsson, Maria C.

doi:10.1111/dom.13138

Cited by 3 publications

(27 citation statements)

References 18 publications

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“…The postprandial TG response of chylomicrons and VLDL‐V6 following a high‐fat meal with placebo treatment was well characterized by the model. The model parameter estimates were comparable with our previously published model, which characterized the TG response in lean, obese and very obese subjects with a similar test meal, but without pharmacological intervention 8 . This provided validity of the application of this lipokinetic model to the data in this study.…”

Section: Discussionsupporting

confidence: 80%

“…As previously published, a semi‐physiological lipokinetic model successfully described the TG concentration versus time profile of both chylomicron and VLDL‐V6 following a high‐ fat meal 8 . This turnover model contained two compartments with rate constants for the production of chylomicron, both first‐ and net zero‐order elimination of VLDL‐V6, and conversion rate of chylomicrons to VLDL‐V6 (k tra ), representing the transfer of TGs released from chylomicrons as non‐esterified fatty acids (NEFAs) that are re‐esterified into TGs in the liver to be released as VLDL.…”

Section: Methodsmentioning

confidence: 77%

“…8 By contrast, total TGs are abundant in the fasted state with a slight postprandial peak. 8 The postprandial TG response of VLDL-V6 was found to represent 80% of the total postprandial TG response (including VLDL V1-V6 subclasses and chylomicrons) after the high-fat meal. 8 Data from this study were used to develop a semiphysiological population lipokinetic model.…”

Section: Introductionmentioning

confidence: 98%

“…Recently, the postprandial TG response following a high‐fat meal was compared among individuals who are lean, obese and very obese (or severely obese) using NMR measurement of lipoprotein particles 8 . Chylomicrons and large VLDL‐V6 particles (VLDL‐V6) were found to represent the postprandial TG response following a high‐fat meal, having low concentrations in the fasted state and a prominent postprandial peak 8 . By contrast, total TGs are abundant in the fasted state with a slight postprandial peak 8 .…”

Section: Introductionmentioning

confidence: 99%

“…Chylomicrons and large VLDL‐V6 particles (VLDL‐V6) were found to represent the postprandial TG response following a high‐fat meal, having low concentrations in the fasted state and a prominent postprandial peak 8 . By contrast, total TGs are abundant in the fasted state with a slight postprandial peak 8 . The postprandial TG response of VLDL‐V6 was found to represent 80% of the total postprandial TG response (including VLDL V1‐V6 subclasses and chylomicrons) after the high‐fat meal 8 .…”

Section: Introductionmentioning

confidence: 99%

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Postprandial triglyceride reduction following acute treatment of a selective 5‐hydroxytryptamine‐2c agonist and characterization using a semi‐physiological model

Leohr

Heathman

Kjellsson

2021

Diabetes Obesity Metabolism

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Aim To investigate the tolerability, pharmacokinetics (PK) and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5‐hydroxytryptamine‐2c (5‐HT2c) agonist in subjects with overweight/obesity and apply mechanistic population pharmacokinetic‐pharmacodynamic modelling to identify a plausible drug mechanism of action. Materials and Methods This phase 1, single‐centre, double‐blind, randomized, placebo‐controlled, four‐period, two‐alternating cohorts study evaluated single escalating oral doses ranging from 5 to 130 mg of LY2140112 (LY) in subjects with overweight/obesity (body mass index: 27–39 kg/m2). Postprandial TG response (total TG, chylomicrons and very low‐density lipoprotein particles [VLDL]‐V6) following a high‐fat meal were assessed for 11 h postmeal for each dose level. The PK profile was assessed for 96 h postdose. Drug exposure and TG concentrations in chylomicrons and VLDL‐V6 were used to characterize the drug mechanism of action using non‐linear mixed‐effect modelling. Results Seventeen subjects entered the study and 16 subjects received at least one dose of LY. LY2140112 was generally well tolerated up to 75 mg. The PK of LY were described by a two‐compartment model with first‐order elimination. The 100 and 130 mg dose levels of LY significantly reduced the postprandial TG of VLDL‐V6 by approximately 50%, while total TG and chylomicrons were not significantly different from placebo. The application of a published lipokinetic model successfully described the postprandial TG response in this study and indicated that LY reduced the conversion of TGs from chylomicron to VLDL‐V6. Conclusions LY significantly reduced the postprandial TG of VLDL‐V6 following a single dose, when food consumption was controlled. The data indicate that a selective 5‐HT2c agonist alters lipid metabolism, beyond the reported reduction in satiety. The application of a semi‐physiological lipokinetic model enabled identification of a plausible drug mechanism of action of LY.

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Section: Discussionsupporting

confidence: 80%

Section: Methodsmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Postprandial triglyceride reduction following acute treatment of a selective 5‐hydroxytryptamine‐2c agonist and characterization using a semi‐physiological model

Leohr

Heathman

Kjellsson

2021

Diabetes Obesity Metabolism

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Impact of Obesity on Postprandial Triglyceride Contribution to Glucose Homeostasis, Assessed with a Semimechanistic Model

Leohr

Kjellsson

2022

Clin Pharma and Therapeutics

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The integrated glucose‐insulin model is a semimechanistic model describing glucose and insulin after a glucose challenge. Similarly, a semiphysiologic model of the postprandial triglyceride (TG) response in chylomicrons and VLDL‐V6 was recently published. We have developed the triglyceride‐insulin‐glucose‐GLP‐1 (TIGG) model by integrating these models and active GLP‐1. The aim was to characterize, using the TIGG model, the postprandial response over 13 hours following a high‐fat meal in 3 study populations based on body mass index categories: lean, obese, and very obese. Differential glucose and lipid regulation were observed between the lean population and obese or very obese populations. A population comparison revealed further that fasting glucose and insulin were elevated in obese and very obese when compared with lean; and euglycemia was achieved at different times postmeal between the obese and very obese populations. Postprandial insulin was incrementally elevated in the obese and very obese populations compared with lean. Postprandial chylomicrons TGs were similar across populations, whereas the postprandial TGs in VLDL‐V6 were increased in the obese and very obese populations compared with lean. Postprandial active GLP‐1 was diminished in the very obese population compared with lean or obese. The TIGG model described the response following a high‐fat meal in individuals who are lean, obese, and very obese and provided insight into the possible regulation of glucose homeostasis in the extended period after the meal by utilizing lipids. The TIGG‐model is the first model to integrate glucose and insulin regulation, incretin effect, and postprandial TGs response in chylomicrons and VLDL‐V6.

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Evaluation of postprandial total triglycerides within the TIGG model for characterizing postprandial response of glucose, insulin, and GLP‐1

Leohr,

Kjellsson

2023

CPT Pharmacom & Syst Pharma

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The TIGG model is the first model to integrate glucose and insulin regulation, incretin effect, and triglyceride (TG) response in the lipoprotein subclasses of chylomicrons and VLDL‐V6. This model described the response following a high‐fat meal in individuals who are lean, obese, and very obese and provided insights into the possible regulation of glucose homeostasis in the extended period following a meal. Often, total TGs are analyzed within clinical studies, instead of lipoprotein subclasses. We extended the existing TIGG model to capture the observed total TGs and determined if this model could be used to predict the postprandial TG response of chylomicron and VLDL‐V6 when only total TGs are available. To assess if the lipoprotein distinction was important for the model, a second model (tTIGG) was developed using only the postprandial response in total TGs, instead of postprandial TG response in chylomicrons and VLDL‐V6. The two models were compared on their predictability to characterize the postprandial response of glucose, insulin, and active GLP‐1. Both models were able to characterize the postprandial TG response in individuals who are lean, obese, or very obese following a high‐fat meal. The extended TIGG model resulted in a better model fit of the glucose data compared to the tTIGG model, indicating that chylomicron and VLDL‐V6 provided additional information compared to total TGs. Furthermore, the expanded TIGG model was able to predict the postprandial TG response of chylomicrons and VLDL‐V6 using the total TGs and could therefore be used in studies where only total TGs were collected.

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Semi‐physiological model of postprandial triglyceride response in lean, obese and very obese individuals after a high‐fat meal

Cited by 3 publications

References 18 publications

Postprandial triglyceride reduction following acute treatment of a selective 5‐hydroxytryptamine‐2c agonist and characterization using a semi‐physiological model

Postprandial triglyceride reduction following acute treatment of a selective 5‐hydroxytryptamine‐2c agonist and characterization using a semi‐physiological model

Impact of Obesity on Postprandial Triglyceride Contribution to Glucose Homeostasis, Assessed with a Semimechanistic Model

Evaluation of postprandial total triglycerides within the TIGG model for characterizing postprandial response of glucose, insulin, and GLP‐1

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