Model-Based Quantification of the Systemic Interplay between Glucose and Fatty Acids in the Postprandial State.

Fianne L P Sips,Gunnar Cedersund,Peter Strålfors,Peter A J Hilbers,Elin Nyman,Martin Adiels,Natal A W Van Riel,Zane Andrews

doi:10.1371/journal.pone.0135665

Abstract

In metabolic diseases such as Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease, the systemic regulation of postprandial metabolite concentrations is disturbed. To understand this dysregulation, a quantitative and temporal understanding of systemic postprandial metabolite handling is needed. Of particular interest is the intertwined regulation of glucose and non-esterified fatty acids (NEFA), due to the association between disturbed NEFA metabolism and insulin resistance. However, postprandial glucose metabolism is characterized by a dynamic interplay of simultaneously responding regulatory mechanisms, which have proven difficult to measure directly. Therefore, we propose a mathematical modelling approach to untangle the systemic interplay between glucose and NEFA in the postprandial period. The developed model integrates data of both the perturbation of glucose metabolism by NEFA as measured under clamp conditions, and postprandial time-series of glucose, insulin, and NEFA. The model can describe independent data not used for fitting, and perturbations of NEFA metabolism result in an increased insulin, but not glucose, response, demonstrating that glucose homeostasis is maintained. Finally, the model is used to show that NEFA may mediate up to 30–45% of the postprandial increase in insulin-dependent glucose uptake at two hours after a glucose meal. In conclusion, the presented model can quantify the systemic interactions of glucose and NEFA in the postprandial state, and may therefore provide a new method to evaluate the disturbance of this interplay in metabolic disease.

Highlights

Dysregulation in the postprandial handling of metabolites plays a central role in the development of metabolic diseases such as Type 2 Diabetes (T2D) and Non-alcoholic Fatty Liver Disease
We developed a new mathematical model for the dynamic interplay of non-esterified fatty acids (NEFA) with insulin and glucose metabolism, as detailed in Materials and Methods
The model demonstrates that inhibition of the endogenous glucose production (EGP) by insulin is progressively reduced when the concentration of NEFA is increased during the different clamp conditions (Fig 3A and 3C), and that the inhibitory effect on insulin-dependent glucose uptake is dependent on the concentration of NEFA (Fig 3B and 3D)

Summary

Introduction

Dysregulation in the postprandial handling of metabolites plays a central role in the development of metabolic diseases such as Type 2 Diabetes (T2D) and Non-alcoholic Fatty Liver Disease. This role can be recognized at a systemic level from the clear correlation between obesity and these metabolic diseases, as well as from the evidence that postprandial dysregulation of PLOS ONE | DOI:10.1371/journal.pone.0135665. Model-Based Quantification of Interplay between Glucose and NEFA have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section

Methods

Results

Conclusion