A mechanistic model of macronutrient and energy metabolism to predict individual response to dietary changes

Samuel Burns samuel.p.burns@pwc.com

Abstract

Generalized diet restriction strategies for weight loss are not equally successful across subjects due to inter-individual variability of response to diet changes. Despite the well-recognized importance of weight loss as a preventative and management strategy for chronic diseases like diabetes and cardiovascular disease, physiologically based strategies for designing individualized diets to facilitate quantifiable weight loss do not exist. Tools that use individual subject data to understand the underlying variability and exploit this understanding to optimize dietary intervention to meet weight loss and other health goals are highly desirable, but equally challenging to develop. To address this, we developed and validated a multi-scale system dynamics model to represent human metabolic physiology using a system of ordinary differential and algebraic equations. A top-down approach was used to construct the model. Some processes, such as development of insulin resistance, are represented at the subcellular level, and others are represented at tissue or organ level, such as macronutrient metabolism in adipose tissue. The model reliably represents the processes of macronutrient metabolism and reproduces changes in body weight, fat mass, fat free mass, and molecular markers, such as blood glucose and insulin, in response to changing diet and physical activity. This allows for the ability to predict the effects of diet and activity interventions at an individual level.

Using data from 38 subjects in a yearlong clinical weight loss study conducted at Stanford University, we demonstrated that our model successfully captures individual response to diet restrictions. Training the model to the first 6 months of individual data enables quantitative prediction of body weight, fasting serum glucose and insulin trends 6 months into the future. Through simulation, we found an ensemble of additional diets that are likely to enable each individual to attain specific weight loss goals with the set of optimal diets being different for each individual. This spectrum can be further constrained by adding the goal of normalizing blood glucose levels. The availability of a range of potential diets, as opposed to a single ideal diet, is not only a novel concept but can also be used to improve adherence to a diet plan by allowing greater day-to-day flexibility.
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