A closed-loop multi-level model of glucose homeostasis

Abstract

BackgroundThe pathophysiologic processes underlying the regulation of glucose homeostasis are considerably complex at both cellular and systemic level. A comprehensive and structured specification for the several layers of abstraction of glucose metabolism is often elusive, an issue currently solvable with the hierarchical description provided by multi-level models. In this study we propose a multi-level closed-loop model of whole-body glucose homeostasis, coupled with the molecular specifications of the insulin signaling cascade in adipocytes, under the experimental conditions of normal glucose regulation and type 2 diabetes.Methodology/Principal findingsThe ordinary differential equations of the model, describing the dynamics of glucose and key regulatory hormones and their reciprocal interactions among gut, liver, muscle and adipose tissue, were designed for being embedded in a modular, hierarchical structure. The closed-loop model structure allowed self-sustained simulations to represent an ideal in silico subject that adjusts its own metabolism to the fasting and feeding states, depending on the hormonal context and invariant to circadian fluctuations. The cellular level of the model provided a seamless dynamic description of the molecular mechanisms downstream the insulin receptor in the adipocytes by accounting for variations in the surrounding metabolic context.Conclusions/SignificanceThe combination of a multi-level and closed-loop modeling approach provided a fair dynamic description of the core determinants of glucose homeostasis at both cellular and systemic scales. This model architecture is intrinsically open to incorporate supplementary layers of specifications describing further individual components influencing glucose metabolism.

An Updated Organ-Based Multi-Level Model for Glucose Homeostasis: Organ Distributions, Timing, and Impact of Blood Flow

“…None of these models have subdivided glucose uptake in the different organs, or included intracellular responses, in multi-level and multiorgan models. There exists one model that does this, developed by Uluseker et al (2018). This multi-level model is based on a version of the Dalla Man model (Dalla Man et al, 2007) connected with our intracellular adipocyte model (Brännmark et al, 2013), while also including hormonal effects on glucose intake/appetite (leptin, ghrelin) and insulin levels (incretin).…”

An organ-based multi-level model for glucose homeostasis: organ distributions, timing, and impact of blood flow

“…None of these models have subdivided glucose uptake in the different organs, or included intracellular responses, in multi-level and multi-organ models. There exists one model that does this, developed by Uluseker et al (Uluseker et al 2018). This multi-level model is based on a version of the Dalla Man model (Dalla Man et al 2007) connected with our intracellular adipocyte model (Brännmark et al 2013), while also including hormonal effects on glucose intake/appetite (leptin, ghrelin) and insulin levels (incretin).…”

A Novel Hybrid Logic-ODE Modeling Approach to Overcome Knowledge Gaps

“…Progresses have been made in implementing hierarchical representations to study how local variations may affect the dynamics at other levels. An example of this approach is the work of Uluseker et al (2018) in which the authors built an ODE model that integrates in a holistic framework the glucose homeostasis together with other regulatory hormones at different levels: gut, liver, and adipose tissue. However, models that span over different levels (e.g., from subcellular to tissue) are difficult to parametrize and implement.…”