The Onset of Type 2 Diabetes: Proposal for a Multi-Scale Model

Abstract

BackgroundType 2 diabetes mellitus (T2D) is a common age-related disease, and is a major health concern, particularly in developed countries where the population is aging, including Europe. The multi-scale immune system simulator for the onset of type 2 diabetes (MISSION-T2D) is a European Union-funded project that aims to develop and validate an integrated, multilevel, and patient-specific model, incorporating genetic, metabolic, and nutritional data for the simulation and prediction of metabolic and inflammatory processes in the onset and progression of T2D. The project will ultimately provide a tool for diagnosis and clinical decision making that can estimate the risk of developing T2D and predict its progression in response to possible therapies. Recent data showed that T2D and its complications, specifically in the heart, kidney, retina, and feet, should be considered a systemic disease that is sustained by a pervasive, metabolically-driven state of inflammation. Accordingly, there is an urgent need (1) to understand the complex mechanisms underpinning the onset of this disease, and (2) to identify early patient-specific diagnostic parameters and related inflammatory indicators.ObjectiveWe aim to accomplish this mission by setting up a multi-scale model to study the systemic interactions of the biological mechanisms involved in response to a variety of nutritional and metabolic stimuli and stressors.MethodsSpecifically, we will be studying the biological mechanisms of immunological/inflammatory processes, energy intake/expenditure ratio, and cell cycle rate. The overall architecture of the model will exploit an already established immune system simulator as well as several discrete and continuous mathematical methods for modeling of the processes critically involved in the onset and progression of T2D. We aim to validate the predictions of our models using actual biological and clinical data.ResultsThis study was initiated in March 2013 and is expected to be completed by February 2016.ConclusionsMISSION-T2D aims to pave the way for translating validated multilevel immune-metabolic models into the clinical setting of T2D. This approach will eventually generate predictive biomarkers for this disease from the integration of clinical data with metabolic, nutritional, immune/inflammatory, genetic, and gut microbiota profiles. Eventually, it should prove possible to translate these into cost-effective and mobile-based diagnostic tools.

Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation

“…Although the causes of b cell dysfunction are multifactorial [4], inflammation, especially the local inflammation in the islets, is thought to play a critical role in the pathogenesis of b cell defects [5À10]. Glucotoxicity, lipotoxicity, oxidative and amyloid stress are prevailing contributors in T2DM islet dysfunction through direct and indirect inflammatory responses [6,11À15].…”

Effects of walking on low-grade inflammation and their implications for Type 2 Diabetes

“…The level of glucose tolerance does not seem to influence the final outcome. An objective assessment in wider population studies, analysing the role played by different duration and intensity could facilitate the definition of a dose–response relationship that could be useful in defining a model of the inflammatory process ( Castiglione et al, 2013 ).…”

A Mathematical Model of Interleukin-6 Dynamics during Exercise

“…This model constitutes the first step in describing the complete immune system response during exercise and paves the way to the mathematical description of the physiological effects of exercise on the metabolic system [14]. …”