Integrated model of metabolism and autoimmune response in β-cell death and progression to type 1 diabetes

PLoS One. 2012;7(12):e51909. doi: 10.1371/journal.pone.0051909. Epub 2012 Dec 14.

Abstract

Progression to type 1 diabetes is characterized by complex interactions of environmental, metabolic and immune system factors, involving both degenerative pathways leading to loss of pancreatic β-cells as well as protective pathways. The interplay between the degenerative and protective pathways may hold the key to disease outcomes, but no models have so far captured the two together. Here we propose a mathematical framework, an ordinary differential equation (ODE) model, which integrates metabolism and the immune system in early stages of disease process. We hypothesize that depending on the degree of regulation, autoimmunity may also play a protective role in the initial response to stressors. We assume that β-cell destruction follows two paths of loss: degenerative and autoimmune-induced loss. The two paths are mutually competing, leading to termination of the degenerative loss and further to elimination of the stress signal and the autoimmune response, and ultimately stopping the β-cell loss. The model describes well our observations from clinical and non-clinical studies and allows exploration of how the rate of β-cell loss depends on the amplitude and duration of autoimmune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / immunology
  • Autoimmunity
  • Cell Death / immunology
  • Cell Death / physiology
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / physiopathology
  • Disease Progression
  • Humans
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Longitudinal Studies
  • Mice
  • Models, Immunological*

Substances

  • Autoantibodies

Grants and funding

The study was supported by Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012–2017, Decision No. 250114, http://www.symmys.fi/). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.