DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

Identification of biomarkers of beta-cell stress and inflammation by exploring inter-organ communication inpreclinical models of obesity and type 2 diabetes – betadiamark

Submission summary

Insulin secretion by pancreatic beta-cell plays a key role in the control of glucose homeostasis by stimulating glucose uptake and utilization by liver, fat, and muscles. The balance between insulin secretion and action on peripheral tissues is in dynamic equilibrium and when insulin resistance develops in peripheral tissues, in conditions such as pregnancy, obesity, or aging, the pancreatic beta-cells increase their insulin secretion capacity and their number. Type 2 diabetes (T2D), a hyperglycemic syndrome, appears when the beta-cells are no longer able to compensate for the insulin resistance of peripheral tissues. In healthy conditions, the beta-cell plasticity required to preserve normoglycemia is controlled by many signals, in particular derived from the insulin-target tissues. Under metabolic stress conditions induced by excess consumption of energy-rich diets, insulin resistance in target tissues leads to the secretion of different types of inflammatory molecules, including several classes of lipids and cytokines. These can combine with cytokines secreted by activated inflammatory cells to negatively impact on beta-cell function and viability. Therefore, changes in insulin target tissues under metabolic stress can induce beta-cell dysfunctions through the release in the blood of beta-cell active molecules.
The overall objective of this research proposal is to investigate the link between metabolic dysfunctions induced in insulin target tissues by calorie-rich diet feeding and the induction of beta-cell dysfunction. To this end two strains of mice (C57Bl6 and DBA2), known for their differential response to metabolic stresses, will be fed a normal chow or a high fat diet (HFD) for different periods of time and key parameters of beta-cell function and insulin action will be determined and plasma lipidomic and cytokine profile will be analyzed. Islets, liver, adipose tissue (visceral and subcutaneous depot), skeletal muscle (soleus and tibialis anterior) will be isolated for mRNA extraction and profiling by RNASeq analysis. These data will be analyzed in four major steps: 1) identification of gene modules in each tissue that correlate with the measured parameters of beta-cell function and of insulin action; 2) identification of plasma lipid and cytokine modules that correlate with the measured physiological parameters; 3) for those plasma lipids and cytokines that correlate with beta-cell dysfunction, analyze their direct effect on mouse islets and human beta-cell lines; 4) identify which lipid metabolic pathways in insulin target tissues may lead to the production of the plasma lipids that impact on beta-cell function. This systems biology investigation of metabolic stress-induced deregulation of glucose homeostasis will generate a new integrated view of changes in insulin target tissue transcriptome that is associated with, and may cause beta-cell demise through production and release in the plasma of bioactive molecules. This approach may lead to the identification of novel biomarkers for progression to T2D, which could also be new targets for drug or lifestyle intervention in treatment of diabetes. This proposal is based on previous work of this group of investigators performed in the frame of a EU IMI project that ends in September 2015.

Project coordination

Magnan Christophe (Unité de biologie fonctionnelle et adaptative)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM Institut National de la Santé et de la Recherche Médicale
SIB SIB Swiss Institute of Bioinformatics
UNIL Center for Integrative Genomics University of Lausanne
BFA Unité de biologie fonctionnelle et adaptative

Help of the ANR 399,965 euros
Beginning and duration of the scientific project: October 2015 - 36 Months

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