Coordinateur: Sergio Polakof  (Equipe Improving)

Context

Diabetes is expanding worldwide, affecting all countries and social classes. In Europe, type 2 diabetes (T2D) is estimated to affect 58.0 M people i.e. 9% of the adult population

One of the particularities of T2D is that it progresses silently for many years before the clinical symptoms and complications appear. The main challenge is therefore to be able to reduce the progression of the disease by promoting a deep population-wide lifestyle change. Unfortunately, the failure to identify at-risk individuals is a barrier to the successful translation of interventions for diabetes prevention into clinical and public health practice. There is therefore, a major need for improving diagnosis and detection of T2D itself, but also new knowledge-based strategies to preclude the occurrence of overt diabetes. However, two major limitations constrain the set-up of these actions:

• T2D is a silent disease that may remain undiagnosed and asymptomatic for many years. Therefore, an earlier detection and diagnosis of T2D onset based on an improved metabolic phenotyping of at risk individuals is evident and urgent, as early interventions might delay or prevent full-blown disease.
• The relative contribution of main organs to T2D onset remains unknown. An improved targeted prevention and therapeutics for T2D based on an organ-specific strategy could be then possible. However,  the current  clinical biomarkers provide whole-body information only, being poorly adapted to investigate the dynamic metabolic role of specific organs during T2D onset.

Objective

The MelODies proposal tackles these two questions by combining integrative physiology with mathematical modelling and network analysis of the metabolism in both animals and humans.

I propose therefore a proof-of-concept based on a novel and innovative approach applying a metabolomics research strategy using quantitative high-throughput arterio-venous differences (AV) across organs involved in the onset of T2D.

The main objective is to determine organ-specific signatures of T2D based on the follow-up of the disease onset in a relevant animal model (multi-catheterized minipig model) and to identify them in routine clinical blood samples (cohorts) that will provide the material for performing liquid metabolic biopsies of the organs implicated in T2D onset.

The resulting insights of MelODies will significantly contribute to the field of T2D research for early diagnosis. It could also lead to the development of innovative early diagnosis tools and organ-targeted therapeutic strategies.

Impact

• Towards personalized diagnosis and treatment. Having access to each organ metabolism from a single blood sample will allow to:

(i) Design personalized (organ-targeted) strategies to preven nutritionally and medicine-free the development of T2D.

(ii) Provide a pharmacological treatment, given that the specificity of biomarkers will allow developing interventions specifically targeting the altered organs or metabolic routes.

 (iii) Apply this strategy in epidemiological studies aiming at predict T2D appearance in population.

• Development of diagnostic tools. Data and results provided by MelODies could also impact the biomedical field thanks to their potential to be integrated in rapid analysis kit aiming at monitoring patients at risk of T2D. A single kit could contain the necessary biomarkers to make available a fast assessment of the phenotype, indicating for a given patient at that time which organ is affected.
• Data availability for the scientific community and integration in more ambitious projects.

(i) After publication, metabolomics data from MelODies will be available to the scientific community in an Open Access way through the European metabolomics repository MetaboLights (ebi.ac.uk/metabolights).

(ii) Since 2018, I participate to the Health EU research initiative (health-eu.eu) aiming at develop a personalized healthcare and disease prevention system based on human avatars. MelODies human data could be integrated in the initiative to “feed” the developed avatars.

• Beyond the metabolic liquid biopsy for T2D. If validated, the proof-of-concept could be applied to other pathophysiological conditions in which metabolic dysregulation of single organs could be expected, such as the steatosis or cirrhosis (liver) or Crohn’s disease (intestine).