Project

Discipline

Intramyocellular lipids; Insulin resistance; Aging; Exercise; Intrahepatocellular lipids; Obesity; Mitochondria

Lead
L’insulino-résistance est un facteur crucial pour le développement du diabète de type 2. La prévalence du diabète augmente avec le vieillissement. Des controverses existent actuellement à propos de la contribution du vieillissement dans le développement de la résistance à l’insuline. En effet, il n’est pas clair si cette association est due au vieillissement lui même ou à d’autres facteurs comme l’obésité et l’inactivité physique.
Lay summary
Contenu et objectifs du travail de recherche Notre objectif principal est de contribuer à une meilleure compréhension des facteurs liant l'obésité et la sédentarité à l'insulino-résistance chez les seniors. Parmi les hypothèses, nous explorerons la présence de graisses ectopiques dans le muscle et le foie, ainsi que la capacité du muscle à utiliser ces dépôts graisseux chez des volontaires sains entre 60 et 80 ans, avant et après un programme d'activité physique supervisé de 4 mois.  Contexte scientifique et social du projet de recherche La prévalence élevée de l’obésité et du diabète de type 2 dans la population âgée a des conséquences importantes sur la morbidité et la mortalité qui ont un impact direct sur l’économie de nos sociétés. Cette étude vise à comprendre les mécanismes permettant de prévenir un diabète chez les seniors par la pratique d'activité physique régulière.

Direct link to Lay Summary

Last update: 02.09.2013

Active participation

Self-organised

Active participation

Title	Year

Number	Title	Start	Funding scheme

Insulin resistance is a crucial factor for the development of type 2 diabetes and a major health problem for older adults. Obesity has been linked with insulin resistance. The increasing prevalence of obesity and type 2 diabetes in the older population has important consequences on the morbidity and mortality as well as on the economic burden on our societies. Ectopic lipid depositions, defined as an excess accumulation of triglycerides in non adipose tissues such as in the liver (intra-hepatic lipids, IHCL) and within the muscle fibers (intramyocellular lipids, IMCL), are positively associated with obesity and insulin resistance. Furthermore, the accumulation of intracellular lipids is often cited as being a key determinant in the underlying mechanisms of insulin resistance. In addition of playing an important role in obesity and type 2 diabetes, these ectopic fat depositions are also observed in common conditions such as aging and physical inactivity. Paradoxically, regular physical activity (i.e. exercise training) inverses this association reducing insulin resistance while increasing IMCL. This situation lead to the hypothesis that these ectopic fat depositions do not directly affect insulin action, but that their deleterious effects depend on their stagnation (i.e. poor mobilization) and the accumulation of potentially damaging lipid metabolites, namely diacylglycerols and ceramides. It is not yet clear whether exercise induces remodeling of these ectopic lipid depots; thus the improvements in insulin resistance may be due to the effect of exercise on substrate utilization (by enhancing the capacity of lipid oxidation) or in the reduced formation of specific damaging fatty acid metabolites. Our intervention trial will test in skeletal muscle, liver and heart of obese, insulin-resistant older subjects the overall hypotheses that exercise improvement of fat oxidation capacity and/or decrease of damaging fat metabolites is a primary factor that predicts the improvement in insulin resistance. We utilize novel magnetic resonance techniques, histochemical and biochemical approaches to quantify changes in lipid and oxidative capacity before and after four months of exercise training. These changes will be measured in conjunction with in vivo measures of insulin resistance and fat oxidation. This project will provide novel and integrative information concerning mechanisms by which exercise, by enhancing the capacity of oxidative metabolism of fatty acids and/or decreasing the formation of damaging fat metabolites, can improves insulin resistance in older adults who are at high risk for the development of type 2 diabetes. Ultimately a better understanding of the mechanisms might help to identify therapeutic targets implicated in this metabolic dysregulation. Furthermore, the relationship between two organ specific fat depositions, i.e. the liver (“fatty liver”) and the heart (“fatty heart”), and insulin resistance before and after exercise training will be explored in older subjects with and without obesity. This is of significance as ICL might provide an important link between insulin resistance, obesity, type 2 diabetes and cardiovascular disease. This follow up proposal will allow finishing in good conditions this ambitious translational study. Implementing clinical research is a very intensive task and requires a strong synergistic setting, not only among the collaborators directly involved but also with the structural environment, namely with the different hospital services (Clinical Research Center, Sports Medicine Center, Radiology, Central labs). Some of the delays taken in the first years were not foreseeable, but we are now in excellent conditions to bring to finish this promising study and bring it to fruition.