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Insulin resistance of aging, ectopic lipid depositions and oxidative capacity: effects of exercise and obesity

Applicant Amati Francesca
Number 149398
Funding scheme Ambizione
Research institution Institute of Sport Science and DSB Department of Biomedical Science Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Endocrinology
Start/End 01.10.2013 - 30.09.2015
Approved amount 299'996.00
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All Disciplines (8)

Discipline
Endocrinology
Pathophysiology
Clinical Endocrinology
Biophysics
Metabolic Disorders
Geriatrics
Sport Medicine
Physiology : other topics

Keywords (7)

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

Lay Summary (French)

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

Responsible applicant and co-applicants

Employees

Publications

Publication
Muscle characteristics and substrate energetics in lifelong endurance athletes
Dubé John J., Broskey Nicholas T., Despines Alex A., Stefanovic-Racic Maya, Toledo Frederico G.S., Goodpaster Bret H., Amati Francesca (2016), Muscle characteristics and substrate energetics in lifelong endurance athletes, in Medicine & Science in Sports & Exercise, 48(3), 472-80.
Exercise efficiency relates with mitochondrial content and function in older adults
Broskey N. T., Boss A., Fares E. J., Greggio C., Gremion G., Schluter L., Hans D., Kreis R., Boesch C., Amati F. (2015), Exercise efficiency relates with mitochondrial content and function in older adults, in Physiol Rep, 3, e12418.
Separation of small metabolites and lipids in spectra from biopsies by diffusion-weighted HR-MAS NMR: a feasibility study
Diserens G., Vermathen M., Precht C., Broskey N. T., Boesch C., Amati F., Dufour J. -F., Vermathen P. (2015), Separation of small metabolites and lipids in spectra from biopsies by diffusion-weighted HR-MAS NMR: a feasibility study, in ANALYST, 140(1), 272-279.
Do Skeletal Muscle Mitochondria Play A Role In Making Us More Efficient For Endurance Exercise?
Broskey Nicholas T., Boss Andreas, Kreis Roland, Boesch Chris, Amati Francesca (2014), Do Skeletal Muscle Mitochondria Play A Role In Making Us More Efficient For Endurance Exercise?, in MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, 46(5), 753-753.
Evidence of systematic and proportional error in a widely used glucose oxidase analyser: impact for clinical research?
Amati Francesca, Broskey Nicholas T., Carnero Elvis A. (2014), Evidence of systematic and proportional error in a widely used glucose oxidase analyser: impact for clinical research?, in CLINICAL ENDOCRINOLOGY, 80(5), 768-770.
Improvement in insulin sensitivity following exercise training is independent of mitochondrial changes in older adults
Amati F., Greggio C., Broskey N. T., Janssens W., Boss A., Kreis R., Boesch C. (2014), Improvement in insulin sensitivity following exercise training is independent of mitochondrial changes in older adults, in DIABETOLOGIA, 57, 254-254.
Skeletal Muscle Mitochondria in the Elderly: Effects of Physical Fitness and Exercise Training (vol 99, pg 1852, 2014)
Broskey Nicholas T., Greggio Chiara, Boss Andreas, Boutant Marie, Dwyer Andrew, Schlueter Leopold, Hans Didier, Gremion Gerald, Kreis Roland, Boesch Chris, Canto Carles, Amati Francesca (2014), Skeletal Muscle Mitochondria in the Elderly: Effects of Physical Fitness and Exercise Training (vol 99, pg 1852, 2014), in JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 99(7), 2619-2619.
The effect of chronic exercise training on exercise efficiency and fat oxidation in older previously sedentary adults
Broskey N. T., Fares E-J., Greggio C., Amati F. (2014), The effect of chronic exercise training on exercise efficiency and fat oxidation in older previously sedentary adults, in DIABETOLOGIA, 57, 254-255.
Triglyceride and HDL: the entangled pair
Amati Francesca, Widmann Christian (2014), Triglyceride and HDL: the entangled pair, in CURRENT OPINION IN LIPIDOLOGY, 25(5), 404-405.
Effect of chronic exercise on skeletal muscle mitochondria dynamics in older adults
Greggio C., Broskey N. T., Boutant M., Canto C., Amati F. (2013), Effect of chronic exercise on skeletal muscle mitochondria dynamics in older adults, in DIABETOLOGIA, 56, 32-32.
Exercise Capacity In Older Adults: A Matter Of Mitochondrial Function, Content Or Efficiency?
Broskey Nicholas T., Boss Andreas, Fares Elie-Jacques, Kreis Roland, Gremion Gerald, Boesch Chris, Amati Francesca (2013), Exercise Capacity In Older Adults: A Matter Of Mitochondrial Function, Content Or Efficiency?, in MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, 45(5), 517-518.
Skeletal muscle mitochondrial and lipid droplet content assessed with standardized grid sizes for stereology
Broskey Nicholas T., Daraspe Jean, Humbel Bruno M., Amati Francesca (2013), Skeletal muscle mitochondrial and lipid droplet content assessed with standardized grid sizes for stereology, in JOURNAL OF APPLIED PHYSIOLOGY, 115(5), 765-770.
The effect of exercise training on skeletal muscle mitochondrial content in older adults correlates with exercise efficiency and fat oxidation
Broskey N. T., Fares E. -J., Greggio C., Amati F. (2013), The effect of exercise training on skeletal muscle mitochondrial content in older adults correlates with exercise efficiency and fat oxidation, in DIABETOLOGIA, 56, 32-32.

Collaboration

Group / person Country
Types of collaboration
University of Bern, Magnetic resonance research center, Suisse Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual meeting of the American College of Sports Medicine Poster Skeletal Muscle Subsarcolemmal But Not Intramyofibrillar Fat Depots Associate With Regional And Overall Body Adiposity 30.05.2015 San Diego, United States of America Amati Francesca;
Symposium Regional Fat Depositions, Effects of Exercise and Lifestyle Interventions. 61th Annual Meeting of the American College of Sports Medicine Talk given at a conference Intramyocellular lipids: novel developments and implications 30.05.2015 San Diego, United States of America Amati Francesca;
European Congress of Obesity, Controversy Session Talk given at a conference Lipotoxicity and Skeletal Muscle: Are Ceramides to Blame? 08.05.2015 Prague, Czech Republic Amati Francesca;
7th annual congress of the Swiss Society of Sport Sciences Talk given at a conference Effects of exercise on the age-related risk for diabetes 12.02.2015 Lausanne, Switzerland Amati Francesca;
Scientific Meeting of the European Association of the Study of Diabetes Talk given at a conference Effect of chronic exercise on skeletal muscle mitochondria dynamics in older adults 23.09.2014 Barcelona, Spain Amati Francesca;
Scientific Meeting of the European Association of the Study of Diabetes Talk given at a conference The effect of exercise training on skeletal muscle mitochondrial content in older adults correlates with exercise efficiency and fat oxidation. 23.09.2014 Barcelona, Spain Amati Francesca;
Annual meeting of the American College of Sports Medicine Poster The effect of chronic exercise training on exercise efficiency and fat oxidation in older previously sedentary adults 30.05.2014 Orlando, United States of America Amati Francesca;
Annual meeting of the International Society for Magnetic Resonance in Medicine Poster Diffusion-weighted HR-MAS of biopsies to obtain separated fat-free metabolite and lipid spectra. A feasibility study 10.05.2014 Milano, Italy Amati Francesca;
Annual meeting of the International Society for Magnetic Resonance in Medicine Poster The effect of spinning rate variation on lipid resonances in HR-MAS spectra of brain and muscle biopsies 10.05.2014 Milano, Italy Amati Francesca;
Invited speaker at the Health and Obesity Research Center, Department of Health and Physical Activity Individual talk From bicycle to bench: is exercise a fountain of youth? 04.04.2014 Pittsburgh, United States of America Amati Francesca;
Invited speaker at the Department of Health Sciences and Technology and Veterinary School, at the Swiss Federal Institute of Technology (ETH) Individual talk From bicycle to bench: desentangling insulin resistance of aging 28.01.2014 Zurich, Switzerland Amati Francesca;
Annual meeting of the Swiss Society of Endocrinology and Diabetology Poster In vivo oxidative capacity vs. Mitochondrial volume density in skeletal muscle of age-matched, elderly athletes and sedentary subjects 14.11.2013 Bern, Switzerland Amati Francesca;
Annual meeting of the Swiss Society of Endocrinology and Diabetology Individual talk Effects of physical fitness and training on skeletal muscle mitochondria content and biogenesis in the elderly 14.11.2013 Bern, Switzerland Amati Francesca;
Lausanne Initiative Metabolism & Nutrition Alliance Talk given at a conference From bicycle to bench, desentangling insulin resistance of aging 31.10.2013 Lausanne, Switzerland Amati Francesca;


Self-organised

Title Date Place
Symposium at the American College of Sports medicine annual meeting entitled Regional Fat Depositions, Effects of Exercise and Lifestyle Interventions 30.05.2015 San Diego, United States of America
Tutorial at the American College of Sports medicine annual meeting entitled The interplay between incretins and glucose homeostasis 30.05.2014 Indianapolis, United States of America

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Obesity and Physical Activity Talk 10.12.2014 Clinique La Lignère, Switzerland Amati Francesca;
Exercise physiology and diabetes Talk 17.11.2014 Clinique La Lignière, Switzerland Amati Francesca;
Exercise prescription for diabetes Talk 17.11.2014 Clinique La Lignière, Switzerland Amati Francesca;


Awards

Title Year
American College of Sports Medicine Fellowship 2014

Associated projects

Number Title Start Funding scheme
132935 Multi-nuclear magnetic resonance spectroscopy (MRS) and imaging (MRI) on a clinical whole-body MR-system: insulin resistance, ageing, and physical activity 01.12.2010 Project funding
128736 High Resolution Magic Angle Spinning (HR-MAS) probe for NMR Spectroscopic Investigations of semi-solid liquid-like materials 01.12.2009 R'EQUIP
126339 Insulin resistance of aging, ectopic lipid depositions and oxidative capacity: effects of exercise and obesity 01.10.2010 Ambizione
170062 The aging mitochondria, dynamic and protective adaptations of exercise 01.12.2016 Project funding

Abstract

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.
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