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Multi-nuclear magnetic resonance spectroscopy (MRS) and imaging (MRI) on a clinical whole-body MR-system: insulin resistance, ageing, and physical activity

English title Multi-nuclear magnetic resonance spectroscopy (MRS) and imaging (MRI) on a clinical whole-body MR-system: insulin resistance, ageing, and physical activity
Applicant Boesch Chris
Number 132935
Funding scheme Project funding
Research institution Abt. Magnetresonanz-Spektroskopie u. Method. Departement für Klinische Forschung Universität Bern
Institution of higher education University of Berne - BE
Main discipline Physiology : other topics
Start/End 01.12.2010 - 30.11.2013
Approved amount 424'044.00
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Keywords (10)

Insulin resistance; Ageing; Magnetic resonance spectroscopy; Magnetic resonance imaging; Liver; Skeletal muscle; Diabetes; Spectroscopy; Metabolism; Magnetic Resonance

Lay Summary (German)

Lead
Lay summary
Die Magnetresonanz Bildgebung (MRI) und Spektroskopie (MRS) erlauben die nicht-invasive (berührungsfreie) und unschädliche Untersuchung von Anatomie und Stoffwechsel des menschlichen Körpers. In dieser Studie werden Skelettmuskel und Leber mittels MRI und MRS untersucht, um den Zusammenhang zwischen Lipid- und Kohlehydrat-Stoffwechsel zu untersuchen, insbesondere um das Problem der Insulin-Resistenz und des Diabetes im Alter besser zu verstehen.Die MRS kann neben vielen anderen Stoffwechselprodukten die Signale von so genannten intramyozellulären Lipiden (IMCL) von Fettgewebe (EMCL, extramyozelluläre Lipide) unterscheiden. Während EMCL sehr langsam auf- und abgebaut wird, ist IMCL ein aktives Stoffwechselprodukt, welches bei Gesunden innerhalb von Stunden verbraucht respektive aufgebaut wird. Bei Patienten, deren Muskulatur nicht genügend auf Insulin empfindlich ist (Diabetes und sog. Metabolisches Syndrom), scheint IMCL nicht mehr für Muskelleistung zu Verfügung zu stehen, was zu dauernd erhöhten IMCL-Konzentrationen führt.In einer Teilstudie wird versucht, mittels diffusionsgewichteter Spektroskopie die IMCL-Tröpfchen im Muskel zu charakterisieren, da beobachtet wurde, dass nicht nur die Menge IMCL, sondern auch die Grösse der IMCL-Tröpfchen sich bei insulin-resistenten Patienten ändert, was auch die reduzierte Verfügbarkeit der IMCL für den Stoffwechsel erklären könnte.Es bestehen Hinweise darauf, dass die Mitochondrien (Kraftwerke der Zelle) bei Insulinresistenz verändert sind. Mittels 31P-MRS können Stoffwechselreaktionen gemessen werden, welche über den Zustand der Mitochondrien Auskunft geben können. Diese Methoden werden in diesem Projekt weiterentwickelt, insbesondere werden sie vom Skelettmuskel auch auf bewegte Organe wie die Leber ausgedehnt, in denen das Signal zudem noch räumlich selektioniert werden muss.Es ist bekannt, dass die Insulinresistenz im Alter häufiger ist. Es ist aber noch nicht bekannt, ob dies auf das Alter per se oder auf die häufig reduzierte körperliche Aktivität im Alter zurückzuführen ist. In dieser Studie werden deshalb vier Gruppen mittels MRS untersucht, die sich einerseits in ihrem Alter, anderseits durch ihre körperliche Aktivität unterscheiden (jung-aktiv, jung-inaktiv, älter-aktiv, älter-inaktiv).Eine Leber mit erhöhtem Fettanteil ("non alcoholic fatty liver disease", NAFLD) kann unter bestimmten Umständen entzündet werden ("non alcoholic steato hepatitis", NASH). Diese Komplikation kann heute nur mittels einer Biopsie sicher diagnostiziert werden. In diesem Projekt soll versucht werden, mittels MRS von mehreren Kernen (1H, 13C, 31P) NASH und NAFLD nicht invasiv zu unterscheiden.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Aerobic exercise but not resistance exercise reduces intrahepatic lipid content and visceral fat and improves insulin sensitivity in obese adolescent girls: A randomized controlled trial
Lee Sojung, Deldin Anthony R., White David A., Kim YoonMyung, Libman Ingrid M., Rivera-Vega Michelle, Kuk Jennifer L., Sandoval Sandra, Boesch Chris, Arslanian Silva A. (2013), Aerobic exercise but not resistance exercise reduces intrahepatic lipid content and visceral fat and improves insulin sensitivity in obese adolescent girls: A randomized controlled trial, in American Journal of Physiology - Endocrinology and Metabolism, 305(10), E1222-E1229.
Effects of beta-alanine supplementation and interval training on physiological determinants of severe exercise performance
Gross Micah A., Boesch Chris, Bolliger Christine Sandra, Norman Barbara, Gustafsson Thomas, Hoppeler Hans H., Vogt Michael (2013), Effects of beta-alanine supplementation and interval training on physiological determinants of severe exercise performance, in European Journal of Applied Physiology, 1-14.
Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans
Lecoultre Virgile, Egli Léonie, Carrel Guillaume, Theytaz Fanny, Kreis Roland, Schneiter Philippe H., Boss Andreas, Zwygart Karin, Lê Kimanne, Bortolotti Murielle, Boesch Chris, Tappy Luc (2013), Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans, in Obesity, 21(4), 782-785.
Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets
Cariou Bertrand, Langhi Cédric, Le Bras Maëlle, Bortolotti Murielle, Lê KimAnne, Theytaz Fanny, Le May Cédric L., Guyomarc'h-Delasalle Béatrice, Zaïr Yassine, Kreis Roland, Boesch Chris, Krempf Michel A., Tappy Luc, Costet Philippe (2013), Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets, in Nutrition and Metabolism, 10(1), 4.
The Effect of Aerobic Exercise on Intrahepatocellular and Intramyocellular Lipids in Healthy Subjects
Egger Andrea, Kreis Roland, Allemann Sabin, Stettler Christoph D., Diem Peter, Buehler Tania, Boesch Chris, Christ Emanuel R. (2013), The Effect of Aerobic Exercise on Intrahepatocellular and Intramyocellular Lipids in Healthy Subjects, in PLoS ONE, 8(8), e70865.
Automatic Scan Planning for Magnetic Resonance Imaging of the Knee Joint
Bauer Stefan, Ritacco Lucas E., Boesch Chris, Nolte Lutz-P., Reyes Mauricio (2012), Automatic Scan Planning for Magnetic Resonance Imaging of the Knee Joint, in ANNALS OF BIOMEDICAL ENGINEERING, 40(9), 2033-2042.
Effect of two β-alanine dosing protocols on muscle carnosine synthesis and washout.
Stellingwerff Trent, Anwander Helen, Egger Andrea, Buehler Tania, Kreis Roland, Decombaz Jacques, Boesch Chris (2012), Effect of two β-alanine dosing protocols on muscle carnosine synthesis and washout., in Amino acids, 42(6), 2461-72.
Effects of aerobic versus resistance exercise without caloric restriction on abdominal fat, intrahepatic lipid, and insulin sensitivity in obese adolescent boys: a randomized, controlled trial.
Lee Sojung, Bacha Fida, Hannon Tamara, Kuk Jennifer L, Boesch Chris, Arslanian Silva (2012), Effects of aerobic versus resistance exercise without caloric restriction on abdominal fat, intrahepatic lipid, and insulin sensitivity in obese adolescent boys: a randomized, controlled trial., in Diabetes, 61(11), 2787-95.
Effects of an overnight intravenous lipid infusion on intramyocellular lipid content and insulin sensitivity in African-American versus Caucasian adolescents.
Lee Sojung, Boesch Chris, Kuk Jennifer L, Arslanian Silva (2012), Effects of an overnight intravenous lipid infusion on intramyocellular lipid content and insulin sensitivity in African-American versus Caucasian adolescents., in Metabolism: clinical and experimental, [Epub ahead of print](N/A), N/A-N/A.
Effects of supplementation with essential amino acids on intrahepatic lipid concentrations during fructose overfeeding in humans.
Theytaz Fanny, Noguchi Yasushi, Egli Léonie, Campos Vanessa, Buehler Tania, Hodson Leanne, Patterson Bruce W, Nishikata Natsumi, Kreis Roland, Mittendorfer Bettina, Fielding Barbara, Boesch Chris, Tappy Luc (2012), Effects of supplementation with essential amino acids on intrahepatic lipid concentrations during fructose overfeeding in humans., in The American journal of clinical nutrition, 96(5), 1008-16.
Intramyocellular lipid variations in active older men: relationship with aerobic fitness.
Rouffet David, Villars Clément, Fissoune Rachida, Sappey-Marinier Dominique, Laville Martine, Ibarrola Danielle, Sothier Monique, Monnet Marie-France, Ovize Michel, Bonnefoy Marc, Boesch Chris, Canet-Soulas Emmanuelle (2012), Intramyocellular lipid variations in active older men: relationship with aerobic fitness., in Acta physiologica (Oxford, England), [Epub ahead of print](N/A), N/A-N/A.
Magnetic resonance imaging based determination of body compartments with the versatile, interactive sparse sampling (VISS) method.
Buehler Tania, Ramseier Nicolas, Machann Juergen, Schwenzer Nina F, Boesch Chris (2012), Magnetic resonance imaging based determination of body compartments with the versatile, interactive sparse sampling (VISS) method., in Journal of magnetic resonance imaging : JMRI, 36(4), 951-60.
Magnetization exchange observed in human skeletal muscle by non-water-suppressed proton magnetic resonance spectroscopy.
Macmillan Erin L, Boesch Chris, Kreis Roland (2012), Magnetization exchange observed in human skeletal muscle by non-water-suppressed proton magnetic resonance spectroscopy., in Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine /, [Epub ahead of print](N/A), N/A-N/A.
Optimizing human in vivo dosing and delivery of β-alanine supplements for muscle carnosine synthesis.
Stellingwerff Trent, Decombaz Jacques, Harris Roger C, Boesch Chris (2012), Optimizing human in vivo dosing and delivery of β-alanine supplements for muscle carnosine synthesis., in Amino acids, 43(1), 57-65.
Restricted or severely hindered diffusion of intramyocellular lipids in human skeletal muscle shown by in vivo proton MR spectroscopy.
Brandejsky Vaclav, Kreis Roland, Boesch Chris (2012), Restricted or severely hindered diffusion of intramyocellular lipids in human skeletal muscle shown by in vivo proton MR spectroscopy., in Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine /, 67(2), 310-6.
Skeletal muscle ¹H MRSI before and after prolonged exercise. I. muscle specific depletion of intramyocellular lipids.
Vermathen Peter, Saillen Pierre, Boss Andreas, Zehnder Monica, Boesch Chris (2012), Skeletal muscle ¹H MRSI before and after prolonged exercise. I. muscle specific depletion of intramyocellular lipids., in Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine /, 68(5), 1357-67.
Skeletal muscle ¹H MRSI before and after prolonged exercise. II. visibility of free carnitine.
Boss Andreas, Kreis Roland, Saillen Pierre, Zehnder Monica, Boesch Chris, Vermathen Peter (2012), Skeletal muscle ¹H MRSI before and after prolonged exercise. II. visibility of free carnitine., in Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine /, 68(5), 1368-75.
Effects of a whey protein supplementation on intrahepatocellular lipids in obese female patients.
Bortolotti Murielle, Maiolo Elena, Corazza Mattia, Van Dijke Eveline, Schneiter Philippe, Boss Andreas, Carrel Guillaume, Giusti Vittorio, Lê Kim-Anne, Quo Chong Daniel Guae, Buehler Tania, Kreis Roland, Boesch Chris, Tappy Luc (2011), Effects of a whey protein supplementation on intrahepatocellular lipids in obese female patients., in Clinical nutrition (Edinburgh, Scotland), 30(4), 494-8.
Fructose and galactose enhance postexercise human liver glycogen synthesis.
Décombaz Jacques, Jentjens Roy, Ith Michael, Scheurer Eva, Buehler Tania, Jeukendrup Asker, Boesch Chris (2011), Fructose and galactose enhance postexercise human liver glycogen synthesis., in Medicine and science in sports and exercise, 43(10), 1964-71.
Noninvasive assessment of exercise-related intramyocellular acetylcarnitine in euglycemia and hyperglycemia in patients with type 1 diabetes using ¹H magnetic resonance spectroscopy: a randomized single-blind crossover study.
Boss Andreas, Kreis Roland, Jenni Stefan, Ith Michael, Nuoffer Jean-Marc, Christ Emanuel, Boesch Chris, Stettler Christoph (2011), Noninvasive assessment of exercise-related intramyocellular acetylcarnitine in euglycemia and hyperglycemia in patients with type 1 diabetes using ¹H magnetic resonance spectroscopy: a randomized single-blind crossover study., in Diabetes care, 34(1), 220-2.
The effect of GH replacement therapy on different fat compartments: a whole-body magnetic resonance imaging study.
Egger A, Buehler T, Boesch C, Diem P, Stettler C, Christ E R (2011), The effect of GH replacement therapy on different fat compartments: a whole-body magnetic resonance imaging study., in European journal of endocrinology / European Federation of Endocrine Societies, 164(1), 23-9.
A plasma global metabolic profiling approach applied to an exercise study monitoring the effects of glucose, galactose and fructose drinks during post-exercise recovery
Bruce Stephen J., Breton Isabelle, Décombaz Jacques E., Boesch Chris, Scheurer Eva, Montoliu Ivan, Rezzi Serge, Kochhar Sunil, Guy Philippe Alexandre (2010), A plasma global metabolic profiling approach applied to an exercise study monitoring the effects of glucose, galactose and fructose drinks during post-exercise recovery, in Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 878(29), 3015-3023.
Effects of a short-term overfeeding with fructose or glucose in healthy young males
Ngo Sock Emilienne Tudor, Lê Kimanne, Ith Michael, Kreis Roland, Boesch Chris, Tappy Luc (2010), Effects of a short-term overfeeding with fructose or glucose in healthy young males, in British Journal of Nutrition, 103(7), 939-943.
Effects of short-term overfeeding with fructose, fat and fructose plus fat on plasma and hepatic lipids in healthy men
Sobrecases H., Lê Kimanne, Bortolotti Murielle, Schneiter Philippe H., Ith Michael, Kreis Roland, Boesch Chris, Tappy Luc (2010), Effects of short-term overfeeding with fructose, fat and fructose plus fat on plasma and hepatic lipids in healthy men, in Diabetes and Metabolism, 36(3), 244-246.
Standardized protocol for a depletion of intramyocellular lipids (IMCL)
Ith Michael, Huber Philipp M., Egger Andrea, Schmid Jean Paul, Kreis Roland, Christ Emanuel R., Boesch Chris (2010), Standardized protocol for a depletion of intramyocellular lipids (IMCL), in NMR in Biomedicine, 23(5), 532-538.
Coffee consumption attenuates short-term fructose-induced liver insulin resistance in healthy men
Lecoultre V, Carrel G, Egli L, Binnert C, Boss A, MacMillan EL, Kreis R, Boesch C, Darimont C, Tappy L, Coffee consumption attenuates short-term fructose-induced liver insulin resistance in healthy men, in Am.J.Clin.Nutr., [Epub ahead of print].
Proton diffusion tensor spectroscopy of metabolites in human muscle in vivo
Brandejsky Vaclav, Boesch Chris, Kreis Roland, Proton diffusion tensor spectroscopy of metabolites in human muscle in vivo, in Magn.Reson.Med., accepted for publication.

Collaboration

Group / person Country
Types of collaboration
Pittsburgh University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institut de Myologie AIM-CEA, Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
University Lyon 1, CarMeN, U1060 INSERM France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
David Geffen School of Medicine at UCLA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
"Nutrients Beyond Nutrition" International Meeting on Nitrogen Substrates in Clinical Care Talk given at a conference Skeletal muscle functional NMR imaging and spectroscopy in health and disease: where do we stand? 08.11.2013 Rezzato / Breschia, Italy Boesch Chris;
ESMRMB 2013 Talk given at a conference Diffusion characteristics of metabolites in human muscle investigated by 1H diffusion tensor spectroscopy in vivo 03.10.2013 Toulouse, France Brandejsky Vaclav; Kreis Roland; Boesch Chris;
ISMRM 2013 Talk given at a conference In vivo oxidative capacity vs. mitochondrial volume density in skeletal muscle of age-matched, elderly athletes and sedentary subjects - A matter of function and content 22.05.2013 Salt lake City, UT, United States of America Boesch Chris; Kreis Roland; Schaffert René;
ISMRM 2013 Poster Water proton relaxation times exhibit muscle fibre orientation dependence, while water to creatine magnetization transfer rates do not 22.05.2013 Salt Lake City, UT, United States of America Boesch Chris; Kreis Roland;
ISMRM 2013 Poster Comprehensive spectroscopic investigation of liver metabolism - A feasibility study. 22.05.2013 Salt Lake City, UT, United States of America Kreis Roland; Boesch Chris; Bühler Tania; Schaffert René; Dokumaci Ayse Sila;
Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) Poster Effects of fructose overfeeding on intrahepatic lipid accumulation and hepatic insulin sensitivity in healthy humans 20.04.2013 Boston, MA, United States of America Kreis Roland; Boesch Chris; Tappy Luc; Schaffert René;
100th Indian Science Congress Talk given at a conference Magnetic resonance imaging (MRI) and spectroscopy (MRS): tremendously versatile tools to study biology in vivo 03.01.2013 Kolkata, India Boesch Chris;
ESMRMB 2012 Poster Production of acetylcarnitine and utilization of IMCL at different exercise intensities - A pilot-study applying SVS and MRSI. 04.10.2012 Lissabon, Portugal Boesch Chris; Kreis Roland; Schaffert René;
ESMRMB 2012 Poster Intra-CardiomyoCellular Lipid (ICCL) Levels Change in Healthy Lean Subjects During the Day and Between Days as Observed by In-Vivo 1H-MR Spectroscopy 04.10.2012 Lissabon, Portugal Boesch Chris; Kreis Roland;
ESMRMB 2012 Talk given at a conference Applying 31P saturation and inversion transfer in human liver and skeletal muscle to measure ATP synthesis exchange rate constants. 04.10.2012 Lissabon, Portugal Kreis Roland; Boesch Chris; Bühler Tania;
15th International Biochemistry of Exercise Congress (IBEC) Poster Is all carnitine available for biochemical processes? A 1H-magnetic resonance study 17.06.2012 Stockholm, Sweden Schaffert René; Kreis Roland; Boesch Chris;
ISMRM 2012 Talk given at a conference Cardiac lipids show diurnal variations: An in-vivo 1H-MR Spectroscopy study in humans 07.05.2012 Melbourne, Australia Kreis Roland; Boesch Chris;
ISMRM 2012 Poster Identification of over-estimated diffusion coefficients obtained with very high b-values in diffusion MRS 07.05.2012 Melbourne, Australia Kreis Roland; Boesch Chris; Brandejsky Vaclav;
ISMRM 2012 Poster Magnetization Transfer Effects from Water to Metabolites in Human Skeletal Muscle Observed by Non-Water-Suppressed MR Spectroscopy. 07.05.2012 Melbourne, Australia Boesch Chris; Kreis Roland;
Workshop ISMRM on Fat-Water Separation: Insights, Applications & Progress in MRI Talk given at a conference Spectroscopy: Skeletal Muscles 19.02.2012 Long Beach, CA, United States of America Boesch Chris;
7th Asian Biophysics Association (ABA) Symposium Talk given at a conference MR Spectroscopy of skeletal muscle metabolism 31.01.2012 Delhi, India Boesch Chris;
Journées Francophones de Nutrition Talk given at a conference Effects d'une supplémentation en acides aminés céto-formateur sur la stéatose hépatique induite par la fructose 07.12.2011 Reims, France Kreis Roland; Tappy Luc; Boesch Chris;
ESMRMB 2011 Talk given at a conference Differences in diffusion behavior of intra- and extramyocellular lipids and their verification using order-statistics filtering. 06.10.2011 Leipzig, Germany Boesch Chris; Kreis Roland; Brandejsky Vaclav;
ESMRMB 2011 Poster MRI based volume determination of single organs using the Versatile, Interactive Sparse Sampling (VISS) method. 06.10.2011 Leipzig, Germany Boesch Chris; Bühler Tania;
Medizinphysik 2011 Talk given at a conference Grundlagen und Anwendungen der Magnetresonanz-Spektroskopie 28.09.2011 Wien, Austria, Austria Boesch Chris;
ISMRM 2011 Poster Is free carnitine visible in 1H-MR spectra of skeletal muscle? 09.05.2011 Montreal, Canada Kreis Roland; Boesch Chris; Schaffert René;
ISMRM 2011 Poster Determination of ATP synthesis exchange rates in human liver and skeletal muscle using 31P magnetization transfer. 09.05.2011 Montreal, Canada Boesch Chris; Bühler Tania; Kreis Roland; Schaffert René;
ISMRM 2011 Talk given at a conference Diffusion measurements reveal a difference in apparent diffusion coefficients of intra- and extramyocellular lipids. 09.05.2011 Montreal, Canada Brandejsky Vaclav; Boesch Chris; Kreis Roland;


Associated projects

Number Title Start Funding scheme
145007 Hyperpolarized Magnetic Resonance Metabolic Imaging - From Bench to Bedside 01.08.2013 R'EQUIP
149398 Insulin resistance of aging, ectopic lipid depositions and oxidative capacity: effects of exercise and obesity 01.10.2013 Ambizione
138428 Modulation of fructose's metabolic effects by environmental factors 01.10.2011 Project funding
109522 The effect of growth hormone (GH) on intramyocellular (IMCL), intrahepatic lipids (IHCL) and visceral fat mass in relation to insulin resistance 01.04.2006 Project funding
149779 Multi-nuclear magnetic resonance spectroscopy (MRS) and imaging (MRI) on a clinical whole-body MR-system: Lipid organelles and mitochondria 01.12.2013 Project funding
135743 Magnetic Resonance Techniques to Investigate Human Brain Physiology: Acquisition and Postprocessing Tools to Advance Spectroscopy at Clinical and High Magnetic Fields 01.06.2011 Project funding
118219 Multi-nuclear magnetic resonance spectroscopy (MRS) and imaging (MRI) on a clinical whole-body MR-system: integration and application of the MR-toolbox for studies on insulin resistance 01.12.2007 Project funding

Abstract

Background:Insulin resistance has been recognized as the common denominator of an interrelated group of diseases with epidemic dimensions, in particular in the elderly population with a prevalence of up to 50%. The increased risk of these patients to develop type 2 diabetes mellitus and cardiovascular diseases, including myocardial infarction and stroke, represents a fatal threat for the individual patient and a major socio-economic problem. Magnetic resonance imaging (MRI) and spectroscopy (MRS) have proven extremely valuable in cohort studies on the pathophysiology of insulin resistance. Thanks to the non-invasive, localized, and thus organ-specific acquisition of data, MRI/MRS can be used repeatedly in studies where the application of invasive methods is limited. The group of the PI has already been able to show that MRS can elucidate the ultrastructure of skeletal muscle far beyond the nominal spatial resolution of gradient-based imaging methods down to the sub-micrometer range.Hypotheses and methodological aims:Three sub-studies shall test the following primary hypotheses around the complex of insulin resistance:A1) Plasticity of intramyocellular (IMCL) and intrahepatocellular (IHCL) lipids: 1) The range between “depleted” and “replenished” IMCL levels is dependent on the peripheral insulin sensitivity. 2) The size of IMCL droplets increases during IMCL replenishment and depends on the peripheral insulin sensitivity in the replenished state.A2) Insulin resistance, physical inactivity, and ageing: 1) Mitochondrial activity in skeletal muscle is more reduced by the sedentary life-style of young and older subjects than by age only. 2) Mitochondrial activity in liver tissue is reduced in the elderly population and correlates with the amount of IHCL and visceral adipose tissue.A3) Non-invasive differentiation of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH): 1) Lipid composition is different between NASH and NAFLD. 2) Mitochondrial activity is reduced in NASH.Numerous MR-methods used for these applications are continuously used by the team of the PI, however, some specific advanced methods need to be developed:M1) Diffusion-sensitized MRS will be used to study the size and ultrastructure of IMCL droplets non-invasively, in particular in view of diet- and activity-induced variations of droplet size.M2) Non-invasive MRS-methods (31P-MR saturation transfer) for an estimation of mitochondrial activity will be developed and evaluated in moving organs, in particular in the liver.M3) A combined score from lipid composition, IHCL, liver volume, visceral adipose tissue, and mitochondrial activity based on 1H-, 13C-, 31P-MRS, and MRI will be developed to characterize the liver non-invasively.Importance and impact:Plasticity and ultrastructure of IMCL droplets: it is hypothesized that the size and structure of IMCL droplets contributes significantly to peripheral insulin resistance. The results of this proposal can elucidate the specific role of these lipid droplets and of the ability of the subject to accumulate and - in particular - to use these lipids. Age, insulin resistance, and saturation transfer methods: while it is known that physical activity improves insulin sensitivity, it is not clear how much ageing per se reduces mitochondrial activity independently. This proposal shall provide advanced MRS methods to estimate mitochondrial function in moving organs and to disentangle the influences of ageing and sedentary lifestyle on insulin resistance. Combined score to differentiate NASH and NAFLD: the non-invasive diagnostic score based on a combination of lipid composition and mitochondrial activity shall complement and eventually even replace invasive examinations.
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