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Can J Diabetes 37 (2013) 109e114

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Review

The 2012 CDA-CIHR INMD Young Investigator Award Lecture: Dysfunctionof Adipose Tissues and the Mechanisms of Ectopic Fat Deposition in Type 2Diabetes

André C. Carpentier MD, FRCPC *

CIHR-GSK Chair in Diabetes Department of Medicine, Division of Endocrinology, Université de Sherbrooke, Centre de recherche clinique Étienne-Le Bel, Centre hospitalier universitairede Sherbrooke, Sherbrooke, Québec, Canada

a r t i c l e i n f o

Article history:Received 28 February 2013Received in revised form12 March 2013Accepted 12 March 2013

Keywords:brown adipose tissuesfatty acidsinsulin resistancetype 2 diabeteswhite adipose tissues

Mots clés:tissus adipeux brunsacides grasinsulinorésistancediabète de type 2tissus adipeux blancs

* Address for correspondence: André C. CarpentieCentre hospitalier universitaire de Sherbrooke, ShCanada.

E-mail address: andre.carpentier@usherbrooke.ca.

1499-2671/$ e see front matter � 2013 Canadian Diahttp://dx.doi.org/10.1016/j.jcjd.2013.03.026

a b s t r a c t

Ectopic fat deposition in skeletal muscles, liver, heart, and other tissues has been closely linked with thedevelopment of lean tissues’ insulin resistance and progression toward type 2 diabetes mellitus.Mechanisms of overexposure of these tissues to fatty acids include increased de novo lipogenesis,impaired fatty acid oxidation and increased fatty acid flux to these organs. White adipose tissues are themain organs responsible for the regulation of circulating fatty acids. It has been clearly demonstratedthat pre-diabetes individuals and individuals with diabetes display impaired adipose tissue dietary fattyacid storage that may lead to increased circulating flux and exaggerated lean tissue fatty acid exposure.Additionally, brown adipose tissue depots are less metabolically active in individuals with type 2 dia-betes. We have developed a series of novel in vivo investigative tools using positron emission tomog-raphy to comprehensively assess postprandial interorgan fatty acid partitioning and white and brownadipose tissue metabolism in subjects with pre-diabetes and type 2 diabetes. Our findings shed newlights into the sophisticated mechanisms that regulate fatty acid partitioning and energy homeostasisduring the development of type 2 diabetes. New links between abnormal dietary fatty acid metabolismand early myocardial metabolic and functional defects are now being uncovered in humans with thehope to find novel ways to predict and avoid the devastating complications of diabetes.

� 2013 Canadian Diabetes Association

r é s u m é

Le dépôt de graisse ectopique dans les muscles squelettiques, le foie, le cœur et les autres tissus a étéétroitement lié au développement de l’insulinorésistance des tissus maigres et à la progression vers lediabète sucré de type 2. Les mécanismes de surexposition de ces tissus aux acides gras incluent l’aug-mentation de la lipogenèse de novo, l’altération de l’oxydation des acides gras et l’augmentation du fluxd’acides gras à ces organes. Les tissus adipeux blancs sont les principaux organes responsables de larégulation des acides gras circulants. Il a clairement été démontré que les individus ayant un prédiabèteou un diabète montrent une altération du stockage des acides gras alimentaires dans le tissu adipeux quipeut mener à l’augmentation du flux circulant et à l’exacerbation de l’exposition des tissus maigres auxacides gras. De plus, les dépôts de tissus adipeux bruns sont moins actifs sur le plan métabolique chez lesindividus ayant le diabète de type 2. Nous avons développé des séries de nouveaux outils d’explorationin vivo utilisant la tomographie par émission de positrons pour évaluer de manière exhaustive lapartition postprandiale des acides gras aux divers organes et le métabolisme du tissu adipeux chez lessujets ayant un prédiabète ou un diabète de type 2. Nos conclusions ont fait la lumière sur les méca-nismes sophistiqués qui régulent la partition des acides gras et l’homéostasie énergétique durant ledéveloppement du diabète de type 2. Les nouveaux liens entre le métabolisme anormal des acides grasalimentaires et les anomalies précoces du fonctionnement et du métabolisme myocardiques sontmaintenant connus chez les humains, suscitant l’espoir de trouver de nouveaux moyens pour prédire etéviter les complications dévastatrices du diabète.

� 2013 Canadian Diabetes Association

r, Division of Endocrinology,erbrooke, Québec J1H 5N4,

betes Association

A.C. Carpentier / Can J Diabetes 37 (2013) 109e114110

Introduction: A Tribute to My Mentors and Collaborators

Malcolm Gladwell captured in his best-seller book “Outliers”what I believe should be in the mind of anyone receivinga biomedical research award nowadays: “Success is grounded ina web of advantages and inheritances, some deserved, some not,some earned, some just plain lucky.” I am a prime example ofa clinician-scientist who is the product of a perfectly favourableenvironment for the development of a biomedical research career.Throughout my training and career, I benefited from my interac-tions with a series of individuals who shaped my professional life.They created the environment that was conducive for the meth-odological innovations and original conceptual insights that led tomy nomination to the CDA-CIHR INMD Young Investigator Award.Two individuals stand out as the most important of them all, asthey not only gave impulse and direction to my research career, butthey also profoundly transformed my values and vision and mademe a true team player and collaborator. The first of these indivi-duals is Dr. Diego Bellabarba who was the Director of the Endo-crinology Training Program at the Université de Sherbrooke when Iwas a medical clerk and, later, an endocrinology resident. Diego notonly transmitted his passion for medicine, endocrinology andresearch, he also introduced me to the humanistic views andculture that are now the motive force of my career and, in manyways, of my personal life. Diego was truly a father figure to me. Thesecond mentor is Dr. Gary Lewis at the University of Toronto, mypostdoctoral fellowship supervisor from 1997 to 2001. Garycommunicated his passion for research on diabetes and lipidmetabolism and truly defined the conceptual path at the basis ofa large part of my independent career thus far (1). At the time of mytrainingwith him, Garywas one of the few integrative physiologistsactive in metabolic research in humans, a discipline that is now inhigh demand. Under his guidance, I learned all of the basic skills inmetabolic research that allowedmy laboratory to develop the novelmethodological tools that will be overviewed in the present article.

Other current collaborators also deserve a special mention asthey were instrumental in the development of some of theconceptual and/ormethodological advances that will be underlinedherein: Dr. Eric E. Turcotte, Head of the Positron Emission Tomog-raphy (PET) Investigation Unit, Dr. Roger Lecomte, Head of thePreclinical PET Investigation Unit and Dre. Brigitte Guérin, Head ofthe Radiochemistry Unit at the Centre de recherche cliniqueÉtienne-Le Bel (CRCEL), Dr. Denis Richard of the Obesity ResearchChair at Université Laval and Dr. François Haman of the Universityof Ottawa. None of the work my laboratory has accomplishedwould have been possible without the outstanding contributionsof these good friends.

The concept of disordered storage of fatty acid in adipose tissues inthe development of type 2 diabetes

Ample evidence from preclinical investigations as well asexperimental studies in humans supports the notion that excessexposure of lean tissues to fatty acids is a key factor leading toinsulin resistance (IR) and impaired glucose-stimulated insulinsecretion (GSIS), the 2 pathophysiological hallmarks of type 2 dia-betes mellitus (see [1e3] for reviews). This process is generallyreferred to as “lipotoxicity” (4). The underlying mechanisms bywhich excess lean tissue fatty acid exposure occurs and the role oflipotoxicity in the natural history of type 2 diabetes in humans havebeen the focus of our laboratory since its inception in 2001. Themost recognized in vivo marker of lean tissue fatty acid over-exposure and lipotoxicity is ectopic fat deposition (i.e. excessintracellular deposition of triglycerides [TG]) (3,5).

Excess exposure of lean tissues to fatty acids may occur via3 categories of potentially overlapping mechanisms (2). The first

category of mechanisms relates to defective lean tissue fatty acidmetabolism, including 1) impaired NEFA oxidation (OxNEFA) thatlikely contributes to ectopic fat deposition in skeletal muscles (see[2] for review), and 2) increased synthesis of fatty acids from othercarbon substrates (de novo lipogenesis [DNL]) that is likely themain contributor of liver ectopic fat deposition (see also [2] forreview). The secondmechanisms are those related to adipose tissuemetabolic dysfunction and/or impaired expansion (see [1e3] forreviews), namely 1) excess intracellular lipolysis of prestored TG,themajor contributor of plasma nonesterified fatty acid appearanceduring fasting (RaNEFA), and 2) impaired adipose tissue storage offatty acids produced by lipolysis of TG-rich lipoproteins (mainlychylomicrons) (6e10), a process referred to as “NEFA spillover” andthat also contributes to RaNEFA in the postprandial and post-absorptive states. Using stable isotopic tracer techniques, we foundclear evidence for increased NEFA spillover in subjects with pre-diabetes and diabetes (9,10). Others have demonstrated usingarterio-venous gradient techniques and/or isotopic tracer methodswith biopsies that NEFA spillover originates in the adipose tissuemicrocirculation from impaired adipose tissue fatty acid storage(see [2] for an extensive and critical review). The third category,excess lean tissue uptake of dietary fat (Uptakedietary fat), mayrelate to impaired adipose tissue postprandial storage of dietaryfatty acids, increased intestinal fat absorption and/or directlyincreased fatty acid uptake in lean tissues. These latter mechanismshave been thus far poorly characterized in humans because ofmethodological limitations. This challenge has been the focus ofnovel methodological developments in our laboratory.

Our contribution to advances in the quantification of organ-specificfatty acid partitioning

PET is a nuclear medicine approach that allows the quantifica-tion of 2 coincident gamma rays emitted from a positron-emittinglabel contained in a tracer tailored to quantify a biological processsuch as uptake of ametabolite or binding to a receptor. For example,14-R,S-18F-6-thia-heptadecanoic acid (18FTHA), a long-chain fattyacid analog that accumulates in oxidative and nonoxidative cellularpathways (11), offers the possibility to measure integrated tissueuptake of long-chain fatty acids in vivo in humans with PET. ThreePET acquisition modalities are useful as part of our metabolicinvestigations: 1) static (or volumetric) acquisition, in which allcoincident radioactive events within a given space (voxel) aresummed up over time to give a single 3-dimensional image todetermine whole body tracer biodistribution; 2) dynamic acquisi-tion, in which each voxel is associated to a time of detection,allowing the reconstruction of 4-dimensional images to study time-dependent processes such as tracer uptake rate and oxidative andnonoxidative metabolic rates; and 3) electrocardiomyographic(ECG)-gated dynamic acquisition, inwhich PET dynamic acquisitionof the heart is synchronized to the cardiac cycle, allowing thedetermination of cardiac volumes to assess ventricular function.

Using PET technology developed by the team of Lecomte et al.(12) and Marriot et al. (13) that is adapted to small animals (mPET),we investigated fatty acid metabolism in the heart of a series ofanimal models, including a nutritional rat model of type 2 diabetesthat we developed using high fructose/high fat feeding combinedwith administration of a small dose of streptozotocin (the HFHFSrat) (14). Like most patients with type 2 diabetes, these animals arecharacterized by insulin resistance, hypoadiponectinemia, mildhyperglycemia and hypertriglyceridemia and adipocyte hyper-trophy (14,15). However, this model is not characterized by signif-icant degree of obesity, allowing the assessment of the effect ofa type 2 diabetes like condition without the confounding effectof obesity. Using sequential dynamic ECG-gated mPET scanningafter the intravenous (i.v.) administration of 11C-acetate, 18FDG

A.C. Carpentier / Can J Diabetes 37 (2013) 109e114 111

and 18FTHA, we measured myocardial blood flow, oxidativemetabolism, glucose and NEFA use and left ventricular function.Wefound that HFHFS rats have reduced left ventricular contractilitywith reduced stroke volume associated with preserved oxidativemetabolism and blood flow (14). This reduced ratio of myocardialmechanical work on oxygen consumption is typical of diabeticcardiomyopathy (16). In euglycemic hyperinsulinemic condition,the heart of the HFHFS rat shows reduced glucose use but normalcardiac NEFA uptake (14). Cardiac NEFA uptake rate was evenreduced in the fasting condition due to significant reduction inRaNEFA from adipose tissue lipolysis. This phenomenon is alsotypical of patients with type 2 diabetes and is likely due to impairedadipose tissue catecholamine sensitivity (see our recent review[17]). These data excluded a significant contribution of RaNEFA tocardiac lipotoxicity in this model, stimulating us to investigate thecontribution of dietary fat from circulating TG-rich lipoproteins inthis process because the heart can efficiently use this source of fattyacids (16,18). We found that HFHFS rats show a marked increase in18FTHA myocardial uptake when this tracer is administered bygavage (14), suggesting an exaggerated channelling of dietary fattyacids toward the myocardium in type 2 diabetes as a contributor ofthe cardiac metabolic abnormalities and cardiomyopathy associ-ated with this disease. This possibility was also supported bymyocardial lipoprotein lipase (LpL) overexpression experiments inmice (19) and by altered cardiac glucose uptake induced by acutehypertriglyceridemia in rats (20).

The results obtained in the HFHFS rat model attracted ourattention to the role of chylomicron-derived fatty acids in ectopicfat deposition during the development of type 2 diabetes. Ourprevious studies in humans also suggested that fatty acid spillover(i.e. excess RaNEFA from chylomicron-TG lipolysis during thepostprandial state) is not fully established in the pre-diabetes statewhereas postprandial hypertriglyceridemia is present (9,10,21). Wealso showed that increased postprandial RaNEFA does notcontribute to increased fatty acid uptake in skeletal muscles ofsubjects with type 2 diabetes because of reduced postprandialmuscle blood flow (22). Given the limitations of available tech-niques to study in vivo TG-derived fatty acid uptake (see [2] forreview), we setup to establish a novel, noninvasive method todetermine whole body, organ-specific dietary fatty acid partition-ing and uptake in humans using oral administration of 18FTHAwith

Figure 1. Organ-specific partitioning of dietary fatty acids. Anterio-posterior whole body18F activity is clearly visible in the thoracic duct outlet (green arrow), stomach (blue arrow),(Noll C, Kunach M, Labbé MS, Turcotte EE and Carpentier AC, unpublished observation).

sequential dynamic and whole body static PET acquisitions. The useof 18FTHA as a tracer for this purpose was justified based on thefollowing rationale: 1) the very high sensitivity of PET, allowingquantification of uptake in all organs, including the heart, skeletalmuscles and adipose tissues, 2) 18FTHA accumulation in oxidativeand non oxidative cellular pathways, allowing the measurement ofintegrated uptake over time, even in organs that oxidize andeliminate fatty acids very rapidly, despite the relatively slow dietaryfatty acid transport rate to organs, and 3) the similar tissue uptakerates of palmitate and 18FTHA in vivo (23,24). We demonstrated inrats and humans that orally administered 18FTHA reaches circula-tion in chylomicron-TG at similar rate than 3H-triolein, that itredistributes to other circulating lipids (NEFA, VLDL-TG, phospho-lipids) as dietary long-chain fatty acids, that it allows the assess-ment of chylomicron-TG production into the thoracic duct anduptake and partitioning of dietary fatty acids in most tissues inhumans (25). An important inherent limitation of this novelmethod is the incapacity to distinguish oxidative from non-oxidative dietary fatty acid metabolism. This method also assumesthat hydrolysis rate of 18FTHA containing chylomicron-TG by LpL isthe same than native chylomicron-TG at the tissue level. It shouldalso be mentioned that assessment of dietary fatty acid uptake overtime in adipose tissues and the liver is underestimated due tosignificant recirculation of 18FTHA as NEFA and VLDL-TG, respec-tively. However, the latter also occurs with endogenous long-chaindietary fatty acids and thus reflects normal physiological dietaryfatty acid partitioning. Intestinal accumulation of 18FTHA further-more limits the measurement of dietary fatty acid uptake in mostintra-abdominal organs due to radioactivity spillover. Finally, theneed for sequential computed tomography (CT) acquisitions limitsthe radioactivity dose of each of these scans that can be safelyadministered using the currently available PET/CT scanners at ourinstitution, thus reducing the CT image quality and our capacity toperform volumetric assessments of most tissues.

Organ-specific dietary fatty acid partitioning in pre-diabetes

We recently applied our novel technique to determine organ-specific dietary fatty acid partitioning in subjects with pre-diabetes (impaired glucose tolerance) (26) (Fig. 1). As expectedfrom finding of other groups using stable or radioactive fatty acid

PET acquisition performed 6 hours after oral administration of 14(R,S)-[18F]-FTHA.liver (red arrow) and bladder (black arrow, from renal excretion of 18FTHA metabolites)

Figure 2. Inverse relationship between shivering intensity determined by electromy-ographyandvolumeof activeBATdeterminedbywholebodyPET/CTscanning30minutesafter i.v.18FDG inhealthy subjects (n¼12,opencircles) and in subjectswith type2diabetes(n¼3, closed circles) analyzed thus far in our laboratory (LabbéMS, Blondin DP, Haman F,Turcotte EE, Richard D, Carpentier AC, unpublished observation). With the exclusion ofone outlier healthy control, the relationship assumes an exponential decay function.

A.C. Carpentier / Can J Diabetes 37 (2013) 109e114112

tracers with the arterio-venous gradient or biopsy techniques(6,8,27), we found reduced dietary fatty acid uptake in abdominalsubcutaneous and visceral (peri-renal) adipose tissues in pre-diabetes subjects directly related to the degree of obesity (26).We, however, did not find any increase in dietary fatty acid uptakein skeletal muscles or in the liver of these subjects. In accordance toour findings in the HFHFS diabetes rat model (14), we foundsignificant increase in dietary fatty acid partition in the heart ofsubjects with impaired glucose tolerance, associated with reducedsystolic and diastolic left ventricular functions (26). Together withresults from experimental animal models (16), these resultssupport a role of increased dietary fatty acid channeling toward theheart in the development of heart failure in subjects with type 2diabetes.

Brown adipose tissue metabolism in humans

Brown adipose tissue (BAT) is a specialized tissue whose func-tion is to produce heat that is found in abundance in interscapular,subscapular, axillary, perirenal, and periaortic regions in smallmammals (28). The presence of functional BAT in adult humanswasonly recently widely acknowledged. Indeed, PET/CT scanninginvestigations aimed at detecting tumoral tissue with the glucoseanalogue 18FDG revealed symmetrical 18FDG fat depots mostlylocated in the supraclavicular and paravertebral regions of the body(29). Those metabolically active fat depots were a posteriorademonstrated to have all the characteristics of BAT (30e32).

The supraclavicular depot is the most prevalent BAT in humansand the onewith the highest 18F-FDG uptake activity after exposureto cold, as we showed in the largest epidemiological study onhuman BAT published to date (29). Higher prevalence of 18FDG BATsites is determined by a series of factors including colder temper-ature preceding PET/CT scanning procedures, female sex, youngerage and lower bodymass index and body fat content (29,31,33). It isalso reduced by the presence of diabetes and use of b-adrenergicblockers (29,33). The prevalence of spontaneously detectable BATby 18FDG (metabolically active) range from 2% to 7% in large cohortsof patients evaluated for cancer (29,31,34). The prevalence of somemetabolically active BAT using 18FDG is, however, much higher (30%to 100%) in small cohorts of acutely cold-exposed healthy subjects(32,33,35,36). The total volume of BAT 18FDG activity (a surrogatebut thus far gold-standard measure of total volume of activatedBAT) amounts to<50 g in most individuals, but this figure dependscritically on the type and intensity of prior cold exposition and ondefinition criteria for positive BAT 18FDG uptake. In the absence ofuniversally accepted definition criteria, it is important to take theseconsiderations into account when comparing results of differentgroups of investigators.

In humans, there is now evidence that BAT not only can useglucose, but is also a bona fide thermogenic organ during acute coldexposure (35e37). The contribution of BAT to energy expenditure,however, is currently debated. Some groups report that, on coldexposure or capsinoid administration, whole body energy expen-diture increases only in those individuals demonstrating the pres-ence of BAT (according to any uptake of 18FDG above a definedthreshold) (38e42). The inverse relationship between BAT preva-lence and body mass index or % adiposity in humans also supportsa possible role for BAT in the regulation of caloric balance in humans(29,31,33,43). Resting metabolism and cold-induced thermogenesiswere also correlated with BAT activity in another study (44). Acutecold exposure was uncontrolled and likely not equivalent betweensubjects in most previously published studies. In fact, it makes littlesense, from the laws of thermodynamics, that, in the face of similarcold stress,whole bodyenergyexpenditurewould rise in onepersonand not in another. One would rather expect, as we demonstrateusing a unique setup to carefully control cold exposurewith a liquid

conditioned suit allowing simultaneous measurement of heatdissipation, muscle shivering activity and skin and body coretemperature (36) that whole body energy expenditure rises equiv-alently but is driven by shivering in those without BAT or by non-shivering thermogenesis in those with BAT. Indeed, we founda significant inverse relationship between BAT total volume ofactivity and muscle shivering activity on identical cold exposure inhealthy men and men with diabetes that have thus far participatedin our investigations (Fig. 2). Our findings suggest that the mainfunction of BATmetabolic activity, at least on acute cold exposure inthe fasting state, is to produce heat to protect against cold.

Is there a role for BAT in postprandial TG and energy metabolism inhumans?

From animal studies, since the pioneering work of Rothwell andStock (45), evidence that BAT adaptive thermogenesis counteractschanges in energy balance and could therefore protect against thedevelopment of obesity and type 2 diabetes has been stronglysupported by some (28,45e51) but firmly contested by otherinvestigators (52,53). Recently, BAT was shown to very efficientlymetabolize TG from circulating lipoproteins in cold-exposed mice(54), consistent with the known induction of LpL expression duringcold and high fat feeding-induced BAT activation (55e57) and withthe role of BAT in the hypolipemic effect of PPARg treatment (58).We also demonstrated that cold-activated BAT uses circulatingNEFA (36), but so far BAT role in TG clearance has not been studiedin humans. In view of the known metabolic inflexibility of whiteadipose tissues, including resistance to both insulin-mediatedstorage of dietary fatty acids and catecholamine-mediated lipol-ysis of intracellular TG, leading to reduced flexibility of systemicfatty acid fluxes duringmeal intake, we recently suggested (17) thatBAT may also display reduced meal and sympathetically-inducedactivation that may contribute to the abnormal dietary fatty acidpartitioning seen in insulin resistant subjects (2,26). Despite thelack of reduction in circulating fasting plasma TG during acute cold-induced activation in our current human investigations (36), onecannot rule out a significant role of BAT in the regulation of post-prandial lipid metabolism in humans at this point.

Future Perspectives

One outstanding question is whether increased dietary fattyacid partitioning to the heart and early cardiac dysfunction in pre-

Figure 3. Whole body PET acquisition after 18FDG injection showing increase in BATactivity and mass in a healthy subject from before (left panel) to after (right panel)4-week cold acclimation. More 18FDG uptake can be noted in the supraclavicular andparavertebral BAT depots after acclimationwhereas lessmuscle (i.e. pectoralismajor andintercostal muscles) 18FDG uptake is seen due to reduced shivering (Blondin DP, LabbéMS, Turcotte EE, Carpentier AC, Richard D and Haman F, unpublished observation).

A.C. Carpentier / Can J Diabetes 37 (2013) 109e114 113

diabetes state can be corrected with improved insulin sensitivity,weight loss and/or lifestyle modifications. Studies are underway inour laboratory to test the effect of weight loss with lifestylemodifications and of 7-day reduction in caloric and saturated fat

Figure 4. Proposed link between impaired dietary fatty acid storage in white adiposetissues and impaired BAT metabolism and overexposure of lean organs (e.g. skeletalmuscles, heart and liver) to chylomicron-TG and NEFA. Disordered storage of dietaryfatty acids in white adipose tissues has been clearly associated with increased cardiacdietary fatty acid uptake, but not with increased uptake in skeletal muscles and liver, inpre-diabetes. At least in the muscle, local regulation of blood flow counters theincrease in dietary fatty acid spillover observed in pre-diabetes and diabetes. Impairedoxidative metabolism through reduced physical activity is the most likely mechanismfor pathological ectopic fat deposition in muscles of subjects with type 2 diabetes. Denovo lipogenesis (DNL) is the most likely mechanism for the increase in ectopic fatdeposition observed in the liver.

intake on dietary fatty acid partitioning and cardiac metabolismand function in subjects with impaired glucose tolerance. We arealso currently testing whether cold acclimation over a 4-weekperiod may increase BAT volume and metabolic activity inhealthy individuals. If this proves to be possible, as our preliminaryresults suggest (Fig. 3), we will then be able to test whetherincreasing BATmetabolic activity may be associated with beneficialsystemic metabolic effects to eventually counter weight gain andabnormal postprandial energy and lipid metabolism in pre-diabetes and diabetes. We will be able to test whether pre-diabetes and diabetes are conditions associated with both WATand BAT metabolic dysfunctions and whether the latter may playa role in the deposition of ectopic fat and development of diabetesand its complications (Fig. 4). The outcome of these investigationswill hopefully be the identification of novel target mechanisms forthe monitoring of progression, prevention and treatment of type 2diabetes and its cardiac complications.

Acknowledgments

ACC is the recipient of the CIHR-GSK Chair in Diabetes.

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