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 REMERCIMENTS

Voici mes 3 années de thèse qui s’achèvent. C’est maintenant le moment de rédiger une partie
très importante: les remerciements. La rédaction de cette partie a commencé dans mon coeur
dès les premiers jours de mon arrivée en France, séparée de mon aimable pays, le Cambodge.

J’adresse tout d’abord ma très sincère reconnaissance à mon directeur de thèse, Monsieur le
Professeur Rémy Burcelin (INSERM 1048), qui m’a accueillie chaleureusement au sein de
son équipe et m’a guidée tout au long de ce travail. C’est dans ce labo, que j’ai découvert de
nouvelles techniques et où j’ai obtenu les premiers résultats. Je le remercie profondément
pour ses conseils éclairés, ses corrections précieuses pour nos articles et pour cette thèse. Je
garderai beaucoup de considération pour sa force de travail.

Je tiens également à exprimer ma reconnaissance à mon co-directeur de thèse Monsieur le

Docteur Eric Serée (INSERM 1062 / INRA 1260) qui m’a invitée à travailler dans son
équipe et m’a proposé ce sujet de thèse très intéressant. Du fond du coeur, je voudrais lui
adresser, mes plus sincères remerciements. Je le remercie également pour sa confiance, son
soutien, et pour sa présence dans tous les moments difficiles de cette thèse.

Je n’aurais pu avoir la possibilité de réaliser ce travail de thèse sans mon encadrant Monsieur
le Professeur Serge Champion (CNRS 7263 – IMBE) qui m’a partagé ses connaissances et
ses compétences en Biochimie et Biologie Moléculaire et qui m’a donné de nombreux
conseils pour mener à bien ce travail. Je le remercie sincèrement pour son aide précieuse dans
la préparation de cette revue de thèse ainsi que des différentes communications réalisées lors
de cette thèse.

Je tiens à remercier également à Monsieur le Professeur Yves Barra qui m’a accepté dans
son laboratoire. Je le remercie tout particulièrement pour sa gentillesse, son soutien et ses
conseils précieux.

Je voudrais remercier Madame le Docteur Catherine Riva, Madame le Professeur Evelyne

Ollivier et Monsieur le Professeur Philippe Piccerelle de m’avoir fait l’honneur d’être
rapporteurs de cette thèse. Je suis très honorée de leur investissement dans la lecture et les
corrections de cette thèse. Je vous prie, Mesdames, Monsieur, de trouver ici le témoignage de
ma reconnaissance et de mon profond respect.

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Je tiens à remercier infiniment à Madame le docteur Béatrice Cousin qui a accepté d’être
une des membres de mon comité de thèse. Je la remercie pour sa participation et ses conseils
précieux.

Tous mes remerciements vont également à Madame le Professeur Marie-Christine Alessi,

la Directrice de l’UMR INRA 1260, pour m’avoir accueillie dans son unité et m’avoir assuré
des conditions de travail de bonne qualité. Je vous prie, Madame, de trouver ici l’expression
de ma reconnaissance.

Les résultats que j’ai la chance de présenter dans cette thèse sont le fruit d’un travail
d’équipes. Je voudrais adresser mes remerciements sincères à tous les personnels et collègues
des équipes ci-dessous:

- L’équipe 2 "Facteurs de Risques Intestinaux, Diabète, Dyslipidémie", INSERM

U1048, I2MC, Institut de Recherche sur les Maladies Métaboliques et
Cardiovasculaires de l'Hôpital Rangueil, Toulouse.
- L’équipe IMBE de Mutagénèse environnementale de l’UMR CNRS 7263, Faculté de
Pharmacie, Aix Marseille Université.
- L’équipe 2 "Micronutriments, Tissu adipeux et Résistance à l’insuline", l’UMR
INSERM 1062 / INRA 1260, "Nutrition Obésité et Risque Thrombotique", Faculté de
Médecine, Aix Marseille Université.
- L’équipe de la Zootechnie, I2MC, Institut de Recherche sur les Maladies
Métaboliques et Cardiovasculaires de l'Hôpital Rangueil, Toulouse.
- La plateforme d’imaginerie, I2MC, Institut de Recherche sur les Maladies
Métaboliques et Cardiovasculaires de l'Hôpital Rangueil, Toulouse.
- Le plateau de Génomique Get-Purpan, IFR150, Institut Fédératif de Recherche Bio-
Médicale de Toulouse (IFR-BMT) de l’Hôpital Purpan, Toulouse.
- L’équipe de Vaiomer, Labege, Toulouse.

Merci à toutes celles et ceux qui m’ont acceptée dans une ambiance agréable, merci pour leur
disponibilité, leur gentillesse et leur soutien permanent souvent technique, parfois moral:
Pascale Loubières: je te remercie infiniment pour ton accueil chaleureux au laboratoire. Je ne
me sens jamais seule avec toi. Merci énormément d’être à mes côtés pour m’écouter, me
rassurer et partager des bons moments. J’aime te raconter des choses et discuter avec toi et

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partager des connaissances sur le monde des bactéries. Je remercie également à toute ta
famille pour leur accueil chaleureux pendant mon séjour à la montagne. J’ai passé une
merveille randonnée avec eux.
Jean-Charles Martin: je vous remercie beaucoup pour les données GC-MS.
Patricia Bremond: sans toi, je n’aurai pas pu apprendre et réussir toutes les cultures de
cellules qui ont été nécessaires. Je te remercie beaucoup.
Vincent Azalbert: merci de m’avoir appris à faire le DGGE qui est une technique
compliquée à réaliser. Je n’aurai pas pu le réussir sans ton aide.
Céline Pomié et Estelle Grasset: je vous remercie de m’avoir partagé vos échantillons pour
mener à bien mes expériences sur les cytochromes.
François Tercé: merci beaucoup pour ton soutien chaleureux et tes conseils précieux
concernant les expériences sur les lipides.
Vincent Blasco: je te remercie de m’avoir appris à faire l’analyse des résultats.
Céline Garret: merci de m’avoir appris les extractions d’ARN.
Matteo Serino: merci beaucoup pour tes conseils et pour m’avoir appris à réaliser
l’extraction d’ADN.
Aurélie Waget: je te remercie pour m’avoir appris les manipulations des souris.
Jean François-Landrier et Frank Peiretti: merci pour votre aide technique.

Mes remerciements vont également à Monsieur le Professeur Philippe Valet et son équipe
du service de l’Ecole doctorale de Biologies Santé et Biotechnologies pour leur sympathie et
leur aide pour surmonter les processus administratifs lors de la soutenance de cette thèse.

Je tiens de remercier l’Université Toulouse III – Paul Sabatier et le coordinateur du Projet

Techno II – Erasmus Mundus pour m’avoir octroyé une bourse afin de réaliser cette thèse. Je
remercie infiniment Monsieur Jean-Michel Baleynaud, Monsieur le Professeur Sovan
Lek, Mademoiselle Laura Verheyleweghen et leur équipe du Projet Techno II.

Je remercie énormément Madame Sophie BOCHET et son équipe du Service d’accueil des
étudiants étrangers du CROUS Aix-Marseille pour leur sympathie et pour les efforts qu’ils
ont consacré à me trouver un logement à Marseille.

Je voudrais adresser mes sincères remerciements au Doyen de la Faculté de Pharmacie du

Cambodge pour son soutien et à Monsieur le Docteur Rothmony Eang pour son aide
administrative pour ma demande de bourse.

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Je tiens à remercier tout particulièrement Monsieur Hot Bun et sa famille et Monsieur
Chhan Siv et son épouse pour leurs conseils précieux, leur soutien et leurs encouragements.

Je voudrais remercier également à l’AEPK (Amicale des étudiants en Pharmacie et des

Pharmaciens Khmer) qui aide techniquement et financièrement les étudiants cambodgiens.

Je remercie spécialement mes deux très bonnes amies, Hanna Ilchmann et Mardy Long qui
sont toujours à mes côtés. Hanna, je te remercie pour m’avoir partagé ta chambre durant
chacun de mes séjours à Toulouse. Merci à toutes les deux pour votre soutien et votre
encouragement. Pour moi, vous êtes comme mes sœurs.

Mes 3 années de thèse en France ont été marquées par l’enthousiasme, la joie, les surprises et
aussi quelquefois les doutes, l’angoisse, la démotivation…Je voudrais remercier tous mes
amis cambodgiens et étrangers d’avoir partagé avec moi ces sentiments. Je vous remercie
profondément pour votre présence, votre patience, votre soutien et votre encouragement.

Du fond du coeur, je tiens à remercier toute ma famille: Papa, Maman, ma grande mère, mes
sœurs, mon petit frère, mon parrain et ma marraine, mon beau frère, mes tantes, mes oncles,
mes cousins, cousines, mon neveu Lin Moon …. Votre amour, votre soutien, vos
encouragements permanents m’ont permis d’aller jusqu’au bout de ce long chemin.

Enfin, merci à toi, mon prince, Sopheap Oeng, de m’avoir assuré que tu es toujours là, pour
moi. Ces années passées en France ont été, pour nous deux, une épreuve à surmonter afin
d’atteindre une relation éternelle. Merci de m’aimer si fort tous les jours.
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`,:! ! f! `>FADNSED>!HRSJ>AI!LASDNI!

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+*0)X"! f! +HD>IXS>JJRJAI!A?M>K@NH!QNJ>SRJ>!"!
+:,o!! ! f! +HD>IL>INH!OAQQA!
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Q<;(.X"!! f! )@SINKNQAJ!FINKDAOJAH?@H!(!KEHDMAK>X"!
Q<2j! ! f! )NRK>!F>JJ>XJ@e>!e@HAK>!
)<7!! ! f! )E>JNF>IN[@?AK>!
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 LISTE DES TABLEAUX
!
!
-ABJ>AR!"f!.NRKXDEF>!?R!?@ABCD>!QNHNOGH@TR>!//////////////////////////////////////////////////////////////////////////////////!Y"!

-ABJ>AR!#f!;CH>K!>D!JNSRK!J>K!FJRK!IGFJ@TRGK!3-#!KRKS>FD@B@J@DG!/////////////////////////////////////////////////!Y#!

-ABJ>AR!$f!*NHD>HR!?>!'.6!?AHK!?@LLGI>HD>K!KNRIS>K!//////////////////////////////////////////////////////////////////////!=%!

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"%!
 LISTE DES FIGURES
!

!"#$%&'()'6N@>K!?>!K@OHAJ@KAD@NH!*BJh*0<!?>!+'!/////////////////////////////////////////////////////////////////////////////////!##!

!"#$%&'*)'6N@>K!?>!K@OHAJ@KAD@NH!<+$j!>D!)0<!e@HAK>!?>!+'.!////////////////////////////////////////////////////////!#$!

!"#$%&'+)'(LL>D!?P@HKRJ@H>!KRI!JPMNQGNKDAK@>!OJRS@?@TR>!/////////////////////////////////////////////////////////////////!#&!

!"#$%&',)!2>K!SNHKGTR>HS>K!FND>HD@>JJ>K!?>K!FMNKFMNIEJAD@NHK!?>K!FINDG@H>K!+'.!KRI!J>K!

.>Ih-MI!/////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////!#=!

!"#$%&'-)!.DIRSDRI>!>D!FAID>HA@I>K!?k@HD>IASD@NH!?>K!+'./!//////////////////////////////////////////////////////////////!#5!

!"#$%&'.)!2k@HM@B@D@NH!?>!JA!WN@>!?>!K@OHAJ@KAD@NH!?>!Jk@HKRJ@H>!FAI!J>!.7*.X"!>D!.7*.X$/!/!$U!

!"#$%&'/)!2>K!WN@>K!@QFJ@TRG>K!?AHK!JP@HKRJ@HNXI>K@KDAHS>!?AHK!J>!QRKSJ>/!///////////////////////////!$8!

!"#$%&'0)!2>K!WN@>K!?R!KDI>KK!?R!IGD@SRJRQ!>H?NFJAKQ@TR>!SNH?R@KAHD!V!RH>!

@HLJAQQAD@NH/!/////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////!%"!

!"#$%&'1)!2P@HLJAQQAD@NH!>D!JA!IGK@KDAHS>!V!JP@HKRJ@H>f!WN@>K!?>!K@OHAJ@KAD@NH!@QFJ@TRG>K/%$!

!"#$%&'(2)!2A!IGFNHK>!@QQRH@DA@I>!?AHK!J>!D@KKR!A?@F>R[!NBCK>K/!///////////////////////////////////////////!&U!

!"#$%&'(()!2PGWNJRD@NH!?>!S>JJRJ>K!Z!?AHK!JA!SNQF>HKAD@NH!?>!JP@HKRJ@HNXIGK@KDAHS>/!///////!&Y!

!"#$%&'(*)!2A!LJNI>!@HD>KD@HAJ>!>D!J>!QGDABNJ@KQ>!?>!JkM\D>/!/////////////////////////////////////////////////////////!=#!

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!"#$%&'(,)!2A!WN@>!QGDABNJ@TR>!?R!'>KWGIADINJ!?AHK!JP@HD>KD@H>!FAI!J>K!>HcEQ>K!4;-K/!=Y!

!"#$%&'(-)!2A!WN@>!QGDABNJ@TR>!?R!'>KWGIADINJ!?AHK!J>!LN@>!FAI!J>K!>HcEQ>K!.42-K/!//////!==!

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!"#$%&'(/)!2>K!S@BJ>K!B@NJNO@TR>K!QNJGSRJA@I>K!KRFFNKG>K!?R!'>KWGIADINJ!?AHK!J>K!

FINS>KKRK!AHD@X@HLJAQQADN@I>K!>D!AHD@XN[E?AHD>K/!////////////////////////////////////////////////////////!5U!

!"#$%&'(0)!2>K!?>R[!@KNQCI>K!?>!*RISRQ@H>/!/////////////////////////////////////////////////////////////////////////////////////!5$!

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K@OHAJ@KAD@NH!S>JJRJA@I>/!//////////////////////////////////////////////////////////////////////////////////////////////////////////////!5Y!

"&!
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!"#$%&'**)!([FI>KK@NH!?>!*EFK!?AHK!J>!SNJNH/!/////////////////////////////////////////////////////////////////////////////////!"&8!

!"#$%&'*+)!([FI>KK@NH!?>!*EFK!?AHK!JP@JGNH/!/////////////////////////////////////////////////////////////////////////////////////!"YU!

!"#$%&'*,)!([FI>KK@NH!?>!*EFK!?AHK!J>!LN@>/!/////////////////////////////////////////////////////////////////////////////////////!"Y"!

!"#$%&'*-)!([FI>KK@NH!?>!*EF#S&&!>D!*EF#>"!?AHK!?@LLGI>HDK!DEF>K!?>!KNRI@K/!///////////////!"Y#!

!"#$%&'*.)!.@D>K!?PASD@NH!FNKK@BJ>K!?R!`:3!>D!?>K!FNJEFMGHNJK!//////////////////////////////////////////////!"Y&!

!"#$%&'*/)!`EFNDMCK>!SNHS>IHAHD!J>K!K@D>K!?PASD@NH!FNKK@BJ>K!?R!`:3!>D!?>K!FNJEFMGHNJK!

>D!J>RIK!I>JAD@NHK!M@GIAISM@TR>K/!/////////////////////////////////////////////////////////////////////////////////////////!"=$!

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 55 èmes Journées Nationales de Diététique et Nutrition

NOUVEAUX TRAITEMENTS ET PERSPECTIVES DANS LE DIABÈTE DE TYPE 2

LE RESVÉRATROL AU SERVICE DU DIABÈTE

Dr N. SRENG1, Dr E. SERÉE1, Pr S CHAMPION2

1INRA, UMR1260 / 1062 INSERM / AMU ; Nutrition, Obésité et risque thrombotique,
27 boulevard Jean-Moulin, Marseille F-13385, France
2IMBE - UMR CNRS 7263 / IRD 237, Mutagenèse Environnementale,
Aix-Marseille Université, Faculté de Pharmacie 27 Bvd Jean Moulin, Marseille F-13385,
France

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 55 èmes Journées Nationales de Diététique et Nutrition

INTRODUCTION ET ÉTIOLOGIE DU DIABÈTE DE TYPE 2

Le diabète de type 2 (DT2) est à ce jour considéré comme une pandémie

selon l’Organisation Mondiale de la Santé. Le nombre de personnes
diabétiques dans le monde est actuellement estimé à environ 250 millions,
et devrait atteindre près de 380 millions en 2025, ce qui représente 7,1 %
de la population adulte âgée de 20 à 80 ans. En Europe, une croissance
de 16 % de la maladie est prévue d’ici à 2025 [1, 2]. Si le diabète est une
pathologie qui préoccupe nos sociétés, il faut tenir compte des pathologies
associées. En effet, les complications cardiaques, vasculaires, rénales et
ophtalmologiques, augmentent également le coût de la prise en charge
du diabète et constituent actuellement, en plus d’un problème de santé
publique, un risque économique pour l’ensemble des pays de l’ouest.
Les causes du développement DT2 sont multiples, à la fois génétique,
environnementale et sociale. La sédentarité associée à un enrichissement
de la proportion de graisses dans les régimes alimentaires est un facteur
aggravant qui, combiné au patrimoine génétique, est sûrement responsable
de l’épidémie. Parallèlement à cela, nous sommes victimes d’une
diminution de la consommation en fibres végétales qui sont impliquées
dans la digestion et l’équilibre alimentaire par l’apport de micronutriments
(vitamines, sels minéraux, etc.). Un autre rôle fondamental joué par ces
fibres végétales concerne leur fonction de substrat à l’égard de notre flore
intestinale. La diminution de leur proportion engendre un changement
qualitatif de la flore intestinale et par voie de conséquence une altération du
métabolisme énergétique [3-13] . Les conséquences physiopathologiques
de ce déséquilibre énergétique se traduisent d’une part par une diminution
de l’action de l’insuline i.e. l’insulinorésistance et d’autre part par une
augmentation de la masse adipeuse. Ces deux conséquences fonctionnelles
insulinorésistance et adipogénèse sont reliées entre elles via un processus
inflammatoire de bas niveau qui apparaît progressivement et qu’on
dénomme inflammation métabolique [3]. En utilisant des modèles animaux
qui développent des maladies métaboliques tels que des souris nourries
par un régime riche en graisse (> 40 % p/p) pendant plusieurs mois, on
observe une augmentation de la sécrétion des cytokines inflammatoires et
de chimiokines. Ces cytokines, notamment le TNF- , l’IL-1, et l’IL-6 [4, 5],
interfèrent avec la signalisation générée par le récepteur à l’insuline. Ceci
se traduit par une diminution de l’utilisation du glucose par les muscles et
une levée d’inhibition de la production hépatique de glucose. Il s’en suit
une augmentation de la glycémie puis l’apparition d’un hyperinsulinisme et
d’une hyperglycémie ce qui induit la redistribution des flux métaboliques
notamment vers les organes de stockage tel que le tissu adipeux et le foie.
Une autre voie récemment mise en évidence montre le rôle que peuvent
avoir des changements de la flore bactérienne, en liaison avec l’alimentation
dans l’installation des maladies métaboliques notamment l’obésité [7, 11] et
le DT2 [3-6]. Il apparaît que la modification de la flore intestinale semble
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 55 èmes Journées Nationales de Diététique et Nutrition

être une des causes de l’obésité. En effet, un régime riche en graisse

favorise, d’une part, l’émergence de bactéries Gram - qui seraient à l’origine
de l’installation de l’inflammation métabolique et d’autre part, diminue le
nombre de germes Gram + [3-5, 7-10]. Des études ont montré que le genre
Bifidobacterium (Gram +) est inversement corrélé à l’incidence du DT2 et
de l’obésité chez des souris soumises à un régime riche en graisse [3-5].
L’utilisation de fibres alimentaires induit une augmentation du nombre de
bactéries à Gram + chez les souris nourries avec un régime riche en graisses,
et parallèlement, on constate une diminution de l’inflammation et un retard
dans l’installation de l’insulinorésistance [14].
La thérapie antidiabétique n’est pas à ce jour efficace. En effet, les
molécules actuellement sur le marché ne donnent pas les résultats
escomptés et il est difficile de régler avec les traitements disponibles la
complexité du désordre métabolique. Il est alors urgent de proposer de
nouvelles stratégies thérapeutiques. Une alternative serait de prévenir
l’apparition de la maladie chez les personnes à risque et/ou d’accompagner
le traitement du diabète déclaré par la prise de compléments alimentaires.
Les approches nutritionnelles et ‘alicamenteuses’ sont ainsi considérées
comme bien tolérées. De nombreuses données, revues ci-dessous,
suggèrent que le resvératrol (RVR) pourrait correspondre à une nouvelle
stratégie thérapeutique et ‘alicamenteuse’. Son mécanisme d’action serait
basé sur des effets à la fois antioxydant et anti-inflammatoire [15,16].

LE RESVÉRATROL : MOLÉCULE DE PRÉVENTION ET/OU THÉRAPEUTIQUE

Le RVR, ou 3,5,4’ transtrihydroxytilbene (figure 1), est un polyphénol naturel

que l’on trouve dans de nombreuses espèces végétales dont le raisin noir,
les cacahuètes, le pin et la renouée chinoise (Polygonum Cuspidatum),
sont les principales sources commerciales. Le RVR est une molécule qui
est synthétisée par les plantes en réponse à un stress par exposition à la
lumière ultra-violette ou une attaque fongique [17, 18]. Le RVR est étudié
depuis de nombreuses années et il possède de nombreuses propriétés
pharmacologiques.

Le resvératrol : un antagoniste compétitif du Récepteur des

Arylhydrocarbures (AhR)
Le Récepteur des Arylhydrocarbures (AhR) est un facteur de transcription
dont les ligands naturels endogènes ne sont pas bien caractérisés.
Le récepteur AhR est impliqué dans la régulation de l’expression de
nombreux gènes lorsqu’il lie divers polluants environnementaux tels que
les hydrocarbures aromatiques du tabac et des gaz d’échappement, les
dioxines (dont la TCDD, Dioxine de Seveso), les polychloro-biphényles
(PCB, isolants électriques) et d’autres xénobiotiques. AhR induit les gènes
de la détoxification des hydrocarbures aromatiques tels que le cytochrome
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 55 èmes Journées Nationales de Diététique et Nutrition

Figure 1 : Structure du resvératrol

P450 1A1 (CYP 1A1) et les enzymes de conjugaison (glutathion S-transférase

Ya, UDP-glucuronyl-transférase, etc.) [19] et un grand nombre de gènes
liés à l’inflammation (interleukines, Cox2, NO synthase) [20]. Certains
ligands comme les PCB augmentent le stress oxydatif et la peroxydation
des lipides, ce qui pourrait être une cause des lésions cellulaires et du rôle
athérogène de ces molécules. Ces composés agissent sur la vascularisation
et provoquent des perturbations métaboliques conduisant à l’insulino-
résistance. Un autre ligand, le TCDD inhibe la différenciation adipocytaire
[21] et le transport du glucose dans le tissu adipeux [22]. Des études
épidémiologiques montrent que l’exposition à la dioxine tétrachlorée
(dioxine de Seveso, TCDD) induit une augmentation significative du risque
de TD2. Bertazzi et al. rapportent dès 1998 un “excès” de cas de TD2 dans la
population féminine de Seveso [23, 24]. Ce lien entre dioxine et TD2 a été
confirmé par les études ultérieures de ce groupe [25] et par des études sur
des anciens combattants du ViêtNam [26, 27] et des travailleurs exposés
[28, 29]. Ces données sont à rapprocher de l’association connue entre TD2
et tabagisme, dont les agents pricipaux (hydrocarbures aromatiques) sont
des ligands du AhR [30, 31]. Le RVR inhibe les effets des divers agonistes du
AhR par inhibition compétitive [32]. Le RVR est le seul antidote efficace et
non toxique contre ces polluants environnementaux.

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 55 èmes Journées Nationales de Diététique et Nutrition

Le resvératrol : molécule antioxydante

Le RVR est connu depuis de nombreuses décennies comme étant un
antioxydant majeur. Mais il faut préciser que c’est le RVR ingéré et non
métabolisé qui possède cette activité. Malheureusement, le RVR est très vite
métabolisé, et les effets de cette molécule sur le syndrome métabolique
proviendraient d’autres propriétés que nous décrirons ultérieurement.

Le resvératrol : un anti-inflammatoire antagoniste des voies NF- B et

AP-1.
Les cascades moléculaires liées à AhR et conduisant à une résistance
à l’insuline ne sont pas identifiées mais l’implication de NF- B, facteur
essentiel de l’inflammation a été suggérée [33, 34]. L’activation du AhR
par les dioxines induit l’induction des cytokines de types IL-1. En inhibant
NF- B par son antagonisme vis à vis du AhR, le RVR inhibe l’induction des
cytokines inflammatoires. Ce composé inhibe également l’expression
de la chimiokine MCP-1 [35, 36] induite par le TNF! et qui est impliquée
dans l’infiltration macrophagique. Il se pourrait donc que le RVR agisse sur
le DT2 via son effet au niveau de l’expression de MCP-1. Le AhR interagit
physiquement avec d’autres facteurs de transcription dont PPAR" [37, 38]
tandis que PPAR! régule l’expression de AhR [39, 40]. Il est important de
noter que le facteur de transcription PPAR" est la cible de médicaments
anti-diabétiques de la famille des thiazolidinediones et PPAR! joue un
rôle dans la lipolyse. Le RVR agit aussi sur l’inflammation en inhibant les
voies NF- B et AP-1 [41-45]. Il diminue l’expression de la cytokine IL-1# et
s’oppose à la production de radicaux oxydants (ROS) [46, 47]. D’autres
voies d’action du RVR ont été mises en avant comme la modification de
la synthèse des eicosanoïdes par inhibition des cyclooxygénases (COX-1 et
COX-2) responsables de la synthèse de médiateurs pro-inflammatoires [48].

Le resvératrol et les mitochondries

Dans le muscle squelettique, une diminution de la synthèse d’ATP et de
l’expression des gènes contrôlant l’activité mitochondriale est en partie, au
moins, associée à une insulinorésistance.
Le facteur PGC-1!$qui est un PPAR"$et le facteur SIRT1 qui est associé à PGC-
1 sont fonctionnellement liés l’un à l’autre et à l’utilisation du glucose. En
effet, une diminution de l’activité de PGC-1 est associée à l’apparition du
diabète et SIRT contrôle le métabolisme glucidique hépatique [49].
Le RVR induit l’expression du gène codant pour PGC-1! via l’activation du
facteur SIRT1 [49]. Par ailleurs, le RVR augmente la taille et le nombre de
mitochondries dans divers tissus. Dans les muscles, en réponse au RVR, les
mitochondries présentent une augmentation du pouvoir oxydant et une
activité métabolique accrue associée à une augmentation de l’activité de
la citrate synthétase.
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 55 èmes Journées Nationales de Diététique et Nutrition

LES DONNÉES DE NOTRE LABORATOIRE

Notre laboratoire s’est impliqué dans l’étude de l’effet d’un traitement au RVR
sur le TD2. Le RVR, dès son administration chez l’homme, est une molécule
qui est très vite éliminée de l’organisme suite à un cycle de métabolisation
entéro-hépatique très fort impliquant les enzymes UGT1A1 et 1A9. Cela se
traduit par l’apparition de métabolites sulfatés et de glucuronoconjugués
éliminés par les urines et les fèces.
Avant de valider l’effet du RVR sur le TD2, nous avons mis au point une
forme galénique permettant au RVR d’être hautement biodisponible [50].
Après validation de cette galénique par des études de pharmacocinétique
(figure 2), nous avons nourri des animaux par un régime diabétogène riche
en graisse supplémenté ou non en RVR.

Figure 2 : Étude pharmacocinétique réalisée chez 15 sujets sains en milieu hospitalier.

40 mg de RVR sont administrés soit sous forme sèche (classique) soit sous forme liquide (formule du laboratoire). Le taux de RVR
sanguin est évalué au cours du temps. Le resvératrol sous forme liquide est toujours dans une concentration thérapeutique active 5
heures après son administration.

!"#$%&'$(&)'*

L’administration de RVR pendant 5 semaines réduit l’intolérance au glucose.

Nous avons mis en évidence les mécanismes moléculaires impliqués dans ce
processus. Nous avons démontré que le RVR induisait, par augmentation de
la transcription, l’expression et ensuite la sécrétion intestinale de Glucagon-
Like Peptide-1 (GLP-1) [51]. Cette hormone entre par la veine porte et
peut alors activer la sécrétion d’insuline. Ce mécanisme a été validé par
l’utilisation d’animaux génétiquement modifiés et présentant un récepteur
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 55 èmes Journées Nationales de Diététique et Nutrition

non fonctionnel au GLP-1. En effet, sur ces animaux, le RVR n’agit plus sur la
tolérance au glucose car le taux d’insuline n’est plus modulé. Parallèlement
à cela, nous avons démontré que le RVR diminue l’inflammation induite
par le régime diabétogène riche en graisse. En effet, l’expression des
cytokines inflammatoires de type IL-1 et IL-6 est diminuée par le RVR et
les cytokines anti-inflammatoires de type IL-10 et TGF sont augmentées
par la même molécule en particulier au niveau hépatique et intestinal [51].
Le RVR étant une molécule antifongique qui possède quelques propriétés
antimicrobiennes, nous avons évalué l’effet du RVR sur la flore intestinale.
Nous démontrons pour la première fois que le RVR est un agent prébiotique
qui diminue le nombre de bactéries inflammatogènes Gram - et qui induit
la prolifération des bactéries Gram + (figure 3) [51].

Figure 3 : Effet de RVR sur la flore intestinale. NC : contrôle ; INFL : régime inflammatogène ; I
NFL + RVR : régime inflammatogène + resvératrol. Le RVR fait disparaître des bactéries qui ont émergé suite au régime
inflammatogène et fait apparaître des bactéries qui ont été tuées par ce régime.

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67)+&)8'+ 89&#'*)-)+ ./012:;2<

="%&'#()*'+ >97?"&9+ 6@AA13B3;

!"#$%&'( )&"*+,0.+/+
=)C)*($"%&'#)9D

Enfin, nous avons testé l’effet d’une association du RVR à la sitagliptine, un

médicament antidiabétique inhibiteur de la dipeptidyl peptidase-4 (DPP-
4). Ce choix fut motivé par le fait que le RVR induit la sécrétion de GLP-1 et
que la sitagliptine inhibe la dégradation du GLP-1. Nos résultats indiquent
finalement que le resvératrol potentialise l’effet de la sitagliptine [51].

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 55 èmes Journées Nationales de Diététique et Nutrition

CONCLUSION

Le RVR sous une forme biodisponible par voie orale, en tant qu’«alicament»,
semble un candidat prometteur dans le domaine du traitement du TD2 et
de l’obésité. Toutes les données cumulées sur cette molécule confirment
que cette molécule peut être utilisée dans la prévention ou l’optimisation
d’une thérapeutique antidiabétique. L’avantage du RVR est d’être un
complément alimentaire naturel et non toxique, utilisable per os et
associable à un médicament anti-diabétique. Son activité sur le TD2 est
médié par ses divers rôles anti-inflammatoire, prébiotique et inducteur
de la sécrétion du GLP-1 et de l’insuline.

Dr Eric SERÉE
!"#""$"#%&'()*%+$&,)
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