SERVICE D'ENDOCRINOLOGIE, DIABETOLOGIE et NUTRITION

Département des spécialités de médecine

Service d’Endocrinologie, Diabétologie, Hypertension et Nutrition

RAPPORT D'ACTIVITE

2015

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PERSONNEL

Médecin-Chef du Service Jacques PHILIPPE HUG+DIP Prof. Ord. Dr Méd

Responsable ad interim de Jacques PHILIPPE l’Unité d’Endocrinologie (UE) Prof. Ord. Dr Méd

Responsable de Jacques PHILIPPE l’Unité de Diabétologie (UD) Prof. Ord. Dr Méd.

Responsable de Claude PICHARD HUG l’Unité de Nutrition (UN) Prof. Associé, Médecin adjoint Responsable de l’Unité Antoinette PECHERE (50 %), C.C. HUG d’Hypertension artérielle (HTA) Prof. Associée, médecin adjointe Responsable de la recherche François PRALONG, CHUV en endocrinologie de la Prof. Ord. Dr Méd reproduction Médecin adjointe agrégée Laurence GENTON-GRAF – UN (80 %) HUG

Chef(fe)s de clinique Giacomo GASTALDI – UD/UE/HTA HUG

Jaafar JAAFAR – UD/UE/HTA HUG

Bettina KOEHLER-BALLAN - UE 80 %

[jusqu’au 31.12.15] HUG

Alessandro LIMONTA – UN HUG

Sarah MALACARNE – UD/UE [80 % dès le 01.11.15] HUG

Médecins internes Michaël EGLOFF – UD/UE/HTA [jusqu’au 31.10.15] HUG

Bénédicte DE KALBERMATTEN – UD/UE/HTA HUG

Marina PORTELA – UD/UE/HTA [dès le 05.02.15] HUG

Sophie MAITRE – UD/UE/HTA [dès le 01.06.15] HUG

Heba AL-ALWAN – UD/UE/HTA [dès le 01.11.15]

Médecins consultants Bertrand JACOT DES COMBES bénévole

Alain PERNET bénévole

Bettina PETER-RIESCH (10 %) HUG

Nicolas VON DER WEID bénévole

Michel GOUMAZ bénévole

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Nathalie JACQUELIN-RAVEL – UN (20 %) bénévole

Dimitrios SAMARAS – UN (20 %) HUG

Patrick MEYER (10 %) HUG

Biostatisticien Yves DUPERTUIS (100 %) HUG Secrétaires Marie-Claire MONNARD (90 %) HUG

Secrétariat du Prof. J. Philippe

Marianne LATAPIE (10 %) HUG Secrétariat du Prof. J. Philippe Chloé COURBARD (100 %) HUG Secrétariat de l’Unité d’Endocrinologie, Diabétologie et Hypertension

Charlotte KREBS (80 %) HUG Secértariat de l’Unité d’Endocrinologie, Diabétologie et Hypertension Marina SCHUTZ (70 %) HUG Secrétariat de l’Unité de Nutrition Carole COWALOOSUR-NOIRAT (30 %) HUG Secrétariat de l’Unité de Nutrition

Laboratoires de Recherche

Laboratoire du métabolisme

Cheffe de groupe Prof. Ord., Françoise ROHNER-JEANRENAUD DIP

Dr. en pharmacie Jordi ALTIRRIBA-GUTTIEREZ DIP

Doctorante Anne-Laure POHER FNRS puis FP

Laborantine (80 %) Aurélie CAILLON DIP

Laborantine (50 %) Jacqueline LYAUTEY (jusqu’au 28.02.2015) DIP

Assistant technique (80 %) Franck BONTEMS (dès le 01.03.2015) FNRS, DIP et Plateforme facult.

Laboratoire des lipides Chef de groupe Prof. Richard W. JAMES DIP

Assistant Dr Miguel FRIAS Fonds Privé 70 % ; DIP 30 %

Laborantine Mme Marie-Claude BRULHART-MEYNET HUG 75%

Stage de laboratoire Dr Jonas BRINCK (Suède)

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Laboratoire de diabétologie moléculaire Responsable Jacques PHILIPPE HUG/DIP

Maître-assistant Yvan GOSMAIN DIP

Assistant Rodolphe DOSAULEY FN

Laborantine Mounia HEDDAD MASSON FN/HUG

Laborantin Florian VISENTIN FP

Assistante Svetlana SKARUPELOVA FN

Laboratoire d’endocrinologie circadienne

Responsable Charna DIBNER HUG/DIP

Assistante Camille SAINI (80 %) EFSD

Assistante de recherche Laurianne GIOVANNONI (30 %) FNRS

Doctorants Anne-Marie MAKHLOUF (50 %) FP

Laurent PERRIN (100 %) FNRS

Bénévole Dr Zhanna CHITIKOVA

Laboratoire de nutrition Médecin T. OSCHIMA 100 %

Biologiste E. JUNIENTES [jusqu’au 31.03.15] 100 %

Biologiste A. PEREZ [dès le 01.01.15] 100 %

Biologiste AM. MAKHLOUF 100 %

Nutritionniste S. GRAF 50 %

Nutritionniste J. MARESCHAL 100 %

Total 6 personnes

(1) Les collaborateurs de recherche sont financés sur les budgets de recherche du Prof. Claude Pichard

Faits marquants du Service :

La Dre Laurence Genton, Chargée de cours, a obtenu un subside du Fond national suisse pour ses travaux sur le microbiote intestinal.

Remerciements Nous tenons également à remercier les collaborateurs suivants : Mesdames Myriam PASCHOUD et Caroline GILBERT DE VAUTIBAULT, infirmières, pour leur aide indispensable et professionnelle dans l’exécution des tests endocriniens ambulatoires et pour toute leur activité dans les consultations d'hypertension artérielle.

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Mesdames Nathalie JULLIARD, Marie-Alice SAVET et Anne-Laure HARIEL SPINELLI, infirmières à l'Unité de Diabétologie, pour leur aide indispensable et de très haute qualité dans la prise en charge des patients diabétiques. Mesdames Luz PERRENOUD, Montserrat CASTELLSAGUE-PERROLINI et Christiane HELARY ainsi que Monsieur Georges CIMARELLI, infirmier(ères) spécialistes dans les soins éducatifs aux patients diabétiques, pour leur aide constante sans laquelle la prise en charge des patients diabétiques serait inconséquente.

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STATISTIQUES D'ACTIVITE CLINIQUE

UNITE D'ENDOCRINOLOGIE

1. Types d'activités

Unité d’hospitalisation (5 CL)

Consultations ambulatoires (endocrinologie, diabétologie, lipidologie, hypertension

artérielle, nutrition)

Consultations intrahospitalières

Unité de curiethérapie

Consultations conjointes avec le Service d'Endocrinologie et Diabétologie pédiatrique

Consultations pluridisciplinaires des nodules thyroïdiens (endocrinologie, pathologie,

chirurgie)

Consultations conjointes avec le Service de Neurochirurgie (tumeurs hypophysaires)

Cours d’Insulinothérapie intensive

Consultations Vaud-Genève d’hypogonadisme

2. Prestations cliniques

2.1. Consultations ambulatoires

2’462 patients ont été vus à la consultation ambulatoire d'endocrinologie, assurée par les

Drs P. Meyer, J. Jaafar, S. Malacarne, B. De Kalbermatten et M. Portela. Cette

consultation est supervisée par la Dre S. Malacarne, médecin-cheffe de clinique. Les

cytoponctions sont effectuées en consultation multidisciplinaire avec les Drs P. Meyer, J.

Jaafar, S. Malacarne, B. De Kalbermatten, J.-C. Pache (pathologie), M. Pusztaszeri

(pathologie) et F. Triponez (chirurgie).

2.2. Consultations hospitalières

Les consultations hospitalières du site Cluse-Roseraie, sur dossier des Trois-Chêne et

de Belle-Idée ont été d’environ 2000. Ces consultations sont effectuées par les internes

en rotation du Service de la Médecine interne générale sous la supervision des cadres

du Service. Il y a eu environ 1000 consultations de diabétologie et 1000 consultations

d’endocrinologie.

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2.3. Unité de curiethérapie

73 patients ont été hospitalisés dans l'Unité de Curiethérapie pour un traitement

d'hyperthyroïdie ou d'un cancer de la thyroïde. L'entrée et la visite journalière sont

effectuées par un interne ou chef de clinique sous la supervision de la Dre S. Malacarne.

3. Interaction avec d'autres spécialités

Des interactions étroites existent avec d'autres départements et services, permettant une

prise en charge multidisciplinaire de nos patients. Ces réunions ont lieu régulièrement à

un rythme d'une à plusieurs fois par mois :

Tumorboard des tumeurs endocrines avec les Drs F. Triponez (Service de Chirurgie

thoracique et endocrinienne), M. Pusztaszeri (Service de Pathologie clinique) et A.

Roth (Service d’Oncologie), 2 x / mois.

Collaboration régulière avec le Service de Génétique médicale pour les patients

présentant une suspicion d'endocrinopathie héréditaire.

Consultation multidisciplinaire des nodules thyroïdiens avec les Drs J.-C. Pache et M.

Pusztaszeri (Service de Pathologie clinique) et le Dr F. Triponez (Service de Chirurgie

thoracique et endocrinienne), 1 x / semaine.

Consultation multidisciplinaire de neurochirurgie et d'endocrinologie avec le Dr S.

Momjian (Service de neurochirurgie).

Consultation LIPO (consultation multidisciplinaire des lipodystrophies chez les patients

VIH +).

Consultation conjointe avec le Service d'Endocrinologie et Diabétologie pédiatrique

(Dre V. Schwitzgebel), 1 x / mois.

4. Consultations multidisciplinaires

4.1. Consultation multidisciplinaire des nodules thyroïdiens

Cette consultation conjointe, mise sur pied fin 2007, permet au patient investigué pour un

nodule thyroïdien de n'avoir qu'une seule consultation puisqu'il est vu par

l'endocrinologue et le chirurgien à la même consultation. En outre, le cytologue donne

une réponse préliminaire immédiate pour ce qui est de la nature du nodule. Ceci permet

d'éviter au patient deux consultations (suivi endocrinologique, chirurgie).

4.2. Chirurgie hypophysaire

L'ensemble des opérations pour tumeurs hypophysaires se faisant à Genève sont

discutées lors d’une consultation conjointe avec les neurochirurgiens.

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UNITE DE DIABETOLOGIE

5. Les consultations de diabétologie

5.1. Consultations hospitalières

110 patients (moyenne du suivi : 8x/patient).

Les consultations hospitalières ont été effectuées par les médecins en rotation du

Service de Médecine interne générale sous la supervision des chefs de clinique et du

Prof. J. Philippe. Ces consultations nécessitent un suivi quotidien et, en dehors du

Service de Médecine interne générale, une prise en charge complète du problème du

diabète. Ceci implique en moyenne 8 consultations de suivi par patient. La responsabilité

de ces consultations est assurée par le Prof. J. Philippe.

Lits hospitaliers (5 CL) :

Environ 3 lits de l'Unité 5-CL sont occupés en permanence par des patients souffrant de

maladies endocriniennes (95% des cas : patients souffrant de diabète). 770 patients ont

été hospitalisés dans ces lits dont la responsabilité médicale incombe au Service.

5.2. Consultations ambulatoires

Elles sont assurées par les Drs S. Malacarne, G. Gastaldi, J. Jaafar, B. De Kalbermatten,

M. Egloff, M. Portela, S. Maître, H. Al-Alwan.

Diabète gestationnel : 1337

Consultations effectuées à la Maternité en collaboration avec le Service d'Obstétrique.

Diabétologie générale : 3’246 consultations ambulatoires.

Pied diabétique, pieds à risque / pédicure : 1498 donc 91 nouveaux cas.

Consultation assurée par les médecins de l'Unité, les infirmières E. Baumann, N.

Juillard et M.-A. Savet et l'assistante médicale M. Latapie en collaboration étroite avec

la Clinique d'orthopédie. En outre, un colloque hebdomadaire multidisciplinaire réunit

les différents médecins impliqués dans les soins. Une pédicure (Mme Sonia Puentes)

assure les soins des ongles 1x/semaine et l’Ecole de Pédicure participe à la

consultation du pied 1x/semaine.

Activités en dehors des consultations hospitalières et ambulatoires :

téléphones (informations médicales) : env. 6-8 / jour

5-AL (Unité de Chirurgie orthopédique septique) : présence quotidienne du

médecin interne de notre service pour suivi.

Enseignement au patient (effectué par l'infirmière, au 4e) : 378

Insulinothérapie (cours FIT)

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Consultation assurée par les médecins de l'Unité, Mme P. Rigoli et C. Renaud

(diététiciennes) et les infirmier(e)s spécialisé(e)s en diabétologie (Mmes L. Perrenoud,

M. Castellsague, C. Helary et M. G. Cimarelli) sous la direction du Dr G. Gastaldi.

enseignement de l'insulinothérapie intensive sous-cutanée

pose de pompe et enseignement

pose de senseur de glucose avec interprétation

Consultation de transplantation

Cette consultation est effectuée avec le Service de transplantation et comprend la

sélection des patients diabétiques pour les greffes d'îlots de Langerhans et de

pancréas ainsi que leur suivi.

Un colloque commun mensuel multidisciplinaire réunit les différents intervenants.

(Environ 100 consultations / an).

Interactions privilégiées avec d'autres structures des HUG.

Service d'enseignement thérapeutique des maladies chroniques

Service d'orthopédie (pied diabétique)

Service d'obstétrique (diabète gestationnel)

Service de transplantation

Unité d'endocrinologie et diabétologie pédiatrique

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UNITE DE NUTRITION

2. ACTIVITES CLINIQUES

*selon données OPALE au 21.01.2016 2.1 Médecins Au total, 9545 consultations de 5 à 75 minutes ont été réalisées par les médecins de l’unité.

Patients hospitalisés : 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Consultations entérales / parentérales

1585 1495 1510 1430 1395 1298 1190 1034 1078 1132

Consultations médicales 1423 1370 1298 1346 1183 1205 1078 1175 1167 1245

Patients ambulatoires* : 273 4820 3715 3143 3942 3998 6137 7167 6893 7168

Total 3281 7685 6523 5919 6520 6501 84051 9376

1 9138

1 9545

1

1avec consultations téléphoniques

Investigations : 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Composition corporelle

Patients hospitalisés 520 524 578 545 511 617 528 454 466 300

Patients ambulatoires* 98 156 128 240 256 202 176 231 241 1085

Total 618 680 706 785 767 819 704 685 707 1385

Calorimétries indirectes

Patients hospitalisés 90 64 82 70 62 191 60 98 176 147

Patients ambulatoires* 12 14 20 25 24 27 14 23 31 54

Total 102 78 102 95 86 208 74 121 207 201

Recettes en milliers de CHF (selon données de Mme V. Barnoud à l’Administration du DSM). Les prestations médicales aux patients privés et ambulatoires s’élèvent à :

2006 2007 2008 2009 2010 2011 2012 2013 2014

257 407 318 383 367 2502 3152 297 3053

2La baisse des recettes entre 2010 et 2011 s’explique par le transfert au DMIRG des recettes des

consultations des diététicien(ne)s (déclarées sur le CGR 42048 depuis le 1er

janvier 2011). 3Les recettes facturées s’élèvent à CHF 315'983, auxquelles sont soustraites les pertes sur les

factures impayées et les provisions pour factures non encore émises au 01.01.2015.

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ACTIVITES CLINIQUES DES MEDECINS ADJOINTS

Prof. Antoinette PECHERE

1. Type d’activités

Expertise dans la prise en charge de patients avec hypertesion artérielle réfractaire, difficiles, en lien avec néphropathies, endocrinopathies, secondaires, etc.

Expertise particulière (nationale et internationale) au niveau des troubles hypertensifs de la grossesse, de l’hypertension chez la femme, de l’hypotension, et des liens entre l’hémodynamique rénale et les hormones stéroides féminines.

2. Prestations clinique

2.1. Consultations ambulatoires et supervision

176 patients ont été vus à la consultation ambulatoire privée d’hypertension, assurée par la Pr A. Péchère.

426 patients ont été vus à la consultation ambulatoire d’hypertension assurée par les médecins internes du service et supervisée par la Pr A. Péchère.

2.2. Interprétations

398 MAPAS et 72 tests endocriniens ont été interprétés par la Pr A. Péchère.

Dr Patrick MEYER

1. Prestations cliniques

1.1 Consultation multidisciplinaire des nodules thyroïdiens avec la chirurgie

thoracique et la pathologie clinique.

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STAGIAIRES POUR L’ANNEE 2015

Endocrinologie Diabétologie

Janvier Daphné Germann Loïc de Nijs

Février Ann-Sophie De Paepe

Mars Antoine Aupaix Beatriz Rodriguez – annulé

(déjà venue en 2014)

Avril Sofia Ines Dias Mateus Axel Jaikin

Mai Julie Rerat

Juin

Juillet Tereza Cislerova

Août Laura Meijers

Guillemette Cottin

Septembre

Octobre Hans Fritschi Velasquez

Novembre Michael Gobitz

Décembre

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ROTATION DES INTERNES POUR 2014-2015

2014

Novembre Dre Sarah Stuckelberger

Dre Ana Rita Forte Marques

Décembre Dre Sarah Stuckelberger

Dre Ana Rita Forte Marques

2015

Janvier Dre Sarah Stuckelberger Dre Ana Rita Forte Marques

Février Dre Sarah Stuckelberger Dre Ana Rita Forte Marques

Mars Dre Cecilia Ferrer Soler

Dre Natacha Abbet

Avril Dre Cecilia Ferrer Soler

Dre Natacha Abbet

Mai Dre Cecilia Ferrer Soler Dre Natacha Abbet

Juin Dre Cecilia Ferrer Soler

Dre Natacha Abbet

Juillet Dr Vincent Poffet

Dre Yassaman Alipour Therany

Août Dr Vincent Poffet


Septembre Dr Vincent Poffet


Octobre Dr Vincent Poffet


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PRESTATIONS DE LABORATOIRE DE ROUTINE

LABORATOIRE DES LIPIDES

Clinique Recherche et Total

Dévelopement

Ultracentrifugation 84 - 84

Dosages lipides

Cholestérol 504 - 504

Triglycérides 504 - 504

HDL-cholestérol 504 - 504

Dosages apolipoprotéines

Apolipoprotéine A-I 34 - 34

Apolipoprotéine B 34 - 34

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TESTS ENDOCRINIENS, PROFILS TENSIONNELS (MAPA)

Mme Myriam PASCHOUD

Résultats des tests Détail des tests fonctionnels

Prises de sang 409 ACTH 19

Profils tensionnels

Injections

398

327

CRH

Cathétérisme sinus pétreux

0

0

Urines 129 Hyperglycémie provoquée 7

Salivettes 5 Hypoglycémie 3

Enseignement 7 HTA (hyperaldostéronisme) ; test de surcharge saline

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Arginine 1

Soif 5

Test Calcium

ECG

Pose de cathétère

2

7

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ENSEIGNEMENT

Prof. Jacques PHILIPPE

Prégradué

- Forum sur les dyslipidémies (1h) et le suivi du diabète (10h) : 11 heures

- Tuteur des UIDC (sémiologie du diabète, sémiologie de la thyroïde) : 20 heures

Postgradué et continu

- Colloques dans le cadre des services hospitaliers et facultaires

- Organisation annuelle de la Journée genevoise de diabétologie, de la Journée

Vaud-Genève de diabétologie, de La Journée Vaud-Genève d’endocrinologie, des

Journées franco-suisses de diabétologie, et de multiples autres colloques de

formation continue

Paramédical

- Cours sur dyslipidémies et nutrition (HES) : 10h

Dr Richard JAMES, P.D. Enseignement

Membre du Comité du Programme Bachelor (gestion des études de 2ème et 3ème année

en Médecine)

Co-responsable de l’Unité « Nutrition et Digestion et Métabolisme » du programme

d’enseignement APP 150h

Tuteur; Unité ''Nutrition, Digestion et Métabolisme'' du programme d'enseignement

APP « Sciences Médicales de Base » ; 2ème année 25h

Tuteur Forum Lipoprotéines, Unité Circulation ; 2ème année 4h

Travaux de stage

1. Stage de recherche en laboratoire, Dr. J. Brinck, Karolinska University Hospital, Sweden.

Organisation de colloques internes

o Colloque de Service; Lipides

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Prof. Antoinette PECHERE-BERTSCHI, C.C. Prégradué

Période 2015 : 54 heures (soit 49 heures d’enseignement/5 heures préceptorat préprofessionnel), dont : Bachelor 2e année Module 2, Excrétion-Homéostasie : 13 heures, Master 1e section, ARC : 10 heures ; Mémoire de Master : 30 heures (cathétérisme veineux surrénalien. Dr Maxime Berney). 02.09.2015 : Examen final de Médecine Interne, 6e année, 6 heures. 17.12.2015 : Examen AMC, 5e année, 5 heures. Post-gradué/Formation continue

Colloque d’Hypertension hebdomadaire structuré avec programme, le jeudi de 12h à13h15, avec crédit de formation continue accordé par la FMH, salle de colloque de cardiologie, 6e étage. 35h/an SMPR, colloque FRCV et enseignement thérapeutique maladies chroniques, mensuel, théorique structuré, 45 minutes le mercredi de 10h15-11h. 14h/an. 22.01.2015 : cours du département de gynécologie-obstétrique , certificate d’obstétrique, 45

minutes “preeclampsia”. 23.01.2015 : Fribourg Université , colloque de l’AGLA, 45 minutes “preeclampsia, a new

cardiovascular risk factor”. 02.02.2015 : cours aux sages –femmes du département d’obstétrique , 45 minutes, données

sur l’étude “reins après une preeclampsia”. 05.02.2015 : Clinique de Carouge, cours sur la MAPA 60 minutes. 10.02.2015 : Lausanne, cours médecins généralistes “ les combinaisons fixes anti-

hypertensives”. 17.02.2015 : Genève, cours/atelier médecins généralistes, 60 minutes “ la chlorthalidone”. 22.02.2015 : Genève, table ronde médecins praticiens, 60 minutes “hiérarchie du tt anti-

hypertenseur”. 04.03.2015 : HUG, SMIG, MKSAP, préparation examen FMH médecine interne, 45 minutes,

problèmes hypertension et néphrologie. 06.03.2015 : HUG, SMPR. Séminaire 60 minutes pour médecins en formation. “Comment

réaliser le fond d'oeil” 18.03.2015 : Berne. Présentation pour médecins post grade sur un nouvel antihypertenseur. 19.03.2015 : Lausanne. Présentation pour médecins praticiens sur “Pulse Wave Velocity,

intérêt pratique?”. 26.03.2015 : HUG, Journée de Nutrition. Présentation 30 minutes “L’eau , le sel, et le reste”.

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30.03.2015 : Neuchâtel. Séminaire pour médecins installés: “Comment obtenir l'observance thérapeutique du patient?

20.04.2015 : Journal Club, Service d’endocrinologie, 30 minutes” nouveaux traitements de

l'hyperkaliémie”. 22.04.2015 : Réunion SKIPOGH à Lausanne. 28.04.2015 : Genève, formation pour médecins post grade: “HTA chez le jeune, le sportif, la

femme: est-ce différent? 13.5.2015 : HUG, SMIG, MKSAP, préparation examen FMH médecine interne, 45 minutes,

problèmes hypertension et néphrologie. 20.05.2015 : SSMI, Bâle. Atelier HTA réfractaire 45 minutes. Réunion de la SSH 90 minutes.

Présentation sur l’edarbyclor 30 minutes. 28.05.2015 : Genève. Présentation pour médecins installés “MAPA.. et ensuite?”. 60 inutes. 09.05.2015 : Genève. Table ronde pour médecins praticiens. 60 minutes. “ Les combinaisons

thérapeutiques”. 23.06.2015 : Genève. Atelier pour praticiens sur les “diurétiques”. 60 minutes. 01.09.2015 : HUG, colloque du mardi. 15 minutes “«La dénervation des artères rénales pour

traiter l'hypertension: condamnée trop vite?». 15.09.2015 : Genève. Atelier pour médecins praticiens. “Antihypertenseurs: comment choisir

les associations?” 24.09.2015 : Clinique de Carouge. Présentation pour les médecins en formation.

“Nouveautés 2015 en hypertension. 08.10.2015 : Arboretum d’Aubonne. Journée romande d’Hypertension. "Faut-il mesurer la

pression centrale à nos patients hypertendus?", 30 minutes. 20.10.2015 : Genève. Les diurétiques thiazide-like, atelier, 60 minutes. 26.10.2015 : Colloque update FRCV. « Mon traitement antihypertenseur initial préféré ». 13.11.2015 : Présentation Pré-éclampsie au colloque du Service de Néphrologie des HUG,

45 minutes. 17.11.2015 : Genève. Atelier sur la MAPA, post grade + assistantes médicales, 90 minutes. 18.11.2015 : Lunch présentation à l’Opéra, HUG, pour les médecins du SMPR. “ La

chlorthalidone, un nouveau vieux médicament”. 23.11.2015 : Hôpital de Couvet, Neuchâtel. Présentation pour le médecins de l’hôpital et

médecins installés: “Guidelines HTA”. 24.11.2015 : Genève, 40 minutes. “La chlorthalidone” presentation pour médecins installés.

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26.11.2015 : Berne. Nouveau médicament combiné statine antihypertenseur. 60 minutes. 16.12.2015 : Berne, Présentation sur l’Edarbyclor, Médecins post grade. 26.12.2015 : Colloque DMIRG - Hôpital des Trois-Chêne. Présentation « Hypertension,

gestion des cas difficiles » 45 minutes.

Prof. Charna DIBNER

Tutor in the course APP “Nutrition, Digestion et Metabolism” - 25h teaching; 5h preparative meetings for co-tutors; student evaluation average 4.8

Tutor the course “Chapitres choisis” for graduate students - 12h ; student evaluation « excellent »

Lecturer in the course “Elements of Molecular Endocrinology” (14C003) - 2h

Lecturer in the MAS course « Toxicology » - 2h

Cours à option « Recherche Cardiovasculaire »

Cours à option « Initiation à la recherche expérimentale »

PhD student supervision : Mrs. Anne-Marie Maklhouf (co-supervision with Prof. Claude Pichard) ; Mr. Laurent Perrin (co-supervision with Prof. Jacques Philippe) – 24h

Prof. Claude PICHARD, MD, PhD, et cheffe de clinique de l'unité de Nutrition Enseignement Au total, 243 heures de formation ont été dispensées par les médecins et le biologiste de l’unité.

Colloques mensuels de formation à l’Unité de nutrition 10

Faculté de Médecine, Genève 41

Facultés de Pharmacie de Genève 16

Faculté de Médecine dentaire de Genève 3

Ecole de Diététique HES 85

Soins intensifs HUG 3

Colloques structurés aux HUG (divers services) 8

Cours Suisse de Nutrition Clinique 48

Journées de formation en nutrition clinique 16

Cours de la Sté. Européenne de Nutrition Clinique et Métabolisme ESPEN 4 Dre Françoise ROHNER-JEANRENAUD

Prégradué

- Cours "Digestion d’un repas et biochimie de la digestion" Module B : Unité "Des organes aux grands systèmes" Baccalauréat universitaire de médecine 1ère année 2 heures

- Cours "Régulation de la glycémie" Module B : Unité "Des organes aux grands

systèmes" Baccalauréat universitaire de médecine 1ère année 2 heures

20

- Tutrice Unité "Nutrition, Digestion et Métabolisme" Programme d’enseignement APP, Baccalauréat universitaire de médecine 2ème année 22 heures

Préparation et corrections des examens de l’Unité 4 heures

- Cours "De la paillasse aux patients : obésité" Baccalauréat universitaire de médecine

2ème année 1 heure

- Cours "Eléments d’Endocrinologie Moléculaire" Baccalauréat universitaire de

médecine 2ème année et Baccalauréat universitaire de biochimie 3ème année 2 heures

- Organisation du cours à option "L’obésité : aspects métaboliques, cliniques et

sociaux" Baccalauréat universitaire de médecine 2ème et 3ème année Organisation du programme annuel et examen 4 heures

- "Bachelor "Filière nutrition et diététique", Haute Ecole Spécialisée, HES

Cours 1ère BSc 4 heures

TOTAL: 41 heures

Organisation d’un cours à option semestriel (2ème et 3ème année médecine) Co-responsable de la plateforme de phénotypage du petit animal Membre de la Commission des prix de la Faculté de médecine Membre de la Commission des Privat-Docents de la Faculté de médecine Membre de la Commission d’éthique de la Faculté de médecine Membre de la Commission des 3R Supervision de diplômes et thèses

o Mademoiselle Anne-Laure Poher (thèse en Biologie). Dre Ildiko DENES-CARPENTIER Prégradué

Tutrice Unité "Nutrition, Digestion et Métabolisme" Programme d’enseignement APP,

Baccalauréat universitaire de médecine 2ème année 20 heures

Reunion preparative pour tuteurs 3 heures

Supervision de diplômes et thèses

Co-supervisor pour Mademe Xi WU (thése MD) Stagiaire en laboratoire

M. Jonathan RICCI

21

RAPPORTS DES

INFIRMIER (ERE) SPECIALISTES CLINIQUES

EN DIABETOLOGIE

Annexe 1 : Activités de soins directs

Tableau 1 - Adultes (1er décembre 2015)

Année 2011 2012 2013 2014 2015

Nombre total patients Cluse Roseraie et (Loex)

361

336

406

422

542

+112

Nombre patients hospitalisés 310 276 356 376 485 +117

Moyenne cs

2.4 2

Nombre patients ambulatoires 51

60

50 57 88 +31

Moyenne cs ambulatoire 3.3 3.2

Nombre total interventions 860 646 995 1069 1391 +322

Nombre heures interventions 738

583

813 876 953+280 +357

Moyenne interventions patients 2.38 1.9 2.52 2.53 2.27 - 0.2

Moyenne temps patients 2.04

1.44

2.h 2H09 2.25 +0.16

Patients non diabétiques 7 0

Parturiente diabète 1,2, gestationnel

10 9

Diabète de type 1 94 35 pompes 161 (+67) 87 pompes

31 CGMS 63 CGMS

Diabète de type 2 246 272 (+26)

Diabète secondaires 65 71

23

Tableau 2 - Enfants (1er décembre 2015)

Année 2011 2012 2013 2014 2015

Total enfants diabétiques suivis en pédiatrie

34 25 32 22 23

Type 1 inaugural 23 17 23 15 17

Type 1 déjà diagnostiqués ailleurs 8 6 5 3 3

Type 2 1 0 2 1 0

Secondaires 2 1 2 2 2

M.O.D.Y 0 1 0 1 1

Autres pathologies 2 3 5 5 4

Nbre interventions - hospitalisation 200 292 137 287

Nbre heures interventions hospitalisation

333 360 389 236 426

Moyenne heures interventions 14,47 21,17 17 enfants

16.91 15,73/ 15 enfants

16,42/ 17 enfants

Nbre interventions autres hospitalisation

104 113

Nbre heures autres hospitalisation 60,83 147

Nbre consultations ambulatoires 172 186 195 208 249

Nbre heures total d’enseignement ambul

199 182 304 225 421

Moyenne heures/ consultation amb 1,24 (172 cst)

1,36 (133 cst)

1,55 (195 cst)

1,08 (208 cst)

1,69 (249 cst)

Pose de capteurs de Glucose (ambul.) 29 24 17 32 36

Temps total pour pose Capteurs (hr) 58 25.5 48 54

Moyenne (hr) par pose Capteurs 2 1,5 1,5 1,5

Enseignement dans les écoles 35 46 15 25

Transfert enfants-adultes 6 6 7 16

Pose de pompe à insuline inaugural 18 15 9 14

Pose pompe à insuline (changement tt) 5 5 5 3

Installation du programme WEBDIA 19

25

26

27

28

DIABETOLOGIE AMBULATOIRE 4ème

ETAGE

STATISTIQUES ACTIVITE INFIRMIERE 2015

STATISTIQUES PODOLOGIE 2015 :

- Patients ambulatoires : 1444

- Patients hospitalisés : 148

- Nouveaux cas : 91

- Patients non venus : 94 STATISTIQUES ARRETES AU 15/12/2015

mois PS

Hba1c urines Enseign. injections pose cgms Lecture cgms

Total patients

Patientes DG NC DG Act >30min colloques divers

Janvier 21 61 13 25 3 10 7 106 90 25 12 8 51

Février 11 35 11 33 0 11 9 103 79 11 39 7 30

Mars 20 65 7 35 1 7 10 133 93 21 45 10 38

Avril 13 49 11 22 2 10 8 113 114 19 32 4 52

Mai 12 28 2 29 1 4 4 66 97 18 23 5 21

Juin 13 42 5 32 1 9 10 90 72 29 9 4 14

Juillet 8 33 4 40 2 7 8 97 88 25 12 1 21

Aout 23 56 10 33 0 5 4 93 127 36 33 0 31

Septembre 14 52 7 39 5 9 8 129 126 17 36 9 37

Octobre 12 59 5 29 9 6 5 107 118 25 31 13 24

Novembre 17 65 13 37 8 4 5 135 85 27 58 12 31

Décembre 9 31 3 24 2 4 6 66 43 12 27 8 14

TOTAL : 173 576 91 378 34 86 84 1238 1132 265 357 81 364

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1. ACTIVITES REALISEES TOUT AU LONG DE L’ANNEE : Notées dans la catégorie DIVERS

Soins : 40

pansements de plaies : 13 ECG : 6 HGPO : 4 Test au glucagon : 1 Traitement per os : 2 Pose DAVI : 1 Glucomètres échangés : 10

Urgences médicales dans le service (hypoglycémie, hyperglycémie) : 2 (notées)

Actions de formation reçue : 32

Formations (assistant bolus+ présentations HUG,…) : 6

Présentation de nouveaux produits (insuline et glucomètre) par les firmes pharmaceutiques

(Lunch teaching : formation à l’utilisation du cgms et connaissance des pompes à insuline par firme pharmaceutique) : 16

Colloques fonctionnement : 10

Gestion administrative et logistique : 257

Gestion de l’activité du 4è étage : matériel, Inventaire armoire, classeurs, matériel, médicaments, documents éducatifs, mails, stats), préparation des analyses

complexes : 65

Gestion des rendez vous de podologie (téléphone et fax) : prise des RDV .réponse aux questions, transmissions téléphoniques et courrier avec infirmières des

services, IMAD et médecins, photos : 88

commande pharmacie, stérilisation, magasin : 25

Gestion des rendez-vous (prise de rdv), du matériel cgms et des résultats CGMS (envoi internet et courrier aux médecins du service et de la ville) : 56

Gestion des CGMS, mis en route dans le service : 4

Gestion, mise à jour et résolution de problèmes des logiciels informatiques : 17

Commande cgms personnel pour patient : 2

Gestion téléphonique patientes DG : 10

Contrôle qualité DCAvantage tous les 3 mois (contrôle interne et CSCQ suisse) + gestion : 6

30

2. ACTIVITES REALISEES DANS L’ANNEE PAR L’EQUIPE INFIRMIERE

Activités : Objectifs :

Participation à la journée genevoise du diabète 2015. Approfondir les connaissances liées à la prise en charge du diabète.

Actualiser les connaissances liées à l’utilisation des CGMS et pompe à insuline.

Participation aux lunches teaching. Communiquer et intéragir pour faire le lien avec nos patients hospitalisés.

Collaboration avec les infirmiers spécialistes cliniques en

diabétologie des HUG.

Approfondir la connaissance de pompes à insuline gérées par les spécialistes.

Découvrir le programme d’enseignement pour les patients diabétiques.

Semaine d’observation dans le service d’enseignement

thérapeutique des maladies chroniques « La Soleillane ». Participer à l’activité de réseau plaies de l’institution.

Participation au groupe plaies et cicatrisation des HUG. Mise à jour des connaissances liées au Diabète.

Présents à la journée Vaud-Genève. Aménagement d’un nouvel « espace » infirmier.

31

Consultation du pied diabétique

STATISTIQUES ACTIVITE 2015

Ambulatoires Hospitalisés Nombre

total de

patients

Dont

nouveaux

cas

Dont

pas venus

Janvier 147 9 156 5 0

Février 139 11 150 6 2

Mars 145 8 153 9 6

Avril 101 10 111 7 2

Mai 107 9 116 7 15

Juin 120 12 132 7 14

Juillet 115 10 125 10 11

Août 114 6 120 4 3

Septembre 115 21 136 6 5

Octobre 122 18 140 8 17

Novembre 121 12 133 14 4

Décembre 98 22 120 8 15

TOTAL 1’444 148 1’592 91 94

Nombre total de patients vus = 1’498 patients (1’592-94)

32

AUTRES ACTIVITES

LABORATOIRES DE RECHERCHE

33

Prof. Jacques PHILIPPE

ACTIVITES SCIENTIFIQUES

1. α-Cell Dysfunctions and Molecular Alterations in Male Insulinopenic Diabetic Mice Are Not Completely Corrected by Insulin.

Abstract

Glucagon and α-cell dysfunction are critical in the development of hyperglycemia during diabetes both in humans and rodents. We hypothesized that α-cell dysfunction leading to dysregulated glucagon secretion in diabetes is due to both a lack of insulin and intrinsic defects. To characterize α-cell dysfunction in diabetes, we used glucagon-Venus transgenic male mice and induced insulinopenic hyperglycemia by streptozotocin administration leading to alterations of glucagon secretion. We investigated the in vivo impact of insulinopenic hyperglycemia on glucagon-producing cells using FACS-sorted α-cells from control and diabetic mice. We demonstrate that increased glucagonemia in diabetic mice is mainly due to increases of glucagon release and biosynthesis per cell compared with controls without changes in α-cell mass. We identified genes coding for proteins involved in glucagon biosynthesis and secretion, α-cell differentiation, and potential stress markers such as the glucagon, Arx, MafB, cMaf, Brain4, Foxa1, Foxa3, HNF4α, TCF7L2, Glut1, Sglt2, Cav2.1, Cav2.2, Nav1.7, Kir6.2/Sur1, Pten, IR, NeuroD1, GPR40, and Sumo1 genes, which were abnormally regulated in diabetic mice. Importantly, insulin treatment partially corrected α-cell function and expression of genes coding for proglucagon, or involved in glucagon secretion, glucose transport and insulin signaling but not those coding for cMAF, FOXA1, and α-cell differentiation markers as well as GPR40, NEUROD1, CAV2.1, and SUMO1. Our results indicate that insulinopenic diabetes induce marked α-cell dysfunction and molecular alteration, which are only partially corrected by in vivo insulin treatment.

2. Functional and molecular adaptations of enteroendocrine L cells in male obese mice are associated with preservation of pancreatic α-cell function and prevention of hyperglycemia

Abstract Glucose homeostasis depends on the coordinated secretion of glucagon, insulin and GLP-1 by pancreas and intestine. Obesity which is associated with an increased risk of developing insulin resistance and type 2 diabetes (T2D) affects function of these organs. Here we investigate the functional and molecular adaptations of proglucagon-producing cells in obese mice and thus better define their involvements in T2D development. We used Gcg-Venus transgenic male mice expressing specifically the Venus fluorochrome in proglucagon-producing cells. Mice were subjected to 16 weeks of control low-fat (LFD) or high-fat (HFD) diets. Groups were defined at the end of diet by measuring glycated haemoglobin.

34

At 16 weeks, HFD mice were separated in 2 groups, mice with impaired glucose tolerance (I-HFD) with HbA1c values similar to LFD mice and hyperglycemic mice (H-HFD) with significant HbA1c increase. Both HFD groups exhibited similar weight gain, hyperinsulinemia and insulin resistance. However, I-HFD glucose intolerant mice displayed functional and molecular adaptations of enteroendocrine L-cells resulting in increased intestinal GLP-1 biosynthesis and release as well as maintained pancreatic α- and β-cell functions. By contrast, H-HFD hyperglycemic mice exhibited dysfunctional L, α and β-cells with increases of β- and L-cell numbers. Administration of the GLP-1R antagonist Exendin9-39 in I-HFD mice led to hyperglycemia and alterations of glucagon secretion without changes in insulin secretion. Our results highlight the cross-talk between islet and intestine endocrine cells and indicate that a compensatory adaptation of L-cell function in obesity plays an important part in preserving glucose homeostasis through the control of pancreatic α-cell function.

SUPPORTS FINANCIERS

FNRS

Subside - No 31003A - 130372 Prof J. Philippe (Requérant principal)

Fonds privés

Industrie pharmaceutique : NovoNordisk

Fondation pour la lutte contre le cancer et pour des recherches médico-biologiques

Fondation romande pour la recherche sur le diabète

ACTIVITES DIVERSES

1. Fonctions hospitalo-universitaires

Médecin-chef, Service d’endocrinologie, diabétologie et nutrition

Président du Collège des Chefs de Service

Membre de la Commission Médicale d’établissement

Membre de la Commission consultative de la direction

2. Fonctions Facultaires

Président et membre de Commissions de nomination

Membre de la Comission hospitalo-universitaire de renouvellement

35

COLLOQUES INTERNES AUX HUG

Colloque du mardi (Dept de Médecine interne)

Colloque du vendredi matin (Service de médecine interne générale)

Colloque de Service

Colloque de Gériatrie : prise en charge du patient diabétique âgé

CONFERENCES ET FORMATION CONTINUE EXTERNE

16 - 17 janvier 2015 16e Rencontre de Diabétologie franco-suisse, Evian. Co-organisateur.

27 janvier 2015 Colloque du service d’endocrinologie, diabétologie et métabolisme, CHUV,

Lausanne

Glucagon et diabète : une relation causale

30 avril 2015 Update Diabetes Mellitus, Genève

Les inibiteures du SGLT-2 en pratique : comment les utiliser et quand ?

12 mars 2015 19e Journée Vaud-Genève de diabétologie, Morges. Co-organisateur.

Les statines augmentent-elles le diabète ?

7 mai 2015 Diabetes Day, Berne

What is the best time to start insulin ?

28 mai 2015 Traitement du diabète en 2015, Grandson

8 octobre 2015 20e Journée genevoise de diabétologie, Genève. Organisateur

Edulcorants et diabète

12 novembre 2015 Congrès SSED, Berne

Diabetes and the heart

3 décembre 2015 Pied diabétique: quelle prevention ? quels traitements ?, Genève. Co-

organisateur.

9 décembre 2015 Symposium Diabète de type 2, Lausanne

Implications de l’étude EMPA-REG OUTCOME dans la pratique

36

ACTIVITES ANNEXES

Membre du Bureau de la Fondation pour Recherches Médicales

Membres du Conseil scientifique du Centre de Recherches en Nutrition Humaine (CRNH)

Rhône-Alpes

Président, Fondation romande pour la recherche contre le diabète

Membre, Commission du Prix Servier d’endocrinologie/diabétologie

Fondation de la Société francophone du diabète, membre du Comité scientifique

Membre du Fonds Chalumeau, Président de la Commission scientifique

Membre du Comité médical de l’Union Cycliste Internationale

Membre de la Fondation pour la lutte contre le cancer et pour des recherches médico-

biologiques

Membre de la Fondation Insuléman

Novartis Consumer Health Foundation, Vice-Président

Membre, Geneva Ambassador Program

COMITE EDITORIAUX

Revue médicale Suisse

Editeur Diabète et Endocrinologie

Cardiovasc

Diabetes Management

Cardiovascular Medicine

Scientific World Journal

ADVISORY BOARD

BMS/ Astra-Zeneca

Lilly/Boehringer Ingelheim

Novo Nodrisk

Sanofi

37

PUBLICATIONS

1. Alpha-cell dysfunctions and molecular alterations in male insulinopenic diabetic mice are not

completely corrected by insulin. Dusaulcy R, Handgraaf S, Heddad-Masson M, Visentin F, Vesin C, Reimann F, Gribble F, Philippe J, Gosmain Y. Endocrinology. 2015 Dec 22 :en20151725. (Epub ahead of print) PMID : 26696123 (PubMed – as supplied by publisher)

2. Free Fatty Acids Impair FGF21 Action in HepG2 Cells.

Asrih M, Montessuit C, Philippe J, Jornayvaz FR. Cell Physiol Biochem. 2015 ;37(5) :1767-78. doi : 10.1159/000438540. Epub 2015 Nov13. PMID : 26584278 (PubMed – in process)

3. Polycystic ovaries : what’s news in 2015 ?

Mavromati M, Philippe J. Rev Med Suisse. 2015 Jun 3 ;11(477) :1242-5. Review. French. PMID : 26211285 (PubMed – indexed for MEDLINE)

4. GLP-1 receptor agonists versus SGLT-2 inhibitors in obese type 2 diabetes patients.

Marques AR, Jaafar J, de Kalbermatten B, Philippe J. Rev Med Suisse. 2015 Jun 3 ;11(477) :1227-8, 1230-3. Review. French. PMID : 26211282 (PubMed – indexed for MEDLINE)

5. Age related dehydroepiandrosterone decrease : clinical significance and therapeutic

interest. Samaras N, Samaras D, Forster A, Frangos E, Philippe J. Rev Med Suisse. 2015 Jan 28 ;11(459) :321-4. Review. French. PMID : 25845195 (PubMed – indexed for MEDLINE)

6. News in endocrinology : Management of asymptomatic primary hyperparathyroidism in

2014. Köhler BB, Philippe J. Rev Med Suisse. 2015 Jan 14 ;11(456-457) :58-61. French. PMID : 25799652 (PubMed – indexed for MEDLINE)

7. News in diabetology.

Malacarne S, Gastaldi G, Philippe J. Rev Med Suisse. 2015 Jan 14 ;11(456-457) :53-4,56-7. French. PMID : 25799651 (PubMed – indexed for MEDLINE)

8. Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without

insulin by disrupting a novel diabetogenic pathway. Wang MY, Yan H, Shi Z, Evans MR, Yu X, Lee Y, Chen S, William A, Philippe J, Roth MG, Unger RH. Proc Natl Acad Sci U S A. 2015 Feb 24 ;112(8) :2503-8. doi : 10.1073/pnas.1424934112. Epub 2015 Feb 9. Erratum in : Proc Natl Acad Sci U S A. 2015 Jul 28 ;112(30) :E4158. Dosage error in article text. PMID : 25675519 (PubMed – indexed for MEDLINE) Free PMC Article

9. Restoration of adrenal function after bilateral adrenal damage due to heparin-induced

thrombocytopenia (HIT) : a case report. Jaafar J, Boehlen F, Philippe J, Nendaz M. J Med Case Rep. 2015 Feb 3 ;9 :18. doi : 10.1186/1752-1947-9-18. PMID : 25645253 (PubMed – in process) Free PMC Article

10. Endogenous endophtalmitis in a patient with diabetes and foot osteomyelitis.

38

Mavrakanas TA, de Haller R, Philippe J. Can J Diabetes. 2015 Feb ;39(1) :18-20. doi : 10.1016/j.jcjd.2014.05.011.Epub 2014 Oct 22. PMID : 25444679 (PubMed – indexed for MEDLINE)

11. Thyroid circadian timing : roles in physiology and thyroid malignancies.

Philippe J, Dibner C. J Biol Rythms. 2015 Apr ;30(2) :76-83. doi : 10.1177/0748730414557634. Epub 2014 Nov 19. Review. PMID : 25411240 (PubMed – indexed for MEDLINE)

12. Diabetes in 2015 : constantly increasing, but with enlarged therapeutics options.

Jornayvaz FR, Philippe J. Rev Med Suisse. 2015 Jun 3 ;11(477) :1219-20. French. No abstract available. PMID : 26211280 (PubMed – indexed for MEDLINE)

13. Statins and Diabetes : The Plot Thickens.

Gastaldi G, Philippe J. J Gen Intern Med. 2015 Nov ;30(11) :1572-3. doi : 10.1007/s11606-015-3399-y. No abstract available. PMID : 25986140 (PubMed – in process)

14. Acute painful diabetic neuropathy : an uncommon, remittent type of acute distal small fibre

neuropathy. Tran C, Philippe J, Ochsner F, Kuntzer T, Truffert A. Swiss Med Wkly. 2015 May 5 ;145 :w14131. doi : 10.4414/smw.2015.14131.eCollection 2015. Review. PMID : 25941879 (PubMed – indexed for MEDLINE) Free Article

15. Inborn errors of metabolism : transition from childhood to adulthood.

Tran C, Barbey F, Pitteloud N, Philippe J, Kern I, Bonafé L. Rev Med Suisse. 2015 Feb 18 ;11(462) :445-9. French. PMID : 25915985 (PubMed – indexed for MEDLINE)

16. Identification of new biomarkers for human papillary thyroid carcinoma employing

NanoString analysis. Chitikova Z, Pusztaszeri M, Makhlouf AM, Berczy M, Delucinge-Vivier C, Triponez F, Meyer P, Philippe J, Dibner C. Oncotarget. 2015 May 10 ;6(13) :10978-93. PMID : 25868389 (PubMed – in process) Free PMC Article

HYPERTENSION

Prof. Antoinette PECHERE-BERTSCHI

ACTIVITES DE RECHERCHE

1. Projet « Reins après une pré-éclampsie», soutenu par un subside pour chercheurs avancés

du Centre de Recherche Clinique de CHF 220'000.- (principale investigatrice, A. Pechère, avec 100% du subside).Ce projet a 2 parties : 1) une étude longitudinale de patientes ayant présenté une pré-éclampsie, avec évaluation complète de la fonction rénale, de la pression artérielle, sérothèque et urothèque, et prélèvements pour la génétique. Le recrutement de 465 femmes a été terminé en octobre 2014, les analyses sont en cours. 2) Une seconde étude, « A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of benazepril in the treatment of persistent renal dysfunction in pre-eclamptic

39

women », dont le recrutement s’est également terminé en octobre 2014, a permis l’inclusion de 122 patientes avec des anomalies rénales persistantes. Les analyses sont en cours.

2. Projet cohorte tri-centrique suisse HTA réfractaire (RAHYCO, Resistant Hypertension

Cohorte study). Inclusion de 68 patients, traitement standardisé et mesure observance thérapeutique, banque ADN, et phénotypage très complet. Sous-étude sur les apnées du sommeil. Soutien partiel (40’000CHF) par SPUM FNRS, (PI Prof Murielle Bochud), et Société Suisse Hypertension (10'000.-).

3. Projet “Dynamics of cardio-pulmonary response to exercise in patients affected by essential

hypertension” soutenu par le FNRS du Prof Guido Ferretti, (CHF 170'000.-) sur la réponse hémodynamique de jeunes sujets hypertendus.

4. Projets SKIPOGH et SPUM FNRS, sur génétique de l’hypertension et du rein. 7 mios. PI

Murielle Bochud.

PUBLICATIONS

1. Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular

Function in the General Population. Pruijm M, Ponte B, Ackermann D, Paccaud F, Guessous I, Ehret G, Pechère-Bertschi A, Vogt B, Mohaupt MG, Martin PY, Youhanna SC, Nägele N, Vollenweider P, Waeber G, Burnier M, Devuyst O, Bochud M. Clin J Am Soc Nephrol. 2016 Jan 7;11(1):70-80.

2. Innovative instruction for assisting patients with arterial hypertension.

Bontemps S, Pechère-Bertschi A. Rev Med Suisse. 2015 Sep 9;11(485):1660-3. 3. Atypical presentation of preeclampsia.

Ditisheim A, Boulvain M, Irion O, Pechère-Bertschi A. Rev Med Suisse. 2015 Sep 9;11(485):1655-8. Review.

4. Screening and management of hypertension in elderly.

Ferrer Soler C, Ehret G, Pechère-Bertschi A. Rev Med Suisse. 2015 Sep 9;11(485):1638, 1640-4.

5. CYP17A1 Enzyme Activity Is Linked to Ambulatory Blood Pressure in a Family-Based

Population Study. Ackermann D, Pruijm M, Ponte B, Guessous I, Ehret G, Escher G, Dick B, Al-Alwan H, Vuistiner P, Paccaud F, Burnier M, Péchère-Bertschi A, Martin PY, Vogt B, Mohaupt M, Bochud M. Am J Hypertens. 2015 Aug 20.

6. Heritability of ambulatory and office blood pressure in the Swiss population.

Alwan H, Ehret G, Ponte B, Pruijm M, Ackermann D, Guessous I, Staessen JA, Asayama K, Kutalik Z, Vuistiner P, Paccaud F, Pechere-Bertschi A, Mohaupt M, Vogt B, Martin PY, Burnier M, Bochud M. J Hypertens. 2015 Oct;33(10):2061-7.

7. Heritabiliy of renal function parameters and electrolyte levels in the swiss population.

http://www.ncbi.nlm.nih.gov/pubmed/26683888








40

Moulin F, Ponte B, Pruijm M, Ackermann D, Guessous I, Ehret G, Bonny O, Pechere-Bertschi A, Staessen JA, Paccaud F, Mohaupt M, Martin PY, Burnier M, Vogt B, Devuyst O, Bochud M. J Hypertens. 2015 Jun;33 Suppl 1

8. Plasma copeptin is associated with insulin resistance in a swiss population-based study.

Canivell S, Ponte B, Pruijm M, Ackermann D, Guessous I, Ehret G, Paccaud F, Pechere-Bertschi A, Mohaupt M, Vogt B, Burnier M, Devuyst O, Martin PY, Bochud M. J Hypertens. 2015 Jun;33 Suppl 1

9. Inactive matrix gla protein is associated with renal resistive index in a population-based

study. Pivin E, Pruijm M, Ackermann D, Guessous I, Ehret G, Pechère-Bertschi A, Paccaud F, Mohaupt M, Vermeer C, Staessen JA, Vogt B, Martin P, Burnier M, Bochud M, Ponte B. J Hypertens. 2015 Jun;33 Suppl 1.

10. Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population-

Based Study. Pivin E, Ponte B, Pruijm M, Ackermann D, Guessous I, Ehret G, Liu YP, Drummen NE, Knapen MH, Pechere-Bertschi A, Paccaud F, Mohaupt M, Vermeer C, Staessen JA, Vogt B, Martin PY, Burnier M, Bochud M. Hypertension. 2015 Jul;66(1):85-92.

11. New anthropometry-based age- and sex-specific reference values for urinary 24-hour

creatinine excretion based on the adult Swiss population. Forni Ogna V, Ogna A, Vuistiner P, Pruijm M, Ponte B, Ackermann D, Gabutti L, Vakilzadeh N, Mohaupt M, Martin PY, Guessous I, Péchère-Bertschi A, Paccaud F, Bochud M, Burnier M; Swiss Survey on Salt Group. BMC Med. 2015 Feb 27;13:40.

12. Accuracy of doctors' anthropometric measurements in general practice.

Sebo P, Haller D, Pechère-Bertschi A, Bovier P, Herrmann F. Swiss Med Wkly. 2015 Feb 21;

13. Association of urinary calcium excretion with serum calcium and vitamin D levels.

Rathod A, Bonny O, Guessous I, Suter PM, Conen D, Erne P, Binet I, Gabutti L, Gallino A, Muggli F, Hayoz D, Péchère-Bertschi A, Paccaud F, Burnier M, Bochud M. Clin J Am Soc Nephrol. 2015 Mar 6;10(3):452-62.

14. Copeptin is associated with kidney length, renal function, and prevalence of simple cysts in

a population-based study. Ponte B, Pruijm M, Ackermann D, Vuistiner P, Guessous I, Ehret G, Alwan H, Youhanna S, Paccaud F, Mohaupt M, Péchère-Bertschi A, Vogt B, Burnier M, Martin PY, Devuyst O, Bochud M. J Am Soc Nephrol. 2015 Jun;26(6):1415-25

15. Ambulatory pulse pressure is negatively associated with excretions of urinary caffeine and

its metabolites. Guessous I, Pruijm M, Ponte B, Ehret G, Ansermot N, Vuistiner P, Staessen JA, Gu YM, Paccaud F, Mohaupt MG, Vogt B, Pechère-Berstchi A, Martin PY, Burnier M, Eap CB, Bochud M. J Hypertens. 2015 Jun;33 Suppl 1:e10-1.

16. Associations of ambulatory blood pressure with urinary caffeine and caffeine metabolite

excretions.











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Guessous I, Pruijm M, Ponte B, Ackermann D, Ehret G, Ansermot N, Vuistiner P, Staessen J, Gu Y, Paccaud F, Mohaupt M, Vogt B, Pechère-Berstchi A, Martin PY, Burnier M, Eap CB, Bochud M. Hypertension. 2015 Mar;65(3):691-6.

ACTIVITES DIVERSES

Commissions

- Membre de la Commission de l’Egalité, Faculté de Médecine, - Membre (Past-Présidente) de la Société Suisse d’Hypertension

RECHERCHE EN NUTRITION

Prof. Claude PICHARD

PROJETS ET REALISATIONS

Le projet « Phase angle » est une étude prospective multicentrique sur la valeur pronostique

de l’angle de phase mesurée par impédancemétrie corporelle bioélectrique à l’admission en

réanimation, pour lequel le Dr Ronan Thibault a reçu un prix de recherche de l’European

Society of Clin Nutr and Metabolism (ESPEN)(50'000 Euros).

Évolution : 957 patients sur 1000 prévus ont été inclus et l’étude est en cours de publication.

Le projet « Development and validation of a new indirect calorimetry device for energy

expenditure measurement in ICU patients: An international multicentric study » du Pr Claude

Pichard a reçu le prix Innovation Technology Award, European Society of Clin Nutr and

Metabolism (ESPEN) (60'000 Euros) et le prix « Established Investigator Award, European

Critical Care Research Network, European Society of Intensive Care Medicine» (ESICM)

(20'000 Euros) et le prix de LA Fondation nutrition 2000Plus (200’000 CHF).

Évolution : Le prototype de calorimètre est en voie d’évaluation chez des sujets sains et de

soins intensifs.

Le projet « Chewing efficiency measured by a two-colour chewing-gum test: a marker of

insufficient nutritional intakes and percutaneous gastrostomy (PEG) necessity in ALS

patients » a reçu un prix de recherche de l’European Society for Clin Nutr and Metabolism

(ESPEN)(20'000 Euros).

Evolution : 24 patients sont inclus. Le protocole vise l’inclusion de 25 patients qui seront

suivis jusqu’au moment de la mise en place d’une gastrostomie percutanée ou pour une

durée de trois ans au maximum.

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Le projet « SPN 2: Impact of supplemental parenteral nutrition (SPN) on the clinical outcome

measured by energy balance, infection rate, duration of mechanical ventilation, and

pharmacoeconomic criteria in intensive care patients underlying metabolic, inflammatory and

immune mechanisms » (317'000 CHF).

Évolution : 24 patients ont complété le protocole et le recrutement se poursuit.

Le projet « NUTRICARD : Approche multimodale de la dénutrition de l’insuffisance

cardiaque chronique: essai contrôlé, randomisé » du Dr Ronan Thibault a reçu le Prix de

recherche du DSM 2013 (50'000 CHF) et le prix de recherche de la Société Francophone de

Nutrition Entérale et Parentérale (SFNEP) (50'000 Euros).

Évolution : En raison de problèmes liés au recrutement multicentrique des patients, l’étude est encore en phase de démarrage.

Le projet « Do branched chain amino acids counteract protein energy wasting through

microbiota changes in hemodialysis patients? » de L. Genton, CC, a reçu le support du

Fonds National Suisse : 311'568 CHF.

Évolution : En phase de démarrage.

Le projet « Effect of dietary intervention on intestinal microbiota in patients with non-alcoholic

fatty liver disease? » de la Dre L. Genton, CC, a reçu du Fonds du Département des

spécialités de médecine, Département de médecine interne, réhabilitation et gériatrie: 28'000

CHF et du Fonds Alfred & Alice Lachmann, Université de Genève, 25'000 CHF.

Évolution : En voie de publication

RECHERCHE

Principaux domaines de recherche

Soins intensifs et nutrition: évolution clinique (infection, durée de séjour, coûts),

composition corporelle, angle de phase.

Cancer et nutriments: de la modulation de la croissance tumorale à la qualité de vie.

Recherches expérimentales in vitro et in vivo, clinique.

Sujets âgés : composition corporelle, capacités fonctionnelles, mortalité.

Réhabilitation cardiaque et nutrition : composition corporelle, capacités fonctionnelles.

Maladies neuromusculaires, pneumologie et nutrition.

Développement d’un nouveau calorimètre indirect.

Microbiote intestinal

Ces travaux ont nécessité la collaboration avec les structures suivantes :

Services de Cardiologie, d’Oncologie, ORL, Pneumologie, Maladies infectieuses,

Education thérapeutique et maladies chroniques, Gastroentérologie, Médecine interne

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et réhabilitation, Service de Médecine de Laboratoire, Neurologie, Radio-oncologie,

Restauration, Soins Intensifs Adultes, Genève.

Faculté de Médecine dentaire, Genève

Filière diététique, HES, Genève

Section des sciences pharmaceutiques, Sciences II, Université de Genève

Service des Soins Intensifs, CHUV, Lausanne

PUBLICATIONS

Au total, 20 publications scientifiques (articles, revues) et 17 communications orales ou

affichées ont été réalisées par l’Unité de Nutrition.

Publications (impact factor)

1. Graf S, Pichard C, Genton L, Oshima T, Heidegger CP. Energy expenditure in mechanically

ventilated patients: the weight of body weight! Clin Nutr 2015. IF 4.476

2. Klek S, Chourdakis M, Bischoff S, Dubrov S, Forbes A, Galas A, Genton L, Gundogdu HR,

Irtun O, Jagmane I, Jakobson-Forbes T, Jirka A, Kennedy N, Klimasauskas A, Khoroshilov

I, Leon-Sanz M, Muscaritoli M, Panisic-Sekeljic M, Kalliopi AP, Schneider SM, Siljamäki-

Ojansuu U, Uyar M, Wanten G, Krznaric Z. The presence of the reimbursement implies the

use of enteral and parenteral nutrition : results from a European multicenter survey. Clin

Nutr 2015. IF 4.476

3. Graf C, Karsegard VL, Spoerri A, Makhlouf AM, Ho S, Herrmann FR, Genton L. Body

composition and all-cause mortality in subjects older than 65 years. Am J Clin Nutr, 101(4):

760-7, 2015. IF 6.918

4. Graf S, Karsegard VL, Viatte V, Heidegger CP, Fleury Y, Pichard C, Genton L. Evaluation of

three indirect calorimetry devices in mechanically ventilated patients: which device

compares best with the Deltatrac II®? Clin Nut. 34(1), 60-65, 2015. IF 4.476

5. Genton L, P. Cani, J. Schrenzel. Alterations of gut barrier and gut microbiota in food

restriction, food deprivation and protein energy-wasting. Clin Nutr, 34(3): 341-9, 2015. IF

4.476

6. Schimmel M, J. Katsoulis, L. Genton, F. Müller. Kaufunktion und Ernährung im Alter. Swiss

Dental Journal, 125, 449-454, 2015.

7. Berger MM, Pichard C. Understanding the Causes of Death in INTACT by Braunschweig et

al. JPEN J Parenter Enteral Nutr 2015, 39(2): 144. IF 3.143

8. Attaix D, Pichard C, Baracos VE. Muscle wasting: is mitochondrial dysfunction a key

target ? Curr Opin Clin Nutr Metab Care. 2015,18 : 213-214. IF 4.378

9. Limonta A, Gastaldi G, Heidegger CP, Pichard C. Insulinothérapie et nutrition parentérale

en soins intensifs: aspects pratiques. Rev Méd Suisse 11, 728-733 : 2015.

10. Dupertuis Y, Delie F, Cohen M, Pichard C. In ovo method for evaluating the effect of

nutritional therapies on tumor development, growth and vascularization. Clin Nutr

Experimental 2, 9-17 : 2015.

11. Coattrenec Y, Harr T, Pichard C, Nendaz M. Bienfaits du régime sans gluten : mythe ou

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réalité ? Rev Méd Suisse 1878-1885: 2015.

12. Buzzi M, Limonta A, Pichard C, Stirnemann J. Syndrome de renutrition inappropriee:

aspects pratiques. Rev Méd Suisse 11, 1886-1991: 2015.

13. Pichard C, Oshima T, Heidegger CP. Energy deficit is a clinically relevant information for

critically ill patients: PRO. Intensive Care Med. 2015: 41: 335-338. IF 5.544

14. Preiser, JC, an Zanten, ARH, Berger MM, Biolo G, Casaer M, Doig G, Griffiths R, Heyland

D, Hiesmayr M, Iapichino G, Laviano A, Pichard C, Singer P, Van den Berghe G,

Wernerman J, Wischmeyer P, Vincent, JL. Metabolic and nutritional support of critically ill

patients: consensus and controversies. Crit Care, 2015: 19, 35. IF 5.040

15. Kyle, U. G, Earthman C.P, Pichard C, Coss-Bu J.A. (2015). Body composition during growth

in children: limitations and perspectives of bioelectrical impedance analysis. Eur J Clin Nutr

2015: 1-8. IF 2.950

16. Thibault R, Azagury DE, Huber O, Pichard C. Twelve key nutritional issues in bariatric

surgery. Clin Nutr 2015. IF 4.476

17. Oshima T, Pichard C: Parenteral nutrition: never say never. Crit Care 2015. IF 4.480

18. Oshima T, Deutz NE, Doig G, Wischmeyer PE, Pichard C. Protein-Energy Nutrition in the

ICU: The Power Couple. Clin Nutr 2015. IF 4.476

19. Héritier AC, Janssens JP, Adler D, Iancu Ferfoglia R, Genton L. Should patients with ALS

gain weight or not during their follow-up? Nutrition 2015. IF 3.046

20. Marini J, Gattinoni L, Ince C, Kozek-Langenecker S, Mehta RL, Pichard C, Westphal M,

Wischmeyer P, Vincent J.L. A few of our favorite unconfirmed ideas. Critical Care.

2015;19:S1. IF 4.480

Abstracts ou Communications orales ou affichées

1. Meyer P, Makhlouf AM, Mondouagne Engkolo LP, Trentaz F, Thibault R, Pichard C, Burri

H. Is it safe to use bioelectrical impedance to assess nutritional status in patients equiped

with implantable cardioverter-defibrillators? Sté Suisse de Cardiologie 2015

2. Meyer P., Makhlouf A.-M., Mondouagne L.P., Trentaz F., Thibault R., Pichard C., Burri H. Is

it safe to use bioelectrical impedance to assess nutritional status in patients equipped with

implantable cardioverter-defibrillators? Clinical Nutrition 2015, 34(Suppl 1): 80

3. Makhlouf AM, Mondouagne Engkolo LP, Testuz A, Trentaz F, Thibault R,Hullin R, Claude

Pichard C, Meyer P. Associations of nutritional status and disease severity in outpatients

with chronic systolic heart failure. Sté Suisse de Cardiologie 2015

4. Makhlouf A-M., Thibault R., Kossovsky M., Iavindrasana J., Chikhi M., Meyer R., Pittet D.,

Zingg W., Pichard C. Healthcare-associated infections (HCAI) are associated with

insufficient dietary intake. Clinical Nutrition 2015, 34(Suppl 1): 20

5. Makhlouf A-M., Thibault R., Mondouagne L.P., Testuz A., Trentaz F., Hullin R., Pichard C.,

Meyer P. Association between nutritional status and disease severity in outpatients with

chronic systolic heart failure. Clinical Nutrition 2015, 34(Suppl 1): 79

6. Makhlouf A-M, Meyer P, Mondouagne L. P, Trentaz F., Thibault R., Pichard C., Burri H. Est-

il prudent d’utiliser l’impédancemétrie corporelle bioélectrique pour évaluer le statut

nutritionnel des patients porteurs d’un défibrillateur cardioverteur implantable? Nutrition

Clinique et Métabolisme 2015, 29(Suppl 1)

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7. Makhlouf A-M., Chikhi M., Mulliez A., Depeyre J., Pichard C., Thibault R. The visual or

verbal analogue scale SEFI® (Simplified Evaluation of Food Intake) SEFI® detects the

insufficient food intake: a substudy of Nutritionday® in one university hospital. Clinical

Nutrition 2015, 34(Suppl 1):90

8. Makhlouf A-M, Thibault R., Mondouagne L. P., Testuz A., Trentaz F., Hullin R., Pichard C.,

Meyer P. Association entre le statut nutritionnel et la sévérité de la maladie chez des

patients ambulatoires insuffisants cardiaques chroniques avec function systolique diminuée.

Nutrition Clinique et Métabolisme 2015, 29(Suppl 1)

9. Oshima T, Graf S, Heidegger CP, Genton L, Karsegard VL, Dupertuis YM, Pichard C. Can

ventilator derived energy expenditure measurements replace indirect calorimetry? En

impression (ESICM).

10. Klek S, Chourdakis M, Bischoff S, Dubrov S, Forbes A, Galas A, Genton L, Gundogdu HR,

Irtun O, Jagmane I, Jakobson-Forbes T, Jirka A, Kennedy N, Klimasauskas A, Khoroshilov

I, Leon-Sanz M, Muscaritoli M, Panisic-Sekeljic M, Kalliopi AP, Schneider SM, Siljamäki-

Ojansuu U, Uyar M, Wanten G, Krznaric Z. Reimbursement affects prescription of enteral

and parenteral nutrition ? Results from European multicenter survey. Clinical Nutrition 2015,

34(Suppl 1):28.

11. Graf S., Genton L., Oshima T., Pichard C. Energy expenditure (EE) in mechanically

ventilated patients: ESPEN equation using different body weights (BW) vs. indirect

calorimetry (IC). Clinical Nutrition 2015, 34(Suppl 1):49

12. Graf S, Genton, T. Oshima, C.-P. Heidegger, C. Pichard. Energy expenditure (EE) in

mechanically ventilated patients: ESPEN equation using different body weights (BW) vs.

indirect calorimetry (IC). Int Care Med. 2015

13. Graf C., Karsegard V.L., Spoerri A., Makhlouf A.-M., Ho S., Herrmann F., Laurence G. Loss

of fat-free mass index has substantial impact on mortality risk for subjects > 65 years.

Clinical Nutrition 2015, 34(Suppl 1):66

14. Graf C.E, Herrmann F, Spoerri A., Makhlouf A.-M., Sorensen T., Ho S., Karsegard V.,

Genton L. Une perte de masse non grasse augmente le risque de mortalité́ chez les sujets

de 65 ans et plus. Nutrition Clinique et Métabolisme 2015, 29(Suppl 1)

15. Graf S, Genton L., Oshima T, Pichard C., Heidegger C. P. Dépense énergétique chez les

patients sous ventilation mécanique: La place du poids corporel dans les formules de

prediction vs calorimétrique indirecte (CI). Nutrition Clinique et Métabolisme 2015, 29(Suppl

1)

16. Pataky Z, L. Genton. S. Terraz, C. Pichard, A. Golay, L. Spahr. Association between NALFD

severity and body composition in obese subjects. Obes Facts, 8 (suppl 1), T1: PO006,

2015.

17. Gonzalez M.C, Pichard C, Thibault R, Bosy-Westphal A., Larsson E., Heymsfield S.B, on

behalf of Group of Studies in Body Composition and Nutrition COCONUT. Similarities and

differences in phase angle reference values from different populations. Clinical Nutrition

2015, 34(Suppl 1): 189

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ACTIVITE EXTRAHOSPITALIERE

L’Unité de Nutrition a représenté les HUG lors de :

Course de l’Escalade de Genève (stand HUG): L’équipe de nutrition a réalisé 814

mesures de composition corporelle lors de cette manifestation.

5ème Symposium romand de nutrition et gériatrie: Yverdon, 19 Novembre 2015.

27ème Journée Annuelle de Nutrition Clinique: Genève, 26 mars 2015.

50ème et 51ème Cours suisse de nutrition : Genève 13-15.5.2015 et 5-7.10.2015.

Dr Françoise ROHNER-JEANRENAUD


I. Effects of oxytocin treatment on obesity, diabetes and adipose tissue inflammation in mice

Oxytocin is a hypothalamic nonapeptide synthetized mainly in the paraventricular and supraoptic nuclei projecting to the pituitary, where it reaches the peripheral circulation, as well as to other brain regions. Moreover, leptin modulates oxytocin levels and activates oxytocin neurons in the hypothalamic paraventricular nucleus, which innervates the nucleus of the solitary tract, partly responsible for the brain-elicited oxytocin effects. Taking into account that oxytocin is located downstream leptin, it was hypothesized that oxytocin treatment would be effective in decreasing body weight in leptin-resistant DIO animals, as well as in those with leptin or with leptin receptor deficiency. Several groups have demonstrated that in such animal models (rats, mice and rhesus monkeys), central or peripheral oxytocin administration decreases body weight, mainly due to a decrease in fat mass, demonstrating that an oxytocin treatment is able to partly overcome leptin deficiency or resistance. Moreover, a pilot clinical study demonstrated the efficiency of oxytocin in the treatment of obesity in human subjects, confirming the results obtained in the different animal models. Larger multicenter studies are now needed to determine whether the beneficial effects of oxytocin treatment can apply not only to obese, but also to type 2 diabetic patients. Further studies carried out in both animals and rodents should also shed some light on the molecular mechanisms of oxytocin action in decreasing body weight and fat mass with concomitant improvement in glucose metabolism. Among these, an effect of oxytocin on the immune system could be envisaged. Indeed, taking into account that obesity induces an insulin-resistant state in adipose tissue, where M1 proinflammatory (producing inflammatory mediators linked to insulin resistance, such as TNFα) prevail over M2 anti-inflammatory macrophage, it could be hypothesized that oxytocin would modulate adipose tissue inflammation, a process that could partly underlie the observed improvement in glucose metabolism. In keeping with this hypothesis, the immunomodulatory effect of oxytocin has been demonstrated in some animal models of atherosclerosis, burn/acid injury, sepsis and myocardial infarction, whereby oxytocin modulates the levels of different

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cytokines in each condition. However, it is still unclear whether the oxytocin effects on the immune system are direct or indirect. We therefore decided to investigate the effects of oxytocin on the macrophage polarization level and the cytokine production, as well as a possible impact of oxytocin on these parameters in adipose tissue in diet-induced obesity with impaired glucose metabolism. To this end, mouse bone marrow cells were differentiated into macrophages and treated during the differentiation process with oxytocin in order to see whether it induces changes in pro-inflammatory M1 and anti-inflammatory M2 macrophage ratio. Another batch of macrophages was treated with oxytocin at the end of the differentiation process, whereby macrophage proliferation was measured by EdU incorporation and cytokine secretion was determined using multiplex. For in vivo experiments, mice were rendered obese by high fat diet and were treated subcutaneously with oxytocin for two weeks. Body weight was followed, body composition was measured by magnetic resonance imaging and glucose tolerance tests were performed. At the end of the treatment, adipose tissue macrophage population was characterized by flow cytometry, plasma cytokine levels were measured by multiplex and cytokine expression in adipose tissue was determined by Real Time PCR. In bone marrow-derived macrophages, oxytocin induced an anti-inflammatory phenotype (decreased M1/M2 ratio, as a consequence of a decreased M1 population without any change at the replication level). Moreover, in M1-derived macrophages, oxytocin decreased TNFα secretion, without major effect on the other cytokines tested and with no effect on cytokine secretion by M2- derived macrophages. In vivo, oxytocin treatment in diet-induced obese mice led to decreased body weight, due to an effect on the fat mass, accompanied by an improvement in glucose tolerance, without changes in plasma cytokine levels. In adipose tissue, oxytocin decreased Tnfα expression without modifying the M1/M2 macrophage ratio. We can therefore conclude that oxytocin decreases adipose tissue inflammation, lowering TNFα production, both in vitro and in vivo. This could at least partly mediate the beneficial effects of oxytocin in reducing the fat mass and improving glucose metabolism. Peer-reviewed review published in Front Endocrinol (Lausanne) 6 (119): 1-7, 2015. Rev Med Suisse 11(456-457): 97-100, 2015. Manuscript submitted for publication in Diabetologia. II. Browning of adipose tissue and its impact on metabolic homeostasis Brown adipose tissue (BAT), characterised by uncoupling protein 1 (UCP1) expression, has been described as metabolically active in humans. It induces an increase in energy expenditure by increasing thermogenesis. Lou/C rats, which originate from the Wistar strain, are resistant to obesity induced by either age or a high fat diet. In subcutaneous white adipose tissue (WAT) of Lou/C rats, we previously demonstrated the presence of ectopically expressed UCP1, as well as of an overexpression of the β3-adrenoreceptor which controls UCP1 expression. The aim of the present study was to investigate the role of UCP1 in the metabolic regulation of Lou/C rats, including the control of body weight gain and the observed improved insulin sensitivity.

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A β3 agonist treatment (CL-316243) was therefore administered in 3 month-old Wistar and Lou/C rats for 2 weeks. Several metabolic parameters were measured. In particular, glucose tolerance, fat mass repartition, overall and tissue-specific insulin sensitivity, as well as energy expenditure were determined. The treatment induced lower food efficiency, a decreased fat volume and enhanced energy expenditure in both strains. It also similarly increased overall insulin sensitivity, as determined using the euglycemic hyperinsulinemic clamp technique. However and interestingly, muscle glucose uptake, measured with labelled 2-deoxy-glucose, was unaltered by the treatment in both groups of animals. On the contrary, insulin-stimulated glucose uptake in different WAT depots was highly increased by the β3 adrenoceptor treatment in the Lou/C group only, an increase that correlated with the expression of UCP1 in these tissues. Regarding this gene, the treatment induced a marked overexpression in subcutaneous WAT of the Lou/C group only. These results were confirmed by Western blot analysis. In BAT, UCP1 increased to a similar extent in Wistar and Lou/C rats in response to the treatment. To go further in the understanding of the role of the β3 agonist treatment on glucose metabolism, the expression of various genes involved in glucose and lipid metabolism was determined in different tissues. This allowed concluding that in Lou/C rats, the decrease in fat mass and the improvement in glucose metabolism involves concomitant inductions of de novo lipogenesis, lipolysis, fatty acid oxidation, as well as glyceroneogenesis in subcutaneous adipose tissue. Such a β3 agonist-induced increase in futile cycling is likely occurring in beige adipocytes within the fat depot, which could therefore play an important role in the regulation of overall insulin sensitivity. To conclude, activation of UCP1 in ectopic tissues, such as beige cells in subcutaneous WAT, may be an interesting therapeutic approach to prevent body weight gain, decrease fat mass and improve insulin sensitivity. Diabetes 64(11): 3700-12, 2015. III. The potassium channel TASK1 modulates β-adrenergic response in brown adipose

tissue through a mineralocorticoid receptor pathway TASK1, a pH-sensitive potassium channel encoded by the kcnk3 gene, is known to be differentially expressed between brown and white adipose tissue, both in rodents and humans. Its knock-down in murine preadipocytes disrupts brown adipocyte function. In this study, we showed that TASK1 expression in rodent BAT is highly correlated to UCP1 expression in obese and cold-exposed mice. In addition, Task1 null mice displayed overweight, mainly due to an increase in WAT mass and to BAT whitening. Task1-/- mice-derived brown adipocytes displayed an impaired β3-adrenergic receptor response compared to WT mice–derived adipocytes, which was characterized by a decrease in oxygen consumption, UCP1 expression and lipolysis. This phenotype was due to an exacerbation of the mineralocorticoid receptor signaling, as it was mimicked by corticoids and reversed by a mineralocorticoid receptor inhibitor. To conclude, the K+ channel TASK1 controls brown adipocyte thermogenic activity through β-adrenergic receptor signaling modulation and appears to be a key component of adipose tissue function, opening new ways in the study of obesity and associated disorders.

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FASEB J. 30(2): 909-22, 2016.

IV. Endocrine control of energy homeostasis Energy homeostasis depends on the balance between the amount of food consumed and the amount of calories used (energy expenditure). The precise coordination between these two processes is essential for the correct maintenance of body composition. Indeed, the physiological control of energy homeostasis involves multiple and compensatory mechanisms located in a large variety of organs. The brain integrates peripheral and central signals to generate satiety or hunger, as well as to regulate nutrient partitioning, energy expenditure and the insulin response of glucose metabolism. Numerous neuronal populations in the hypothalamus, brainstem, hindbrain and forebrain have the ability to control multiple aspects of metabolism. Recently, several new sophisticated technologies have been developed to unravel the role of specific neural circuits in the control of body energy balance and glucose homeostasis. Dr. R. Nogueiras and myself are co-editors of a whole issue of Molecular and Cellular Endocrinology, which includes 9 reviews on various aspects of the Endocrine Control of Energy Homeostasis, ranging from the role of the brain, adipose tissue, the gastrointestinal tract, the liver, as well as that of circadian rhythms. Mol Cell Endocrinol. 418 Pt 1:1-2, 2015.

V. Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways

The gut-brain axis is of great importance in the control of energy homeostasis. Uroguanylin is a peptide released in the intestines that is regulated by the nutritional status and exerts anorectic actions. It is the endogenous ligand for the guanylyl cyclase 2C receptor and, together with its receptor, it represents a new system in the regulation of energy balance. In this study, we show that chronic central infusion of uroguanylin reduces weight gain and adiposity in diet-induced obese mice. These effects were independent of food intake and involved specific efferent autonomic pathways. On one hand, brain uroguanylin induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. On the other hand, brain uroguanylin augments fecal output through the vagus nerve. These findings are of relevance, as they suggest that the beneficial metabolic actions of uroguanylin through the sympathetic nervous system do not involve nondesirable gastrointestinal adverse effects, such as diarrhea. The present work provides mechanistic insights into how uroguanylin influences energy homeostasis and suggests that uroguanylin action in the brain represents a feasible pharmacological target in the treatment of obesity. Diabetes 65(2): 421-32, 2016.

http://topics.sciencedirect.com/topics/page/Homeostasis

http://topics.sciencedirect.com/topics/page/Insulin

http://topics.sciencedirect.com/topics/page/Glucose

http://topics.sciencedirect.com/topics/page/Hypothalamus

http://topics.sciencedirect.com/topics/page/Brainstem

http://topics.sciencedirect.com/topics/page/Rhombencephalon

http://topics.sciencedirect.com/topics/page/Prosencephalon


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VI. Enhanced postnatal leptin signaling prevents the worsening of glucose tolerance and

the development of diet-induced obesity following perinatal high fat feeding in obesity-resistant Lou/C rats

Physiological processes at adulthood, such as energy metabolism and insulin sensitivity may originate before or weeks after birth. This raised the concept of fetal programming of adult diseases, which is particularly relevant in the case of obesity and type 2 diabetes. The aim of this study was to determine the impact of a perinatal high fat diet on energy metabolism and on leptin, as well as insulin sensitivity, early in life and at adulthood in two strains of rats presenting different susceptibilities to diet-induced obesity. The impact of a perinatal high fat diet on glucose tolerance and diet-induced obesity was also assessed. The development of glucose intolerance and of increased fat mass was confirmed in the obesity-prone Wistar rat, even after 28 days of age. On the contrary, in obesity-resistant Lou/C rats, an improved early leptin signaling may be responsible for the lack of deleterious effect of the perinatal high fat diet on glucose tolerance and increased adiposity in response to high fat diet at adulthood. The understanding of the mechanisms involved in the protection against the development of diet-induced obesity seen in Lou/C rats could be of therapeutical importance for the treatment of obesity and T2D in humans. Submitted for publication in Diabetologia.

PUBLICATIONS

Peyrou M., Bourgoin L., Poher A.-L., Altirriba J., Maeder C., Caillon A., Fournier M., Montet X., Rohner-Jeanrenaud F., Foti M. Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice. J Hepatol 62(2): 421-9, 2015. Molica F., Morel S., Kwak B.R., Rohner-Jeanrenaud F., Steffens S. Adipokines at the crossroad

between obesity and cardiovascular disease. Thromb Haemost. 113(3), 553-66, 2015. Poher A.-L., Altirriba J., Veyrat-Durebex C., Rohner-Jeanrenaud F. Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance. Front Physiol. 6: 4, 2015. Review. Altirriba J., Pataky Z., Golay A., Rohner-Jeanrenaud F. [Oxytocin: metabolic effects and potential use for obesity treatment ]. Rev Med Suisse 11(456-457): 97-100, 2015. French. Asrih M., Altirriba J., Rohner-Jeanrenaud F., Jornayvaz F.R. Ketogenic Diet Impairs FGF21 Signaling and Promotes Differential Inflammatory Responses in the Liver and White Adipose Tissue. PLoS One 10(5): e0126364, 2015. Poher A.L., Veyrat-Durebex C., Altirriba J., Montet X., Colin D.J., Caillon A., Lyautey J., Rohner-Jeanrenaud F. Ectopic UCP1 Overexpression in White Adipose Tissue Improves Insulin Sensitivity in Lou/C Rats, a Model of Obesity Resistance. Diabetes 64(11): 3700-12, 2015.













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Altirriba J., Poher A.L., Rohner-Jeanrenaud F. Chronic Oxytocin Administration as a Treatment Against Impaired Leptin Signaling or Leptin Resistance in Obesity. Front Endocrinol (Lausanne) 6:119, 2015. Review. Rohner-Jeanrenaud F., Nogueiras R., editors. Endocrine control of energy homeostasis. Mol Cell Endocrinol. 418 Pt 1:1-2, 2015. Pisani D.F., Beranger G.E., Corinus A., Giroud M., Ghandour R.A., Altirriba J., Chambard J.C., Mazure N.M., Bendahhou S. Duranton C., Michiels J.F., Frontini A., Rohner-Jeanrenaud F., Cinti S., Christian M., Barhanin J., Amri E.Z. The K+ channel TASK1 modulates β-adrenergic response in brown adipose tissue through the mineralocorticoid receptor pathway. FASEB J. 30(2): 909-22, 2016. Folgueira C., Beiroa D., Callon A., Al-Massadi O., Barja-Fernandez S., Senra A., Fernø J., López M., Dieguez C., Casanueva F.F., Rohner-Jeanrenaud F., Seoane L.M., Nogueiras R. Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways. Diabetes 65(2): 421-32, 2016. Submitted for publication Asrih M., Veyrat-Durebex C., Anne-Laure Poher A.-L., Lyautey J., Rohner-Jeanrenaud F. Jornayvaz F. R. Leptin as a potential regulator of FGF21. Submitted to Cell Physiol Biochem J. Garrido-Urbani S., Deblon N., Poher A.L., Caillon A., Ropraz P., Imhof B., Rohner-Jeanrenaud F., Altirriba J. Inhibitory role of oxytocin on adipose tissue TNFα expression assessed in vitro and in vivo. Submitted to Diabetologia. Veyrat-Durebex C., Poher A.L., Asrih M., Jornayvaz F., Rohner-Jeanrenaud F. Enhanced postnatal leptin signaling prevents the worsening of glucose tolerance and the development of diet-induced obesity following perinatal high fat feeding in obesity-resistant Lou/C rats. Submitted to Diabetologia. Altirriba J., Deblon N., Garrido-Urbani S., Caillon A., Veyrat-Durebex C., Disse E., Cristino G., Wahli W., Di Marzo V., Rohner-Jeanrenaud F. Central oxytocin regulates feeding behavior by increasing oleoylethanolamide production in the hypothalamus. In preparation.

MEMBERSHIPS

Member of the American Endocrine Society

Member of the American Diabetes Association

Member of the French Society of Neuroendocrinology

Member of the Swiss Society of Endocrinology and Diabetology (SSED)

Member of the Swiss Physiological Society








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Member of the Swiss Society for Neuroscience

CONFERENCES ET SEMINAIRES

February 26 Colloque de recherche du Service d’Endocrinologie, Diabétologie, Hypertension et Nutrition, Geneva, Switzerland. "L’activation du tissu adipeux brun comme cible potentielle du traitement de l’obésité et du diabète de type 2" F. Rohner-Jeanrenaud. June 24 Séminaire du Département de Physiologie Cellulaire et Métabolisme, Geneva, Switzerland. "Characterization of a new tool: FVB mice expressing luciferase under the hUCP1 promoter" A.-L. Poher. October 26 Fourth Annual Meeting of the DIABAT European consortium, Prague, Czech Republic. "White adipose tissue UCP1 expression in lean/obesity resistant Lou/C rats" A.-L. Poher. October 27 Second UNIGE Diabetes Workshop, Geneva, Switzerland. "Role of oxytocin in diabetes and metabolism" J. Altirriba. October 29 Symposium Diabésité, Morges, Switzerland. "Ocytocine: hormone de l’attachement et de la perte de poids" F. Rohner-Jeanrenaud.

SUPPORTS FINANCIERS

- FNRS N° 310030_160290/1 (avril 2015 – septembre 2017). - Collaborative european project : "Activation of brown adipocytes as therapy for type 2

diabetes" "DIABAT", FP7, HEALTH-2010-2.4.3-2 (octobre 2011 – septembre 2015). - European Foundation for the Study of Diabetes, EFSD (avril 2013 – juin 2015). - Bo & Kerstin Hjelt Foundation for Type 2 diabetes grant research to J. Altirriba.

LABORATOIRE DES LIPIDES, UNITE DE DIABETOLOGIE CLINIQUE

Dr Richard W. JAMES


Summary

The research activities of the group centre on the role of high density lipoproteins (HDL) in cardio-protection. Their protective role appears to be compromised in diabetic patients, where

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serum concentrations are significantly reduced compared to non-diabetic subjects. We are particularly interested in factors and mechanisms by which HDL are protective. We have two objectives. One series of studies is investigating the anti-oxidant function of HDL. They focus on an enzyme associated with HDL, termed paraoxonase. Its anti-oxidant role is well established, and it has been shown to be an independent risk factor for vascular disease. Its activity is lower in diabetic patients. The second objective is a direct effect of HDL on the heart. Our studies have shown that HDL can reduce the consequences of ischemia-reperfusion injury, which is a major problem during re-vascularisation after a myocardial infarction. Using in vitro, ex vivo and in vivo models, we have demonstrated that HDL can reduce the size of the infarct area, limiting damage to heart function and future risk of heart failure. One particular component of HDL, the lipid sphinogosine-1-phosphate (S1P) appears essential for the protective effect of HDL. Our recent studies have focused on HDL from diabetic patients. Modifications to HDL contribute to the greatly increased risk of vascular disease in diabetes. We have shown that diabetic HDL has a significantly reduced ability to protect the heart from ischemia. Further investigation revealed that glycation caused loss of S1P from HDL, which, as a consequence, was less efficient in activating intracellular survival pathways. Loss of S1P from HDL was significantly correlated with patient HbA1c levels. Our results suggest that measures of HDL-associated S1P may be a better indicator of HDL functionality.

PUBLICATIONS

1. Kunutsor, S.K., Bakker S.J.L., James R.W. and Dullaart, R.P.F. (2015) Serum paraoxonase-1 and risk of incident cardiovascular disease: findings from the PREVEND study and new meta-analysis. Atherosclerosis 245:143-154

2. Mannic, T., Satta, N., Pagano, S., Python, M., Virzi, J., Montecucco, F., Frias, M.,

James, R.W., Maturana, A.D., Rossier, M.F. and Vuilleumier, N. (2015) CD14 as a mediator of the mineralocorticoid receptor - dependent anti-apolipoproteinA-1 IgG positive chronotropic effect on cardiomyocytes. Endocrinology 156, 4707-19.

3. Calmy, A., Montecucco, F. and James, R.W. (2015)

Evidence on the protective role of high-density lipoprotein (HDL) in HIV-infected individuals. Curr Vasc Pharmacol 13, 167-72.

4. Martin, P., Palmer, G., Rodriguez, E., Woldt, E., Mean, I., James, R.W., Smith, D.E.,

Kawk, B.R. and Gabay, C. (2015) Atherosclerosis severity is not affected by a deficiency in IL-33/ST2 signalling. Immun Inflamm Dis 3, 239-46

5. Brulhart-Meynet, M-C., Braunersreuther, V., Brinck, J., Montecucco, F., Galan, K.,

Pelli, G., Pedretti, S., Vuilleumier, N., Mach, F., Lecour, S., James, R.W. and Frias, M.A. (2015)

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Improving reconstituted HDL composition for efficient post-ischemic reduction of ischemia reperfusion injury. PLOS ONE 10:e0119664.

6. Papageorgiou, I., Viglino, C., Brulhart-Meynet, M-C., James, R.W., Lerch, R and

Montessuit, C. Impaired stimulation of glucose transport in cardiac myocytes exposed to Very Low-Density Lipoproteins. Nutri Metab Cardiovasc Dis In press

7. Morel, S., Christoffersen, C., Axelsen, L.N., Montecucco, F., Rochemont, V., Frias,

M.A., Mach, F., James, R.W., Naus, C.C., Chanson, M., Lampe, P.D., Nielsen, M.S., Nielsen, L.B. and Kwak, B.R. Sphingosine-1-Phosphate reduces ischemia/reperfusion injury by phosphorylating the gap junction protein Connexin43. Cardiovasc Res In press

8. Moren, X., Lhomme, M., Bulla, A., Sanchez, J-C., Kontush, A. and James, R.W.

Proteomic and lipidomic analyses of paraoxonase defined high density lipoprotein particles: association of paraoxonase with the anti-coagulant, protein S. Proteomics Clin Applic In press

9. Brinck, J.B., Thomas, A., Prost, J.C., Jornayvaz, F.R., Brulhart Meynet, M-C., Lauer,

E., Löfgren, P., Hoffstedt, J., Pataky, Z., Morel, M., Kwak, B.M., van Eck, M., James, R.W. and Frias, M.A. Glycation is associated with reduced HDL sphingosine-1-phosphate content and impaired HDL cardiac cell protection. Arterioscler Thromb Vasc Biol In press

CONFERENCES / COLLOQUES DONNES

1. "HDL-induced cardioprotection is independent of the HDL receptor, Scavenger Receptor BI", Cardiovascular and Metabolic research meeting, Fribourg, 22-23 janvier.

2. Colloque du service: "Lipides : « Hypertriglycéridémie, facteur de risque ou pas ?", 26 mars.

3. Colloque du service: "Physiopathologie du HDL-cholestérol dans le diabète", 28 mai.

4. "Diabetes compromises the HDL cardioprotective capacity: a new pathophysiological mechanism", Cardiovascular Biology seminar series, CMU, 13 octobre.

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COMMISSIONS OU SOCIETES EXTRA-MUROS

1. Membre du comité du groupe de travail lipides et athérosclérose (AGLA; Société Suisse de Cardiologie)

2. Editeur pour “Nutrition, Metabolism and Cardiovascular Disease”, Naples, Italy.

3. Membre, Singapore National Medical Research Council international expert panel.

SUPPORTS FINANCIERS

Fondation Wolfermann-Nägeli, Zurich (Dr. M. Frias)

Fondation Gustave et Simone Prévot (Dr. M. Frias)

Jubiläumsstiftung, Rentenanstalt / Swiss Life (Dr. M. Frias)

Prof. Charna DIBNER

SCIENTIFIC ACTIVITIES

1. Molecular and functional analysis of the interplay between circadian clock work and

metabolism in pancreatic islet and skeletal muscle

(funded by individual FN project 31003A_146475)

Circadian oscillation of biological processes has been described in most of the light-sensitive organisms. It reflects the existence of intrinsic biological clocks with near 24 hour oscillation periods. It is well established that circadian clocks play a crucial role in the regulation of key metabolic processes. Moreover, there is a growing body of evidence for connection between metabolic pathologies, including obesity and diabetes, and the circadian clockwork. My newly established research group succeeded in setting up the experimental system for long-term recording of circadian reporter oscillations in human primary cultured cells from different tissue types. Using this powerful approach, we have revealed the presence of a robust circadian oscillator in human pancreatic islets and islet cells. Human islet oscillator entrainment properties and its impact on islet gene transcription have been characterized. Our major current research focus is on the physiological function of α- and β-cell clocks, their impact on glucagon and insulin secretion, their interaction, and potential role in T2D etiology. We have established triple reporter mouse allowing isolating pure alpha- and beta-cells (proGlucagon-Venus and Insulin-Cherry reporters) allowing to characterize circadian rhythm in thus isolated cells (Per2::luciferase reporter) at the population and single cell levels. Employing this model, we identified subsets of islet genes expressed in a circadian manner in both alpha- and beta-cells, and those oscillating in alpha- or beta-cells only (collaboration with Prof. Dermitzakis, CMU and Prof. Gachon, NIHS/EPFL). This data shed a new light on the alpha- and beta-cell differential circadian transcriptome. Importantly, we show that circadian clock is indispensable for proper insulin secretion by analyzing blood insulin content in clock proficient

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and deficient (Bmal1KO and Cry1/Cry2KO) mice (collaboration with Prof. Gachon, NIHS/EPFL). Our in vivo and in vitro studies in genetic mouse models are combined with in vitro experiments in synchronized human islet cells, allowing exploring alpha- and beta-cell clock work and function. We have recently extended our study to explore the impact of circadian oscillators on the human skeletal muscle function in physiology, and alterations in this system possibly contributing to the pathogenesis of T2D. Human islets for this study are provided from Geneva Islet Transplantation center; human muscle biopsies are provided by our collaborators Dr. E. Lefai and Prof. H. Vidal, Lyon, INSERM, and locally by Prof. T. Berney. The prevalence of obesity and diabetes in modern society is taking on enormous proportions. It is therefore of major importance to identify the molecular basis of circadian rhythmicity in rodent and human peripheral tissues in physiology, and upon obesity/T2D. 2. Human muscle circadian rhythm and lipid homeostasis in physiology and insulin

resistance

(funded by Sinergia FN project CRSII3_154405)

Lipid homeostasis is critical for whole body metabolism, due to the central role of membranes in cellular biology and the broad effects of lipid signaling molecules. The prevalence of obesity and diabetes in modern society is taking on epidemic proportions. As defects in lipid metabolism are central to the pathophysiology of obesity and diabetes, it is of great importance to investigate lipid homeostasis of these metabolic disorders. Furthermore, there is accumulating evidence for a tight reciprocal connection between a number of metabolic syndromes, including obesity and diabetes, and the circadian clockwork. Ongoing studies in mouse models suggest that peripheral circadian clocks, notably those functional in liver and pancreatic islets, play a critical role in lipid homeostasis. However, the molecular link between circadian clocks, lipid homeostasis and metabolic disorders in humans remains unknown. Skeletal muscle is the largest insulin sensitive organ in the body, representing the most important site of insulin resistance in Type 2 Diabetes (T2D). It is therefore of major importance to identify the molecular basis of circadian rhythmicity and its links with lipid metabolism in human skeletal muscle under physiological conditions, and upon obesity and T2D. Essential to the success of this project is the combination of the expertise of my group (mammalian circadian oscillator molecular studies, with recent focus on human peripheral clocks and their roles in metabolic diseases) combined with the lipidome studies, with recent focus on role of the lipids in metabolic diseases (Riezman’s lab, Science, UniGe); and studies of the human primary myotube culture under physiological conditions and different types of insulin resistance (Lefai-Vidal’s group, INSERM, Lyon). If we can determine that obesity and T2D in human beings are indeed associated with circadian clock disruptions, as it has been lately reported to be the case in rodents, it will open new and important avenues for these disease treatments. Of note, recent extensive search for clock modulator molecules, conducted by academic laboratories and pharmaceutical companies, revealed a number of potent clock modulators. If we succeed in establishing a molecular link between the circadian clock and etiology of T2D, these clock modulators can certainly be regarded as new potential T2D therapeutic compounds. Comprehensive analysis of the impact of the circadian system on human skeletal muscle function, with a specific focus on lipid homeostasis and membrane changes, should prove to be of high scientific importance and clinical relevance. By dissecting the human oscillator function in the context of lipid homeostasis we will advance the understanding of clockwork connection to metabolic disorders and T2D.

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3. Interactions between the human circadian clock, diabetes, and metabolic syndrome: Study of human circadian clock in obesity and type 2 diabetes employing primary skin fibroblasts

(funded by Sinergia FN project CRSII3_160741)

Concomitant with increasingly irregular sleep schedules and mealtimes, the recent past has shown a worldwide explosion in the incidence of metabolic disorders and Type 2 diabetes (T2D). Both biological and epidemiological studies suggest a direct link between the two phenomena: rodent studies show that metabolic pathways influence daily “circadian” timing, and epidemiological studies suggest that disrupted daily rhythms correlate with both obesity and diabetes. However, the genetic and biochemical links between circadian clocks and metabolic disorders remain entirely unknown in humans. It has been shown that human circadian clock properties can be measured in vitro in skin fibroblasts. Moreover, our first results (Makhlouf et al., manuscript in preparation) suggest a link between clock properties measured in vitro and in vivo, and diabetic parameters in the same subjects. We now plan to link and expand these results to provide a comprehensive picture of the human cellular mechanisms connecting circadian clock variance with the risk of metabolic disease, using a combined approach of human genetics (collaboration with E. Dermitzakis, CMU), in vitro cellular analyses, and circadian metabolomics (my group and collaboration with S. Brown, UniZurich) in a longitudinal cohort of diabetic and obese individuals, and healthy matched controls. This study would provide significant tangible benefits, both to the circadian and metabolic fields, in basic research and medicine. 4. Application of circadian oscillator studies to the diagnostics of malignancy in

suspicious thyroid nodules

(funded by Ligue Genevoise pour la lutte contre le Cancer, CRC clinical research grant)

The overall goal of this translational research project is to characterize the roles of the circadian clock components in the pathogenesis of thyroid malignancies, employing genetic mouse model and human primary thyrocyte culture. This knowledge will be applied to the identification and validation of reliable biomarkers for FTC and PTC diagnostics, by retrospective and prospective studies. The following aspects have been addressed in this study: 1) Exploring cellular mechanisms of circadian clock disruption in thyroid malignancies. Characterization of thyroid clock synchronization properties, clock-controlled gene (CCG) pattern, thyroid hormone secretion, and connection between circadian and cell cycles in in vitro synchronized primary thyrocytes established from healthy tissue biopsies, and from benign and malignant thyroid nodules; 2) Search for reliable thyroid malignancy preoperative markers. The biomarkers will be identified by a retrospective study (Nanostring analysis of postoperative FFPE samples), and validated in preoperative FNA samples. Exploring human thyroid clock function and its potential role in thyroid nodule malignant transformation represents an important step forward in our understanding of the molecular link between clock function, thyroid tissue physiology and pathophysiology of malignant thyroid nodules. In the modern era of personalized medicine the knowledge on individual chronotype may be critical for the treatment and, probably, have to be included as an important component of diagnostic procedures. This approach might bring new insights into the role of clocks for the malignant transformation of human thyroid cells, and have important clinical perspectives.

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PEER-REVIEWED PUBLICATIONS

Original articles in preparation

1. Makhlouf AM, Meyer P, Tran C, Pataky Z, Pichard C, Brown SA, Philippe J, Dibner C. “HbAc1 levels in Type 2 diabetic individuals predict cellular circadian clock properties.” In preparation for submission to Diabetes

2. Chitikova Z., Makhlouf A.-M., Pusztaszeri M., Bercy M., Delucinge-Vivier C., Triponez F.,

Meyer P., Philippe J., and Dibner C. “Cell cycle regulator CHEK1 is a new biomarker for human follicular thyroid carcinoma” In preparation for submission to Cancer Research

Original articles in revision

1. Saini C., Petrenko V., Perrin L., and Dibner C. “Studying impact of circadian clockwork on the human endocrine regulation in physiology and pathophysiology“ Journal of Visualized Experiments (JoVE). Invited manuscript, in revision.

2. Loizides-Mangold U., Koren-Gluzer M., Skarupelova S., Makhlouf A.-M., Hayek T., Aviram

M., Dibner C. “Paraoxonase 1 (PON1) and pomegranate influence circadian gene expression and period length.” In revision in Chronobiology International; Impact Factor 3.343

Original articles

1. Saini C., Petrenko V., Pulimeno P., Giovannoni L., Berney T., Hebrok M., Howald C., Dermitzakis E., and Dibner C. “A functional circadian clock is required for proper insulin secretion by human pancreatic islet cells.” Accepted for publication in Diabetes, Obesity and Metabolism; Impact Factor 6.360

2. Perrin L., Loizides-Mangold U., Skarupelova S., Pulimeno P., Chanon S., Robert M., Bouzakri

K., Moudoux C., Roux-Lombard P., Vidal H., Lefai E. and Dibner C. “Human skeletal myotubes display a cell-autonomous circadian clock implicated in basal myokine secretion.” Molecular Metabolism 2015, 4 (11), 834-845. Impact Factor: not yet received; the Journal recently indexed in PubMed Central, 1 citation

3. Chitikova Z., Pusztaszeri M., Makhlouf A.-M., Bercy M., Delucinge-Vivier C., Triponez F.,

Meyer P., Philippe J., and Dibner C. “Identification of new biomarkers for human papillary thyroid carcinoma employing NanoString analysis.” Oncotarget 2015 May 10;6(13):10978-93. Impact Factor 6.368, 1 citation

Review articles

1. Dibner C. and Schibler U. “A pancreatic clock times insulin release” Science (2015) 350 (6261), 628-629. Impact Factor: 33.611

2. Dibner C. and Gachon F. “Circadian dysfunction and obesity: is Leptin the missing link?” Cell

Metabolism (2015) Vol. 22(3) 359-360. Impact Factor: 17.565

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3. Saini C., Brown S. and Dibner C. “Skin fibroblast clocks: applications to studying human circadian phenotypes in physiology and pathophysiology.” Frontiers in Neurology (2015) May 13;6:95. Impact Factor: not yet received; the Journal recently indexed in PubMed Central, 5 citations

4. Dibner C., Schibler U. “Circadian clocks: roles in endocrinology and metabolism” Journal of

Internal Medicine Impact Factor: 6.455, 23 citations 5. Philippe J. and Dibner C. “Thyroid circadian timing: roles in physiology and thyroid

malignancies” J Biol Rhythms (2015) Apr;30(2):76-83. Impact Factor: 3.309, 4 citations 6. Lefai E. and Dibner C. “Horloges Circadiennes“ Diabète 2015, 10 (88), 95.

SOCIETY MEMBERSHIPS

European Association for the Study of Diabetes (EASD); Société Francophone du diabète (SFD); The Society for Research on Biological Rhythms (SRBR); Société Suisse d’Endocrinologie et de Diabétologie (SSED); European Biological Rhythms Society (EBRS), G2L2 Association, Vice president.

OTHER PROFESSIONAL ENGAGEMENTS

Research group composition

1. Dr. Ursula Loizides-Mangold, scientific collaborator, 100% acitivity, 3 year contract (till 12/2017), paid by Sinergia grant (with Howard Riezman and Etienne Lefai);

2. Dr. Camille Saini, postdoctoral assistant, 80% acitivity, paid by Novartis Consumer Health Foundation;

3. Dr. Laurianne Giovannoni, scientific collaborator, 30% activity, paid from individual FN grant;

4. Dr. Volodymyr Petrenko, maître assistant, 100%, from 04/2015 till 12/2016 at least; paid by DIP (5 months exceptional subside), Bo-Hjelt Foundation, HUG Foundation;

5. Mrs. Anne-Marie Makhlouf, PhD student from October 2012; 50% activity, shared engagement with Prof. Pichard; mid-term defense June 2014 (successful), paid from Fondation pour la lute contre le cancer grant;

6. Mr. Laurent Perrin, PhD student from September 2013, 100% activity; mid-term defense May 2015 (successful); presumable (earliest) end date 30/09/2017, paid from individual FN grant;

7. Dr. Zhanna Chitikova, volunteer, 01/2014 – 12/2015;

8. Mr. Kenzo Tamura, rotation student, Yamaguchi University International MD programme.

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PARTICIPATION IN THE SCIENTIFIC MEETING / INVITED LECTURES

1. 12-13/03/2015 EFSD/EASD & Boehringer Ingelheim Symposium, Biberach, Germany.

Invited lecture “Pancreatic alpha cell clockwork: roles in glucagon secretion, islet physiology and pathophysiology”.

2. 3-7/05/2015 EASD Islet Study Group & Beta Cell Workshop (ISG), Jerusalem, Israel. Poster

presentation “Roles of the circadian clock in alpha- and beta-cell transcriptome and hormone secretion in mouse and human pancreatic islet”.

17. 29/05/2015 BIOCAPS SEMINAR “Melatonin and the circadian system” Vigo, Spain. Invited

lecture “Pancreatic islet clockwork: roles in physiology and pathophysiology”. 18. 5-9/06/2015 American Diabetes Association’s (ADA) 75th Annual meeting, Bostin, US.

Poster presentation “Pancreatic alpha cell clockwork: roles in glucagon secretion, islet physiology and pathophysiology”.

19. 16/06/2015 G2L2/ LIMNA symposium, Lausanne, Switzerland. Invited lecture “Roles of the

circadian clock in α- and β-cell transcriptome and hormone secretion in mouse and human pancreatic islet”. Selected oral presentation by the PhD student Laurent Perrin “Human skeletal myotubes display a cell-autonomous circadian clock implicated in basal interleukin-6 secretion”.

20. 18/06/2015 Seminar Series of the Department of Endocrinology, Diabetes, Hypertension and

Nutrition, HUG. “Identification of new biomarkers for human papillary thyroid carcinoma employing NanoString analysis”.

21. 19/06/2015 iGE3 genomics platform user meeting, Geneva, Switzerland. Invited lecture

“Identification of new biomarkers for human papillary thyroid carcinoma employing NanoString analysis”.

22. 6/10/2015 INSERM, Lyon, France. Invited presentation "Impact of the circadian oscillator on

human skeletal muscle lipid homeostasis" (delivered by the group member Dr. Loizides). 23. 8-9/10/2015 Islet cell plasticity in diabetes therapy Conference, Copenhagen, Denmark.

Poster presentation by the group member Dr. Petrenko “Functional circadian clock regulates insulin secretion in human islet cells”.

24. 27/10/2015 2nd UNIGE Diabetes Workshop, Geneva. Oral presentation "Impact of the

circadian oscillator and metabolic disorders on human skeletal muscle lipid homeostasis” (delivered by the group member Dr. Loizides).

25. 29/10/2015 « La journée de recherche et prix Gilles Mentha sur le foie et le pancréas, HUG,

Geneva. Selected oral presentation: « Functional circadian clock is required for proper insulin secretion in human pancreatic islet »

26. 10/11/2015 iGE3 Center annual meeting, Geneva. Invited speaker” Impact of the circadian

oscillator on human skeletal muscle lipid homeostasis” (delivered by the group member Dr. Loizides).

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OBTAINED FINANCIAL SOURCES

1. FNRS three year individual project funding 100’000CHF/year (2013-2015); applied for

continuation 30/09/2015; 2. FNRS Sinergia (leading applicant Prof. Howard Riezman; co-applicant Dr. Etienne Lefai);

total funding of 1.4 mln CHF; funding for Dibner’s lab ca. 620’000CHF (206’000CHF/year; 01.01.2015 -31.12.2017);

27. FNRS Sinergia (leading applicant Prof. Steven Brown), total funding of 1.8 mln CHF; funding

for Philippe//Gissous/Dibner lab ca. 600’000 CHF (200’000 CHF/annum); 28. 04/2015 Bo Hjelt Foundation research grant, 50’000 EUR; 29. 06/2015 Fondation Ernst et Lucie Schmidheiny equipment grant, 15’000 CHF; 30. 06/2015 Ligue Genevoise pour la lutte contre le Cancer, 50’000 CHF; 31. 07/2015 La Fondation privée des HUG, collaborative starting grant for 2 years, 200‘000

CHF (leading applicant; collaboration with E. Dermitzakis); 8. 08/2015 Olga Mayenfisch Stiftung, 50‘000 CHF; 9. 10/2015 SNRF R'Equip (co-applicant; leading scientist Prof. Karl Heinz Krause), 139'000

CHF;

5. Division of Endocrinology, Department of Internal Medicine, HUG: 5’500 CHF, for one year.

Total financing obtained for 2015: ca. 850'000 CHF

Dre Ildiko DENES-CARPENTIER

ACTIVITES DE RECHERCHE

The research projects of our group are centered around the function of diverse isoforms of the reactive oxygen-producing NADPH oxidase enzymes (NOX-es) in diabetes, obesity andf their metabolic complications. 1. Project « The role of the NADPH oxidase 5 in islet hormone secretion»

The project is aimed at establishing the role of the reactive oxygen species-producing NADPH oxidase 5 (NOX5) in islet insulin, glucagon and somatostatin secretion. NOX5 may affect islet function through a direct effect in beta cells and/or through an indirect effect on delta cells by modulating the intra-islet somatostatin-mediated paracrine crosstalk. NOX5 is expressed in humans but not in rodents, thus, compared to other NOX enzymes, knowledge about its physiological function and relevance in pathological conditions is very limited. In specific, no study addressed the role of NOX5 in islet function so far. Our project employs

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human islets and mice with doxycycline-inducible beta- and delta-cell specific NOX5 transgenic mice that were developed in our laboratory to study the implication of NOX5 in islet function in vivo. The ultimate goal of the project is to explore the possibility of targeting NOX5 to improve glycemic control, and suppress hyperglucagonemia in Type1 diabetic subjects. The project is conducted in collaboration with the Cell Isolation and Transplantation Centre of the HUG, the Kidney Research Centre, Ottawa and the Department of Biomedicine, University of Basel.

2. Project « The role of the NADPH oxidase 5 in cell survival and apoptosis»

Islet failure in diabetic conditions is linked to enhanced β-cell apoptosis. This project is aimed at uncovering the molecular pathways mediating the effect of NOX5-derived reactive oxygen species (ROS) on cell survival and apoptosis. Our previous investigations revealed a unique and high level expression of NOX5 in a specific class of childhood tumors termed anaplastic large cell lymphomas (ALCLs). ALCLs are aggressive, fast-growing peripheral T-cell or unidentified (null) cell type lymphomas. The aggressive growth of these tumors has been linked to their very low apoptotic rate. Cell lines established from ALCL patients are commercially available and provide excellent surrogate models for human islets for in vitro investigations to assess the effect of NOX5 on apoptosis and to explore hypothetical signaling pathways. The ultimate goal of this project is to establish NOX5 as a potential novel/adjuvant pharmaceutical target to promote islet beta cell survival in Type2 diabetic patients. The project is conducted in collaboration with the Service of Pediatric Onco-hematology and the members of the CANSEARCH research groups.

3. Project « The role of the NADPH oxidase 4 in the modulation of macrophage anti-

inflammatory differentiation in obesity and diabetes»

Two major components involved in the pathogenesis of obesity and its related complications are the deregulation of cellular redox homeostasis and the onset of chronic, low-grade inflammation in the white adipose tissue (WAT). Deletion of one particular NOX isoform, NOX4 in mice predisposes towards pathological adipose tissue accumulation and the development of insulin resistance. Interleukins 4 and 13 (IL-4, IL-13) are two main anti-inflammatory cytokines modulating the activity of diverse immune cells to decrease and resolve inflammatory reactions. IL-4 and IL-13 exert their actions through the activation of the Signal Transducer and Activator of Transcription 6 (STAT6). STAT6 signaling is sensitive to reactive oxygen species (ROS)-mediated regulation. Our project is aimed at investigating the role of crosstalk between NOX4-derived ROS production and STAT6-mediated signaling in the development of obesity in response to calorie-rich diet challenge and the role of decreased macrophage anti-inflammatory differentiation in this process. These investigations are conducted in NOX4/STAT6 double knock-out mice that were created in our laboratory. The ultimate goal of this project is to explore the involvement of a ROS-mediated inflammatory signaling network in the development of obesity-related complications and to

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assess the suitability to harness this network to hamper or delay the development of complications in Type2 diabetic patients.

SUPPORT FINANCIERES

- Fondation Ernst and Lucie et Schmidheiny

- Fondation George Lemaitre

- Société Francophone du Diabète

- Fondation pour Recherche Medicales

COLLOQUES INTERNES AUX HUG

- Colloque de service : The role of NADPH oxidases in diabetes

ACTIVITES DIVERSES

1. FONCTION HOSPITALIERE

- Membre de la “Commission d’alimentation” 2. OCCASIONAL REVIEWER:

- Free Radical Biology and Medicine - Experimental Cell Research, Molecular and Cellular Biochemistry - PLoS Biology - American Journal of Physiology - PLoS One

PUBLICATIONS

1. S. Carnesecchi, A. L. Rougemont, J. H. Doroshow, M. Nagy, S. Mouche, F. Gumy-Pause and

I. Szanto : The NADPH oxidase NOX5 protects against apoptosis in ALK-positive anaplastic large-cell lymphoma cell lines. Free radical biology & medicine, 2015, 84, 22-29. IF: 5.71

2. Tatjana Sajic, Emmanuel Varesio, Ildiko Szanto, Gérard Hopfgartner: Comparison of

fractionation strategies for offline 2D-LC-MS/MS analysis of proteins from mouse adipose

tissueAnalytical Biochemistry, 2015 Sep 1;484:122-32. doi: 10.1016/j.ab.2015.05.015. Epub

2015 May 30. IF: 2.31

Documents

SERVICE D'ENDOCRINOLOGIE, DIABETOLOGIE et NUTRITION