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Obesity, ectopic lipids, and insulin resistance

ter Horst, K.W.

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Citation for published version (APA):ter Horst, K. W. (2017). Obesity, ectopic lipids, and insulin resistance: Tissue-specific defects in nutrient handling

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Nederlandse samenvatting


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SAMENVATTING

Dit proefschrift beschrijft studies naar 3 belangrijke thema’s binnen het metabole on-derzoeksveld. In DEEL 1 t/m 3 presenteren we onderzoeksresultaten naar achtereen-volgens de klinische aspecten van insulineresistentie, de rol van voedingsstoffen en de mechanismen op celniveau. In DEEL 4 plaatsen we de resultaten in een breder per-spectief. De klinische studies waren gericht op het identificeren van insulineresistentie in hoog-risicopatiënten en de bijdrage van insulineresistentie in specifieke organen aan het totale klinische beeld. In de studies naar voedingsstoffen en mechanismen hebben we dieper gezocht naar de moleculaire oorzaken van insulineresistentie in deze orga-nen. Deze onderzoeken zijn ook in mensen uitgevoerd en hadden als extra doel om te toetsen of eerdere bevindingen van laboratorium- en proefdieronderzoek daadwerke-lijk relevant zijn voor mensen. Op deze manier proberen we te achterhalen welke cellen, genen, eiwitten, voedingsstoffen en/of afvalstoffen leiden tot ziekte in mensen, zodat we gericht kunnen zoeken naar nieuwe behandelingen.

DEEL 1: De klinische beoordeling van insulineresistentie in verschillende organenInsulineresistentie ontstaat wanneer de werking van insuline in het lichaam afneemt. Insuline wordt gemaakt in de β cellen van de alvleesklier en heeft een belangrijke hor-monale functie in de suiker-, vet- en energiehuishouding. Het stimuleert de opname van glucose (druivensuiker) uit het bloed en de opslag van vetstoffen in de cellen. Te-gelijkertijd onderdrukt het de aanmaak van nieuw glucose en de afbraak van reeds opgeslagen vetten. Dit is nodig, zodat voedingsstoffen, bijvoorbeeld na een maaltijd, in de cellen worden gebruikt en niet in het bloed ophopen.

Insulineresistentie is de belangrijkste reden dat mensen met obesitas op den duur gezondheidsproblemen krijgen. Het kan onder andere leiden tot type 2 diabetes (ou-derdomssuikerziekte), bloedvetafwijkingen, leververvetting en hart- en vaatziekten. Het liefst zouden we mensen met insulineresistentie daarom in een vroeg stadium opspo-ren en behandelen, omdat de stofwisselingsstoornissen daarmee voorkomen of ver-beterd zouden kunnen worden. Helaas zijn er op dit moment geen simpele testen om insulineresistentie in de kliniek te diagnosticeren.

De hyperinsulinemische, euglycemische clamp-methode is een betrouwbare, maar in-gewikkelde techniek om de werking van insuline in mensen te meten. Deze methode werkt uitstekend in onderzoeksverband, maar is, mede gezien de hoge kosten en lange duur van een meting, niet geschikt voor in de kliniek. In Hoofdstuk 2 beschrijven we dat obese mensen met insulineresistentie ook kunnen worden herkend met behulp van een simpele bloedtest. Hiervoor hebben we de insulinegevoeligheid van een groot aantal gezonde vrijwilligers gemeten. Vervolgens hebben we gekeken hoe de insulinegevoe-ligheid van obese mensen zich verhoudt tot de normale variatie in een gezonde popu-latie. De overgrote meerderheid had een sterk verminderde insulinewerking, oftewel insulineresistentie. We laten zien dat de obese mensen met insulineresistentie kunnen worden herkend door de nuchtere insulinewaarde in het bloed te meten. Een uitslag


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>74 pmol/l duidt op insulineresistentie. Mogelijk kan de nuchtere insulinewaarde als marker worden gebruikt om mensen met insulineresistentie in de kliniek op te sporen.

Insulineresistentie kan ontstaan in verschillende organen, met verschillende gevolgen. Een verminderde insulinewerking in vetweefsel leidt tot een verhoging van de vetaf-braak, waardoor een teveel aan vrije vetzuren aan het bloed wordt afgegeven. Vetzuren veroorzaken insulineresistentie doordat zij het insulinesignaalsysteem in spierweefsel remmen. Bovendien kan een overschot aan vrije vetzuren bijdragen aan ectopisch vet (vetstapeling op plekken waar dat niet hoort) en dit is schadelijk voor de lever, spieren en andere organen. Zo lijkt insulineresistentie in vetweefsel een centrale rol te spelen bij het krijgen van metabole ziekte in de rest van het lichaam.

De snelheid van vetafbraak kan bij de mens betrouwbaar worden gemeten met be-hulp van stabiele isotopen, maar dit is kostbaar en arbeidsintensief. Insulineresistentie in vetweefsel wordt dan ook weinig bestudeerd. In Hoofdstuk 3 tonen we aan dat de werking van insuline in vetweefsel ook goed kan worden gekwantificeerd met behulp van simpelere meetmethoden, waarbij geen stabiele isotopen of insuline-infusies no-dig zijn. De simpelste van deze tools is gebaseerd op een enkele nuchtere bloedaf-name en voldoende betrouwbaarheid voor toepassing in de wetenschap en klinische praktijk. Simpele meetmethoden zijn essentieel voor grootschalige onderzoek naar de rol van vetweefsel in het ontstaan van metabole ziekte. Met ons validatieonderzoek zijn we daar een stap dichterbij.

Mensen die type 2 diabetes krijgen hebben vaak al jaren een verminderde insulinewer-king: insulineresistentie ontstaat veel eerder dan een verhoogde bloedsuikerspiegel. Ten tijde van de diagnose hebben patiënten met diabetes insulineresistentie in de le-ver, vetweefsel, spieren en andere organen. Al deze gebreken kunnen ervoor zorgen dat de bloedsuikerspiegel stijgt. Het is echter niet bekend hoeveel elk van de orgaan-specifieke gebreken bijdraagt aan het ontstaan van diabetes. Mensen met prediabe-tes hebben verhoogde glucosewaarden in het bloed, maar voldoen (nog) niet aan de criteria voor type 2 diabetes. Deze mensen hebben een hoog risico voor het krijgen van diabetes. Sommige prediabetici hebben hoge nuchtere glucosewaarden, terwijl anderen juist hoge glucosewaarden hebben na een maaltijd. In Hoofdstuk 4 onder-zochten we de bijdrage van insulineresistentie in de lever, vetweefsel en spieren aan het ontstaan van prediabetes in obese mensen. We maakten hiervoor gebruik van de hy-perinsulinemische, euglycemische clamp-methode in combinatie met stabiele isotoop-technieken. Onze resultaten laten zien dat mensen met hoge nuchtere glucosewaarden gekenmerkt zijn door sterk verminderde insulinewerking in de lever, maar niet in vet- of spierweefsel. Het effect van insuline om de glucoseproductie in de lever te remmen lijkt in deze mensen het belangrijkste probleem. In eerder onderzoek was al aangetoond dat mensen met hoge glucosewaarden na een maaltijd juist gekenmerkt zijn door insu-lineresistentie in de spier; in die mensen lijkt de glucose-opname het belangrijkste pro-bleem. Zo kunnen orgaanspecifieke effecten van insuline het klinische beeld bepalen. Op vergelijkbare wijze laten we in Hoofdstuk 5 zien dat mannen met morbide obesitas zich van vrouwen met hetzelfde gewicht onderscheiden door insulineresistentie in de


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lever, maar niet in vet- of spierweefsel. Mogelijk is dit een van de redenen waarom di-abetes wereldwijd meer voorkomt bij mannen. Bovendien is het, gezien de verschillen in de onderliggende gebreken, te verwachten dat mensen met verschillende vormen van (pre)diabetes baat hebben van verschillende behandelingen. Een beter begrip van deze processen kan ons helpen om meer doeltreffend naar nieuwe behandelingen te zoeken en bestaande patiënten meer doeltreffend te behandelen.

DEEL 2: De rol van voedingsstoffenVoedingsstoffen, zoals glucose, fructose (fruitsuiker), triglyceriden (neutrale vetstof be-staande uit glycerol en 3 vetzuren) en vrije vetzuren, worden constant afgebroken, aan het bloed afgegeven, tussen de organen vervoerd, uit het bloed opgenomen, opgesla-gen en verbrand. De grootte van deze voedingstoffenstromen, ook wel fluxen genaamd, bepaalt of er nettowinst of -verlies is voor een cel of een orgaan. Hierboven beschreven we al dat vetafbraak in vetweefsel kan bijdragen aan vetstapeling in de lever en spieren, omdat er een (netto) flux van vetweefsel richting andere organen kan ontstaan. Volgens een vergelijkbaar principe kan glucose, wanneer dit door insulineresistentie niet goed in de spieren wordt opgenomen, naar andere organen worden omgeleid. Dit stimuleert dan bijvoorbeeld de vetaanmaak in de lever. De manier waarop voedingsstoffen tussen de organen onderling en het bloed stromen lijkt in belangrijke mate bepalend voor het krijgen van metabole ziekte.

De afgelopen jaren is er veel ophef over de gemeende gezondheidsgevaren van fruc-tose. Mensen consumeren steeds meer toegevoegde fructose en fructoseconsumptie is epidemiologisch geassocieerd met overgewicht, insulineresistentie en leververvet-ting. Fructoseonderzoek is echter uitdagend en niet alle onderzoeksresultaten in men-sen wijzen in dezelfde richting. Fructose en glucose zijn allebei simpele koolhydraten met energiewaarden van 3.75 kcal/g, maar worden op totaal andere wijze door ons lichaam verwerkt. Na inname wordt glucose door vrijwel alle lichaamscellen opgeno-men en verbrand. Fructose wordt daarentegen voornamelijk door de lever opgenomen en verwerkt. Deze inherente verschillen in de fructose- en glucosestofwisseling kunnen ervoor zorgen dat fructoseconsumptie meer gezondheidsproblemen geeft dan de con-sumptie van andere suikers en/of koolhydraten. In Hoofdstuk 6 t/m 8 beschrijven we studies naar de gezondheidseffecten van acute en chronische fructose-inname. Om het effect van fructoseconsumptie op de insulinegevoeligheid te bepalen hebben we eerst op systematische wijze de wetenschappelijke literatuur geanalyseerd. Onze meta-ana-lyse van 46 gecontroleerde studies in opgeteld 1005 mensen met een gezond gewicht of overgewicht staat beschreven in Hoofdstuk 6. De gepoelde resultaten van al deze dieetstudies tonen aan dat fructoseconsumptie bijdraagt aan het ontwikkelen van insu-lineresistentie in de lever. In onze analyse gold dit zowel voor studies waarin fructose met eenzelfde hoeveelheid glucose werd vergeleken als voor studies waarin fructose aan een standaarddieet werd toegevoegd. Fructose draagt overigens niet bij aan in-sulineresistentie in de spieren. Deze bevindingen ondersteunen het idee dat fructose causaal verbonden is met het krijgen van metabole ziekte, met name insulineresistentie in de lever.


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In Hoofdstuk 7 gingen we op zoek naar de moleculaire en cellulaire oorzaken van de gezondheidsgevaren van fructose. De consumptie van veel fructose zou kunnen lei-den tot leververvetting en insulineresistentie, deels doordat fructose de vetaanmaak en glucoseproductie in de lever kan stimuleren. Zoals gezegd wordt ingenomen fructose voornamelijk door de lever verwerkt. In de levercellen kan het als grondstof dienen voor de aanmaak van vet en glucose. Onze hypothese was dat fructose de vetaanmaak meer stimuleert dan glucose en dat mensen met veel levervet gevoeliger zijn voor fruc-tose. Om deze hypothese te toetsen hebben we obese vrijwilligers zonder levervet en obese vrijwilligers met levervet onderzocht. Deze groepen waren gelijk in de mate van overgewicht en de meeste klinische parameters. Desondanks waren vrijwilligers met levervet gekenmerkt door beduidend meer insulineresistentie in de lever, vetweefsel en spieren, wat erop wijst dat ectopisch vet in de lever onderdeel is van een metabool probleem in het hele lichaam. Toediening van 75 g fructose aan de vrijwilligers zorgde voor een acute stijging van de triglyceriden in het bloed. Dat gebeurde niet na toe-diening van glucose. Vervolgens namen we biopten van de lever en vetweefsels na toediening van fructose of glucose. In de lever zorgde fructose, maar niet glucose, voor een stimulatie van genen die betrokken zijn bij de vetaanmaak en glucoseproductie. Opvallend was dat er geen grote verschillen waren tussen vrijwilligers met of zonder levervet in deze effecten van fructose. Mensen met veel levervet hadden daarentegen een verminderd effect van suikerinname op genen in vetweefsel, wat erop kan duiden dat de glucoseopname en -opslag in vetweefsel gestoord is in mensen met levervet. Deze resultaten duiden op cellulaire mechanismen waarmee fructoseconsumptie en stoornissen in vetweefsel kunnen leiden tot levervet en insulineresistentie.

Fibroblast groeifactor 21 is een nieuw hormoon met gemeende gunstige effecten op de suiker-, vet- en energiehuishouding. Eerder onderzoek in proefdieren suggereert dat dit hormoon nodig is voor de normale verwerking van fructose door de lever, maar het is onbekend hoe dit zit in mensen. In Hoofdstuk 8 onderzochten we het effect van fructose-inname op fibroblast groeifactor 21 in obese mensen. De concentratie in het bloed steeg direct na inname van fructose en was na 5 uur weer op het basale niveau. Voor zover wij weten is dit het enige hormoon dat reageert op fructose-inname. Dit suggereert dat het een regulerende functie heeft in de fructosestofwisseling, maar de precieze functie moet in volgend onderzoek worden uitgezocht.

Mensen met obesitas zijn vatbaar voor vitamine D-tekort. Er zijn ook aanwijzingen dat vi-tamine D een gunstig effect heeft op de werking van insuline, maar er is weinig bekend over de actieve vorm van vitamine D. Wij onderzochten of de voorloper en actieve vorm van vitamine D in verband stonden met insulinegevoeligheid in de lever, vetweefsel en spieren (Hoofdstuk 9). In onze groep van obese vrouwen was de mate van overgewicht inderdaad geassocieerd met laag vitamine D, maar dit gold alleen voor de voorloper en niet voor de actieve vorm. Bovendien laten we zien dat beide vormen van vitamine D niet gerelateerd zijn aan de werking van insuline. Het lijkt erop dat vitamine D geen belangrijke rol speelt in het krijgen van insulineresistentie. Echter, gezien de hoge pre-valentie van vitamine D-tekort in mensen met overgewicht, doen artsen er goed aan hier bedacht op te zijn.


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DEEL 3: Moleculaire oorzakenEctopisch levervet lijkt een belangrijke oorzaak van insulineresistentie in de lever, maar de onderliggende mechanismen zijn nog niet duidelijk in mensen. De klinische studie in Hoofdstuk 10 was ontworpen om de relatie tussen verschillende vetstoffen en insu-lineresistentie in de lever te onderzoeken. We waren daarbij ook geïnteresseerd in de mogelijke oorzaken van dat verband op moleculair niveau. In een grote groep obese mensen was het hebben van leververvetting inderdaad geassocieerd met insulineresis-tentie in de lever, vetweefsel en spieren. De resultaten laten echter ook zien dat levervet niet strikt voldoende en niet strikt noodzakelijk was voor het krijgen van insulineresis-tentie. Dit betekent dat er andere factoren moeten zijn die een verband tussen lever-vet en insulineresistentie verklaren. Uit recent proefdieronderzoek blijkt dat stapeling van diacylglycerol (vetstof bestaande uit glycerol en 2 vetzuren) leidt tot activatie van eiwitkinase C. Dit enzym remt het insulinesignaalsysteem in de levercellen, waardoor insulineresistentie ontstaat. Onze resultaten komen hiermee overeen: mensen met in-sulineresistentie in de lever waren gekenmerkt door stapeling van diacylglycerol in de levercellen. Deze stapeling was sterk geassocieerd met de activatie van eiwitkinase C. Deze resultaten ondersteunen een mechanisme waarmee de stapeling van een kleine hoeveelheid specifieke vetstof in de lever, via activatie van eiwitkinase C, kan leiden tot insulineresistentie. Wij kijken nu uit naar de ontwikkeling van gerichte geneesmiddelen die de stapeling van diacylglycerol of activatie van eiwitkinase C tegengaan.

BELANGRIJKSTE CONCLUSIES VAN DIT PROEFSCHRIFT

1. Insulineresistentie is een dynamische wisselwerking tussen voedingsstoffen, regel-systemen en organen.

2. De klinische gevolgen van insulineresistentie zijn afhankelijk van het celtype waarin het defect bestaat.

3. Simpele testen, zoals een nuchtere bloedafname, kunnen worden gebruikt om in-sulineresistentie met voldoende betrouwbaarheid te herkennen in obese mensen.

4. De consumptie van veel fructose draagt bij aan de ontwikkeling van insulineresis-tentie in de lever.

5. Dit komt deels doordat fructose de vetaanmaak en suikerproductie in levercellen stimuleert.

6. Door stapeling van specifieke vetstoffen, zoals diacylglycerol, kan het insulinesig-naalsysteem in levercellen onderdrukt worden.

7. Nieuwe behandelingen voor insulineresistentie en type 2 diabetes kunnen zich het best richten op het verbeteren van de vetopslag in vetweefsel en het voorkomen van vetstapeling in organen als de lever en spieren.


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Abbreviations


218

1,25(OH)2D 1,25-dihydroxycholecalciferol (calcitriol)

25(OH)D 25-hydroxycholecalciferol (calcidiol)

ACACA acetyl-CoA carboxylase 1

ACLY ATP citrate lyase

ADA American Diabetes Association

Adipo-IR Adipose tissue Insulin Resistance index

ALDOB aldolase B

ALT alanine aminotransferase

ANCOVA analysis of covariance

ANOVA analysis of variance

ApoB apolipoprotein B100

aROC area under ROC curve

AST aspartate aminotransferase

ATIRI Adipose Tissue Insulin Resistance Index

AUC area under the curve

BMI body mass index

ChREBP carbohydrate response element-binding protein

CI confidence interval

CRP C-reactive protein

DAG diacylglycerol

DALY disability-adjusted life-year

DNA deoxyribonucleic acid

DNL de novo lipogenesis

EASD European Association for the Study of Diabetes

EGP endogenous glucose production

FA fatty acid

FAHFA branched fatty acid ester of hydroxy fatty acid

FASN fatty acid synthase

FFA free fatty acid

FFM fat-free mass

FGF21 fibroblast growth factor 21

FOXO1 forkhead box protein O1

G6PC glucose-6-phosphatase

GLP1 glucagon-like peptide 1

GLUT glucose transporter

HDL high-density lipoprotein1H-MRS proton magnetic resonance spectroscopy

HOMA2-%B computer-based homoeostasis model assessment of beta cell function

HOMA-IR homeostasis model assessment of insulin resistance


219

Abbr

evia

tions

11

IFCC International Federation of Clinical Chemistry and Laboratory Medicine

IFG impaired fasting glucose

IGT impaired glucose tolerance

IHTG intrahepatic triglyceride

INSR insulin receptor

IQR interquartile range

IRS insulin receptor substrate

KHK ketohexokinase

LC-MS/MS liquid chromatography–tandem mass spectrometry

LDL low-density lipoprotein cholesterol

LoA limits of agreement

LPL lipoprotein lipase

MD mean difference

MQS Heyland methodological quality score

NAFLD non-alcoholic fatty liver disease

NASH non-alcoholic steatohepatitis

NFG normal fasting glucose

OffT2D offspring of parents with type 2 diabetes

OGTT oral glucose tolerance test

PEPCK phosphoenolpyruvate carboxykinase

PKC protein kinase C

PKLR pyruvate kinase

q-RT-PCR quantitative real-time polymerase chain reaction

QUICKI quantitative insulin sensitivity check index

Ra rate of appearance

Rd rate of disappearance

REE resting energy expenditure

RNA ribonucleic acid

ROC receiver-operator characteristic

SAT subcutaneous adipose tissue

SD standard deviation

SE(M) standard error (of the mean)

SMD standardized mean difference

SREBP sterol regulatory element binding protein

VAT visceral adipose tissue

VCO2 carbon dioxide production rate

VLDL very low-density lipoprotein

VO2 oxygen consumption rate


Contributing authors’ affiliations


222

Mariette T. Ackermans Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, Amsterdam, The Netherlands

Myrte Brands Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Ahmet Demirkiran Department of Surgery, Red Cross Hospital, Beverwijk, The Netherlands

Ralph J. DiLeone Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

Susanne E. la Fleur Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, Amsterdam, The NetherlandsDepartment of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The NetherlandsMetabolism and Reward Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

Katy A. van Galen Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Pim W. Gilijamse Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Pieter F. de Groot Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

Annick V. Hartstra Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

Annemieke C. Heijboer Department of Clinical Chemistry, Endocrine Laboratory, VU University Medical Center, Amsterdam, The Netherlands

Mark A. Herman Division of Endocrinology, Metabolism and Nutrition, Duke University School of Medicine, Durham, NC, USA

Rebecca Holman Department of Medical Informatics, Academic Medical Center, Amsterdam, The Netherlands

Murat Kilicarslan Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Karin E. Koopman Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Ruud S. Kootte Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

Eleftheria Maratos-Flier Division of Endocrinology and Metabolism, Beth Isreal Deaconess Medical Center, Boston, MA, USA

Aart J. Nederveen Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands

Max Nieuwdorp Department of Internal Medicine, VU University Medical Center, Amsterdam, The NetherlandsDepartment of Vascular Medicine, Academic Medical Center, Amsterdam, The NetherlandsInstitute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands


223

Cont

ribut

ing

auth

ors’

affil

iatio

ns

11

Kitt F. Petersen Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

Johannes A. Romijn Department of Medicine, Academic Medical Center, Amsterdam, The Netherlands

Varman T. Samuel Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

Merle R. Schene Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Mireille J. Serlie Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Gerald I. Shulman Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USAHoward Hughes Medical Institute, Yale University, New Haven, CT, USADepartment of Medicine, Yale University School of Medicine, New Haven, CT, USA

Maarten R. Soeters Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Richard Trinko Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

Fleur M. van der Valk Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

Daniel F. Vatner Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

Joanne Verheij Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands

Ruth I. Versteeg Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Bart A. van Wagensveld Department of Surgery, OLVG, Amsterdam, The Netherlands

Barbara A. de Weijer Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Dongyan Zhang Howard Hughes Medical Institute, Yale University, New Haven, CT, USA


Portfolio


226

JOURNAL ARTICLES IN THIS THESIS

2017 ter Horst KW, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, Romijn JA, Nieuwdorp M, Zhang D, Samuel VT, Vatner DF, Petersen KF, Shul-man GI, Serlie MJ. Hepatic diacylglycerol-associated protein kinase Cε transloca-tion links hepatic steatosis to hepatic insulin resistance in humans. Cell Rep 2017; 19: 1997-2004

2017 ter Horst KW*, van Galen KA*, Gilijamse PW, Hartstra AV, de Groot PF, van der Valk FM, Ackermans MT, Nieuwdorp M, Romijn JA, Serlie MJ. Methods for quan-tifying adipose tissue insulin resistance in overweight/obese humans. Int J Obes 2017; doi: 10.1038/ijo.2017.110 *contributed equally

2016 ter Horst KW, Schene MR, Holman R, Romijn JA, Serlie MJ. Effect of fructose con-sumption on insulin sensitivity in nondiabetic subjects: a systematic review and meta-analysis of diet-intervention trials. Am J Clin Nutr 2016; 104: 1562-76

2016 ter Horst KW*, Versteeg RI*, Gilijamse PW, Ackermans MT, Heijboer AC, Romijn JA, la Fleur SE, Trinko R, DiLeone RJ, Serlie MJ. The vitamin D metabolites 25(OH)D and 1,25(OH)2D are not related to either glucose metabolism or insulin action in obese women. Diabetes Metab 2016; 42: 416-23 *contributed equally

2016 ter Horst KW, Gilijamse PW, Ackermans MT, Soeters MR, Nieuwdorp M, Romijn JA, Serlie MJ. Impaired insulin action in the liver, but not in adipose tissue or mus-cle, is a distinct metabolic feature of impaired fasting glucose in obese humans. Metabolism 2016; 65: 757-63

2015 ter Horst KW, Gilijamse PW, de Weijer BA, Kilicarslan M, Ackermans MT, Ned-erveen AJ, Nieuwdorp M, Romijn JA, Serlie MJ. Sexual dimorphism in hepatic, adipose tissue, and peripheral tissue insulin sensitivity in obese humans. Front Endocrinol 2015; 6: 182

2015 ter Horst KW, Gilijamse PW, Koopman KE, de Weijer BA, Brands M, Kootte RS, Romijn JA, Ackermans MT, Nieuwdorp M, Soeters MR, Serlie MJ. Insulin resist-ance in obesity can be reliably identified from fasting plasma insulin. Int J Obes 2015; 39: 1703-9

OTHER JOURNAL ARTICLES

2016 Serlie MJ, ter Horst KW, Brown AW. Addendum: Hypercaloric diets with high meal frequency, but not increased meal size, increase intrahepatic triglycerides: a randomized controlled trial. Hepatology 2016; 64: 1814-6

2010 ter Horst KW. Stem cells and cell therapy: popular belief? Cardiology 2010; 117: 199

2010 ter Horst KW. Stem cell therapy for myocardial infarction: are we missing time? Cardiology 2010; 117: 1-10


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BOOK CHAPTER

2012 ter Horst KW. Bone marrow-derived stem cell therapy for myocardial infarction. In: Hayat MA (ed). Stem cells and cancer stem cells. Dordrecht, The Netherlands: Springer 2012; 1: 163-71

CONFERENCE PRESENTATIONS

2017 ter Horst KW, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, Romijn JA, Nieuwdorp M, Groen AK, Zhang D, Samuel VT, Vatner DF, Peters-en KF, Shulman GI, Serlie MJ. Hepatic diacylglycerol-associated protein kinase Cε translocation links hepatic steatosis to hepatic insulin resistance in humans. Noordwijkerhout, The Netherlands: Dutch Endocrine Meeting 2017

2017 van Galen KA, ter Horst KW, Gilijamse PW, Hartstra AV, de Groot PF, van der Valk FM, Ackermans MT, Nieuwdorp M, Romijn JA, Serlie MJ. Methods for quantifying adipose tissue insulin resistance in humans. Noordwijkerhout, The Netherlands: Dutch Endocrine Meeting 2017

2016 ter Horst KW, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, Romijn JA, Nieuwdorp M, Groen AK, Zhang D, Samuel VT, Vatner DF, Peters-en KF, Shulman GI, Serlie MJ. Hepatic diacylglycerol-associated protein kinase Cε translocation links hepatic steatosis to hepatic insulin resistance in humans. Oosterbeek, The Netherlands: ADDRM 2016 Best Abstract Award

2016 van Galen KA, ter Horst KW, Gilijamse PW, Hartstra AV, de Groot PF, van der Valk FM, Ackermans MT, Nieuwdorp M, Romijn JA, Serlie MJ. Methods for quantifying adipose tissue insulin resistance in humans. Oosterbeek, The Netherlands: AD-DRM 2016 Best Abstract Award

2016 ter Horst KW, Gilijamse PW, Versteeg RI, de Weijer BA, van der Valk FM, Acker-mans MT, Nederveen AJ, la Fleur SE, Romijn JA, Nieuwdorp M, Serlie MJ. The relationship between hepatic steatosis and insulin resistance in obese humans follows a threshold model. New Orleans, LA, USA: ADA Scientific Sessions 2016

2016 ter Horst KW*, Gilijamse PW*, Ackermans MT, Romijn JA, Nieuwdorp M, Mara-tos-Flier E, Herman MA, Serlie MJ. The FGF21 response to fructose predicts met-abolic health in obese humans. New Orleans, LA, USA: ADA Scientific Sessions 2016 *contributed equally

2016 Gilijamse PW*, ter Horst KW*, Ackermans MT, Romijn JA, Nieuwdorp M, Serlie MJ. Higher postprandial GLP1 responses are associated with improved insulin action in liver and muscle but not in adipose tissue in morbidly obese nondiabet-ic subjects. New Orleans, LA, USA: ADA Scientific Sessions 2016 *contributed equally

2015 ter Horst KW, Gilijamse PW, de Weijer BA, van der Valk FM, Ackermans MT, Ned-erveen AJ, Romijn JA, Nieuwdorp M, Serlie MJ. Liver fat content and hepatic in-sulin resistance are not directly related in obese humans. Boston, MA, USA: ADA Scientific Sessions 2015


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2015 ter Horst KW, Gilijamse PW, de Weijer BA, Ackermans MT, Nieuwdorp M, Soeters MR, Romijn JA, Serlie MJ. Reduced hepatic insulin sensitivity is a distinct feature of obese humans with impaired fasting glucose. Boston, MA, USA: ADA Scientific Sessions 2015

2015 ter Horst KW, Gilijamse PW, Ackermans MT, Nieuwdorp M, Soeters MR, Romijn JA, Serlie MJ. Reduced hepatic insulin sensitivity is a distinct feature of obese humans with impaired fasting glucose. Lunteren, The Netherlands: ACM Meeting 2015

2014 ter Horst KW, Gilijamse PW, Koopman KE, de Weijer BA, Brands M, Ackermans MT, Romijn JA, Nieuwdorp M, Soeters MR, Serlie MJ. Identifying insulin-sensitive and resistant obesity in humans. Oosterbeek, The Netherlands: ADDRM 2014

2011 de Boon WMI, ter Horst KW. Quality of anaesthesiology-related information on the Internet: a systematic review. Amsterdam, The Netherlands: Euroanaesthesia 2011

2010 ter Horst KW, de Boon WMI, Boerma EC, Balestra GM. Doctors’ alertness during night: nocturnal attentional performance (NAP) pilot study. Barcelona, Spain: ES-ICM Annual Congress 2010

COURSES

2017 Patents and Intellectual Property Rights 0.1 ECTS

2016 Advanced qPCR 0.7 ECTS

2015 Advanced Topics in Biostatistics 2.1 ECTS

2015 Searching for a systematic review 0.1 ECTS

2014 Expert Management of Medical Literature 0.1 ECTS

2014 Observational Epidemiology 0.9 ECTS

2014 Practical Biostatistics 1.1 ECTS

2014 Integrated Analysis of Tumor Genomics Data with R2 0.3 ECTS

2014 Improving Accuracy of qPCR Results 0.2 ECTS

2014 Clinical Data Management 0.2 ECTS

2014 AMC World of Science 0.7 ECTS

2014 Basiscursus Regelgeving en Organisatie voor Klinisch onderzoekers (BROK) 0.9 ECTS

LECTURES

2016 Novel mechanisms of human insulin resistance. Amsterdam, The Netherlands: Mastercourse Endocrinology 2016

2015 Mechanisms of insulin resistance. Amsterdam, The Netherlands: Mastercourse Endocrinology 2015

2014 Diabetes: diagnosis and management. Amsterdam, The Netherlands: Just-in-time learning 2014


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SUPERVISING

2016 van Galen KA. Central regulation of appetite and feeding behavior in obesity. PhD candidate in Medicine

2015 van Galen KA. Adipose tissue insulin resistance in obese subjects. Master’s thesis in Medicine

2015 Summer research program for high school students2014 Schene MR. The effect of fructose on insulin sensitivity. Bachelor’s thesis in Med-

icine


DankwoordAcknowledgements


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Dit proefschrift had niet tot stand kunnen komen zonder de onvoorwaardelijke steun en hulp van talloze mensen. Ik ben jullie eeuwig dankbaar en wil deze laatste woorden graag tot jullie richten.

Proefpersonen, dank voor jullie inzet en interesse tijdens de lange en intensieve onder-zoeksdagen. De vooruitgang van medisch-wetenschappelijk onderzoek is enkel en alleen mogelijk door de onbaatzuchtige deelname van proefpersonen; jullie hebben deze studies mogelijk gemaakt.

Dr. M.J.M. Serlie, Mireille, jouw aanstekelijke enthousiasme en briljante wetenschap-pelijke inzicht hebben mij gestimuleerd dit pad in te slaan. Niemand weet haar promov-endi beter te prikkelen dan jij. Door jou heb ik het beste uit mezelf kunnen halen en ik had me geen betere plek kunnen voorstellen. Dank voor de mogelijkheden, vrijheden en uitdagingen die je me hebt gegeven. Ik verheug me op de plannen die we nog hebben.

Prof. dr. J.A. Romijn, Hans, ik dank je voor alle steun en advies die je me de afgelopen jaren hebt gegeven. Je enorme kennis, efficiëntie en helderheid zijn bewonderenswaar-dig. Ik ben blij, vereerd en trots om dit proefschrift onder jouw supervisie af te ronden.

Prof. dr. M. Nieuwdorp, Max, dank voor je advies, feedback en sturing. Jouw betrokken-heid lijkt elk project vruchtbaar te maken en jouw indrukwekkende persoonlijkheid en loopbaan zijn een inspiratie voor me.

Hooggeleerde leden van de promotiecommissie, prof. dr. E. Fliers, prof. dr. J.H. de Vries, prof. dr. U.H.W. Beuers, prof. dr. E.E. Blaak en prof. dr. S.E. la Fleur, dank voor jullie deskundige beoordeling van dit proefschrift. Ik kijk uit naar een uitdagende ge-dachtenwisseling. Prof. dr. G.I. Shulman, your expert assessment of this work means a lot to me. Thank you for taking part in this.

Collega’s in het AMC en elders, dank voor jullie enorme bijdrage aan het opzetten, uit-voeren en afronden van deze studies. Pim, jij hebt me geleerd te clampen en niemand heeft meer bijgedragen aan deze studies dan jij. Dank voor de goede samenwerking en de vriendschap die we hebben opgebouwd. Susanne, de translationele samenwerking met jouw groep is fantastisch. Je enthousiasme in de wetenschap, scherpe blik en prak-tisch inzicht zijn een inspiratie. Dank voor alles wat je me hebt geleerd over metabo-lisme, de rol van het brein en onderzoek in het algemeen. Mariette, An, Yvonne, Unga, Geesje, Hans en collega’s, jullie uitmuntende laboratoriumexpertise is het fundament waarop metabool onderzoek in de regio Amsterdam is gebouwd. Ik prijs me gelukkig met jullie te kunnen samenwerken. Bert, Maarten, Peter, Ruth, Sam, Annick, Hannah, Dirk Jan, Murat, Myrtille, Merel, Anne, Maarten, Martine, Charlotte, Eelkje, Yvonne, Tessel, Simon, Katy, Emma en alle onderzoekers van de Endocrinologie en Vasculaire, ik heb ervan genoten van jullie te leren en/of samen met jullie door dit traject te wor-stelen. Jullie gezelligheid maakt het AMC een geweldige werkplek. Birgit en Martine,


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ik kon altijd op jullie support rekenen (en heb dat ook veelvuldig gedaan). Ik ben jullie zeer dankbaar.

Chirurgen in de deelnemende centra, Bart van Wagensveld, Ahmet Demirkiran, Huib Cense en collega’s, dank voor jullie interesse en inzet om aan deze studies mee te werken. Ik ben me ervan bewust dat de studiehandelingen niet altijd makkelijk in jullie normale werkzaamheden in te passen waren en stel jullie enthousiaste deelname des te meer op prijs.

International collaborators, Gerald Shulman, Ralph DiLeone, Rich Trinko, Barbara Kahn, Mark Herman, Terry Maratos-Flier and other lab members, thank you for the exciting collaborations. These projects have taught me that working together across nations and areas of expertise may lift any scientific endeavor to the next level.

Mijn paranimfen, dank dat jullie hierin, letterlijk en figuurlijk, naast me staan. Lieve Doris, misschien wel mijn grootste fan, ik ben trots op jou en jouw waardering betekent alles voor me. Bote, we hebben inmiddels bewezen dat deze vriendschap wel wat afstand aankan, maar ik vind het fantastisch dat je hier bij wil zijn. Thanks for all the good times.

Lieve ouders, Emil en Ivon, jullie hebben me geleerd om met een vleugje humor en een nieuwsgierige, open blik naar de wereld te kijken. Van ver of dichtbij, in goede of slechte tijden, jullie zijn er altijd voor me. Dank voor jullie eeuwige en onvoorwaardelijke steun.

Emma, your love, support, happiness, and crazy spontaneity make my day, every day. Mar sin, beidh mé i ngrá leat go deo. Thank you for being you.

Kasper ter Horst


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511975-L-os-terHrst511975-L-os-terHrst511975-L-os-terHrst511975-L-os-terHrst Processed on: 26-7-2017Processed on: 26-7-2017Processed on: 26-7-2017Processed on: 26-7-2017

511975-L-os-terHrst511975-L-os-terHrst511975-L-os-terHrst511975-L-os-terHrst Processed on: 26-7-2017Processed on: 26-7-2017Processed on: 26-7-2017Processed on: 26-7-2017

Kasper ter Horst

OBESITY, ECTOPIC LIPIDS,AND INSULIN RESISTANCETissue-specific defects in nutrient handling

OBESITY, ECTO

PIC LIPIDS, A

ND

INSU

LIN RESISTA

NCE

Kasper ter H

orst

UITNODIGING

voor het bijwonen van de openbare verdediging van het proefschrift

OBESITY, ECTOPIC LIPIDS,AND INSULIN RESISTANCE

door Kasper ter Horst

opwoensdag 20 septemberom 10:00 uurin de Agnietenkapel van de Universiteit van Amsterdam

Oudezijds Voorburgwal 331 1012EZ Amsterdam

Aansluitend is er een receptie.

Paranimfen

Doris ter [email protected]

Bote Bruinsma [email protected]

UvA-DARE (Digital Academic Repository) Obesity, ectopic ... · PDF fileopgeslagen vetten. ......

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Transcript of UvA-DARE (Digital Academic Repository) Obesity, ectopic ... · PDF fileopgeslagen vetten. ......