THE IMPACT OF DEGRADATION INHIBITOR OF GLUCAGON LIKE POLYPEPTIDE 1 ON BODY WEIGHT AND BETA-CELL FUNCTION IN OBESE WOMEN WITH POLYCYSTIC OVARIAN SYNDROME

Ferjan, Simona (avtor), Jensterle Sever, Mojca (mentor)

Obesity is highly prevalent in polycystic ovary syndrome (PCOS). It worsens reproductive and metabolic abnormalities of the syndrome, in particular insulin resistance (IR), Weight manegment and decreasing IR with lifestyle modification and metformin are well-addressed targets in this population, yet a conversion rate to prediabetes in obese women with PCOS remains 2-3 times higher when compared to the expected conversion rate of 1%–5% per year in the general obese population. Unmet goals imply that potential new modifiable risk factors and novel treatment strategies should be addressed in this metabolically high-risk population. Lately, the mounting evidences indicate that impairments of glucagon-like peptide 1 (GLP-1) axis have an important role in deregulation of appetite and glucose homeostasis. Enhancement of impaired GLP-1 axis by individually tailored strategies should be considered in a subset of women with PCOS with the highest metabolic risk and expected fast conversion rate toward diabetes. In the following doctoral dissetation we focused on the relationship between incrtein axis and metabolic disorders in obese women with PCOS and the potential impact of enhancement of the GLP-1 effect with dipeptidyl peptidase-4 (DPP-4) inhibitors on body weight and beta-cell function in the subset of women with PCOS with the highest metabolic risk. The first part of the disseratation consists of the case control study where the post-load GLP-1 response in obese women with normal glucose tolerance (NGT) was compared to post load GLP-1 response in obese women with PCOS and prediabetes. 26 obese women with PCOS phenotype A were included in the study. Thirteen of them had NGT and 13 had prediabetes defined as having impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or both. They were matched for BMI and age. Serum glucose, insulin, C-peptide, total GLP-1 and total glucose-dependent insulinotropic peptide (GIP) were sampled during oral glucose tolerance test (OGTT). Model-derived static and dynamic parameters for the assessment of beta-cell function and IR were determined. All patients underwent measurement of androgen profile and whole-body composition by a Hologic Dual Energy X-ray Absorptiometer (DXA). In the second and third part of the dissertation we considered the potential role of enhancement of endogenous GLP-1 with DPP-4 inhibitor in PCOS population Firstly we assessed the relevance of the intervention with DPP-4 inhibitors in metformin-intolerant woman with PCOS and high metabolic risk. A 12-week prospective randomized open-label clinical study with 30 obese metformin-intolerant women with PCOS was conducted. After metformin withdrawal, they were randomized to lifestyle intervention and DPP-4 inhibitor sitagliptin (SITA) or lifestyle intervention alone as controls (CON). All participants underwent anthropometric, endocrine measurements and OGTT. Model-derived indexes of IR and beta-cell function were calculated. Secondly a 12-week prospective randomised open-label study was conducted to evaluate the effect of DPP-4 inhibitor addition to metformin therapy on body weight maintenance after discontinuation of treatment with GLP-1 receptor agonist liraglutide, that has been established as an antiobesity treatment and is often discontinuated in clinical practice due to development of treatment resistence. The study was conducted with 24 obese women with PCOS who had been pretreated with liraglutide 3.0 mg due to anti-obesity management. They were randomized to combined treatment (COMBO) with sitagliptin and metformin or metformin monotherapy (MET). Lifestyle intervention was promoted in both groups. Eating behaviour was assessed by a Slovenian translation of Three-Factor Eating Questionnaire (TFEQ-R18). In the first part we demonstrated that GLP-1 response to oral glucose load was reduced in obese PCOS with prediabetes, independent of age, BMI and disease phenotype, when compared to obese PCOS with NGT. Values of total GLP-1 at 120 min below 3.0 pM predicted prediabetes. Plasma GLP-1 level at 120 min was negatively correlated with visceral adipose tissue and positively correlated with oral glucose insulin sensitivity index. Furthermore, the correlation between the ΔAUCGLP-1 and the family history of at least one first-degree relative affected with type 2 diabetes (T2D) was confirmed. It was demonstrated in the second part that enhancement of endogenous GLP-1 effect with DPP-4 inhibitor sitagliptin in metformin-intolerant obese PCOS lead to preservation of beta-cell function and seemed to delay development of impaired glucose homeostasis. In addition to preservation of beta-cell function, treatment with sitagliptin also assisted with maintenance of body weight in particular due to prevention of increasing in visceral adiposity after metformin withdrawal. Beneficial effect of enhancement of endogenous incretin effect with DPP-4 inhibitor was demonstrated also after cessation of anti-obesity treatment with liraglutide in obese women with PCOS, where DPP-4 inhibitor added to metformin resulted in prevention of weight regain. In addition women treated with DPP-4 inhibitor sitagliptin had greater ability to resist emotional eating when compared to women treated with metformin monotherapy. Our results indicate that impaired GLP-1 response could be a new separate risk factor for prediabetes in PCOS independent of BMI, age and disease phenotype. We demonstrated that DPP-4 inhibitors are a promising therapy to prevent weight regain after cessation of anti-obesity treatment with GLP-1 analoge liraglutide and also seem to be an alternative treatment in PCOS women with high metabolic risk that have failed with lifestyle intervention and are metformin-intolerant

• Jezik: Angleški jezik
• Ključne besede: PCOS, prediabetes, GLP-1 response, DPP-4 inhibitor, sitagliptin, weight maintenance, GLP-1 receptor agonist, liraglutide
• Vrsta gradiva: Doktorsko delo/naloga
• Organizacija: MF - Medicinska fakulteta
• Leto izida: 2018
• PID: 20.500.12556/RUL-100899
• COBISS.SI-ID: 294520320
• Datum objave v RUL: 19.04.2018

Sekundarni jezik

• Jezik: Slovenski jezik
• Naslov: VPLIV ZAVIRALCEV RAZGRADNJE GLUKAGONU PODOBNEGA POLIPEPTIDA 1 NA TELESNO MASO IN DELOVANJE BETA-CELIC PRI ŽENSKAH Z DEBELOSTJO IN S SINDROMOM POLICISTIČNIH JAJČNIKOV

Izvleček

Za sindrom policističnih jajčnikov (PCOS) je značilna visoka prevalenca prekomerne telesne mase, ki poslabšuje izraženost reproduktivnih in presnovnih zapletov PCOS, zlasti inzulinske rezistence (IR). Zmanjševanje telesne mase in IR s spremembo življenjskega sloga in metforminom je za zmanjševanje zapletov PCOS ključnega pomena. Kljub zdravljenju ostaja stopnja razvoja prediabetesa pri debelih ženskah s PCOS 2-3-krat večja v primerjavi s pričakovano 1% -5% letno stopnjo konverzije v splošni populaciji ljudi s prekomerno telesno maso, kar kaže na to, da je v populaciji debelih žensk s PCOS potrebno vpeljati nove strategije zdravljenja s targetiranjem potencialnih novih dejavnikov tveganja. Izsledki dosedanjih raziskav kažejo, da ima oslabljen odgovor hormonske osi glukagonu-podobnega peptida 1 (GLP-1) pomembno vlogo pri deregulaciji apetita in glukozne homeostaze. Ojačenje oslabljene GLP-1 osi bi morda lahko predstavljalo individualno prilagojeno alternativno farmakološko strategijo v podskupini žensk s PCOS z visokim presnovnim tveganjem in pričakovanim hitrim razvojem prediabetesa. V doktorski disertaciji smo se osredotočili na potencialno vlogo oslabljenega odgovora inkretinske hormonske osi pri presnovnih zapletih debelih bolnic s PCOS in na vpliv z zaviralci dipeptidil peptidaze-4 (DPP-4) povečanega učinka GLP-1 na telesno maso in beta-celično funkcijo pri podskupini žensk s PCOS in visokim presnovnim tveganjem. V prvem delu disertacije smo v presečni študiji primerjali odziv GLP-1 po oralnem glukozno tolerančnem testu (OGTT) pri debelih PCOS z normalno toleranco za glukozo (NGT) in debelih PCOS s prediabetesom. V raziskavo smo vključili 26 debelih žensk s PCOS fenotipa A. Trinajst od njih je imelo NGT, 13 pa jih je imelo prediabetes, ki je bil opredeljen kot motena bazalna glikemija, moteno tolerance za glukozo, ali oboje. Preiskovanke se niso razlikovale v indeksu telesne mase (ITM) in starosti. Vse preiskovanke so opravile OGTT, med katerim so bili odvzeti vzorci krvi za določitev serumske glukoze, C-peptida, inzulina, celokupnega GLP-1 in celokupnega od glukoze odvisnega insulinotropnega polipeptida (GIP). Za oceno beta-celične funkcije in IR smo uporabili statične in dinamične modelne indekse. Vse preiskovanke so opravile merjenje sestave celega telesa s pomočjo rentgenskega absorptiometra Hologic Dual Energy (DXA). V drugem in tretjem delu disertacije smo preučili potencialno vlogo z DPP-4 zaviralci podaljšanega endogenega GLP-1 učinka v populaciji PCOS. Najprej smo ocenili smiselnost zdravljenja z DPP-4 zaviralci pri metabolno visoko ogroženih ženskah s PCOS, ki ne prenašajo metformina. V 12-tedensko prospektivno randomizirano odprto raziskavo smo vključili 30 preiskovank s PCOS in debelostjo, ki ne prenašajo metformina. Po prekinitvi terapije z metforminom, so bile randomizirane v skupino, ki je poleg promocije zdravega življenjskega sloga prejemala DPP-4 zaviralec sitagliptin (SITA), in kontrolno skupino (CON), ki je bila deležna promocije zdravega življenjskega sloga. Pri vseh preiskovankah smo opravili antropometrične in endokrinološke meritve ter OGTT. IR in beta-celično funkcijo smo izračunali na podlagi statičnih modelnih indeksov. V nadaljevanju smo z 12-tedensko randomizirano odprto klinično raziskavo želeli proučiti učinkovitost kombiniranega zdravljenja z DPP-4 zaviralcem in metforminom pri vzdrževanju telesne mase po zaključeni terapiji z agonistom GLP-1 receptorja liraglutidom. Uporaba liraglutida je ustaljena terapija za zdravljenje debelosti, vendar je v klinični praksi zdravljenje z liraglutidom po določenem času pogosto prekinjeno zaradi razvoja odpornosti na zdravljenje oziroma pojava neučinkovitosti pri redukciji telesne mase. V raziskavo smo vključili 24 preiskovank s PCOS in debelostjo, ki so bile predhodno zaradi debelosti zdravljene z liraglutidom 3mg/dan. Po ukinitvi liraglutida so bile randomizirane v skupino, ki je prejemala kombinirano terapijo s sitagliptinom in metforminom (COMBO skupina) in skupino, ki je prejemala monoterapijo z metforminom (MET skupina). V obeh skupinah je bil promoviran zdrav življenjski slog. Po randomizaciji in na koncu študije so vse udeleženke opravile standardne antropometrične in endokrine meritve. S slovenskim prevodom trifaktorskega vprašalnika (TFEQ-R18) je bil ocenjen vedenjski vzorec prehranjevalnih navad V prvem delu smo ugotovili, da je v primerjavi z bolnicami s PCOS in NGT, pri bolnicah s PCOS, ki imajo prediabetes inkretinski odgovor pomembno znižan in je neodvisen od ITM; starosti in fenotipa bolezni. Vrednosti GLP-1 po obremenitvi z glukozo pod 3,0 pM so značilne za prediabetes. Vrednost GLP-1 v 120 min OGTT je bila negativno povezana s količino visceralnega maščobnega tkiva ter pozitivno z oralnim indeksom občutljivosti glukoze na insulin. Potrjena je bila tudi negativna povezava med razliko v odgovoru GLP-1 na glukozno obremenitev in družinsko anamnezo vsaj enega prvostopenjskega sorodnika s SB2. V drugem delu smo s podaljšanjem endogenega učinka endogenega GLP-1, ki smo ga dosegli z zaviralcem DPP-4 sitagliptinom pri debelih ženskah s PCOS, ki ne prenašajo metformina, dosegli ohranitev beta-celične funkcije in zdi se, da tudi upočasnitev razvoja motene glukozne homeostaze. Poleg ohranitve beta-celične funkcije je intervencija s sitagliptinom po ukinitvi metformina pripomogla pri vzdrževanju telesne mase, zlasti pri preprečevanju povečanja visceralne maščobe. Ugoden učinek podaljšanega endogenega inkretinskega učinka, ki smo ga dosegli z zaviralcem DPP-4 smo prikazali tudi pri intervenciji z zaviralcem DPP-4 po ukinitvi zdravljenja debelosti z liraglutidom pri debelih ženskah s PCOS, kjer smo ob kombinirani terapiji z zaviralcem DPP-4 in metforminom dosegli učinkovitejše preprečevanje ponovnega porasta telesne mase, hkrati je bila dokazana tudi večja sposobnost upiranja čustvenemu prehranjevanju. Naši rezultati nakazujejo da bi lahko oslabljen GLP-1 odziva predstavljal nov samostojen dejavnik tveganja za razvoj prediabetesa pri ženskah s PCOS, neodvisen od BMI, starosti in fenotipa bolezni. Prikazali smo, da zaviralci DPP-4 predstavljajo obetavno zdravljenje za preprečevanje ponovnega pridobivanja telesne mase po prenehanju zdravljenja debelosti z analogom GLP-1 receptorja liraglutidom. Glede na izsledke disertacije se zdi, da so zaviralci DPP-4 smiselno alternativno zdravljenje pri ženskah s PCOS in visokim presnovnim tveganjem, ki ne prenašajo metformina.

• Ključne besede: PCOS, prediabetes, GLP-1 odziv, DPP-4 zaviralec, sitagliptin, vzdrževanje telesne mase, agonist GLP-1 receptorja, liraglutide