Bovbjerg, Kirsten Katrine Lindegaard

Fedme-associeret type 2 diabetes (T2D) er karakteriseret ved en tilstand af lav kronisk inflammation med overdreven sekretion af pro-inflammatoriske mediatorer, så som IL-6, TNF-α og leptin fra fedtvævet og en reduktion i anti-inflammatorisk adipokine adiponectin. Med T2D følger et sæt metaboliske abnormaliteter, bestående af det metaboliske syndrom, så som forhøjet blodtryk, dyslipidimi og insulin resistens. Selvom de eksakte årsager til påbegyndelsen af klinisk sygdom er stort set uvisse, tyder nye beviser på at fedme-induceret inflammation, specielt i fedtvævet, er involveret i den metaboliske dysregulering og derfor spiller en vigtig rolle i patogenesen af denne forværrede sygdom.Fedme kirurgi, herunder Roux-en Y gastrisk bypass (RYGB), er en af de mest effektive behandlinger af svær overvægt. Ud over vægttab er RYGB proceduren associeret med øjeblikkelig forbedring i glykæmisk kontrol og insulin sekretion. Den eksakte mekanisme bag den øjeblikkelige og langsigtede positive effekt af RYGB på glukose metabolisme og fedme relaterede co-morbiditet forbliver uklar. Efter RYGB er der fundet ændringer i inflammatoriske cellulære og molekylære mediatorer, hvilket indikerer én potentiel mekanisme med hvilken bariatric kirugi genetablerer insulin sensitivitet.RYGB øger også cirkulerende niveauer af visse mavetarm-hormoner, især postprandial sekretion af glucagon-like peptide-1 (GLP-1). En voksende mængde af litteratur rapporterer om anti-inflammatoriske og andre immunologiske effekter af GLP-1 i dyr og i mennesker, hvilket tyder på at GLP-1 virker ud over glucoregulatoriske mekanismer. Den øgede postprandiale GLP-1 sekretion, som opstår efter RYGB, er derfor muligvis involveret i de gavnlige metaboliske effekter, både direkte via den glucoregulatoriske pathway og indirekte via anti-inflammatoriske og immunregulatoriske mekanismer.Fund af direkte GLP-1-medieret effekt på lymfocyt subpopulationer in vitro og in vivo og de få, men interessante case reports om kliniske forbedringer i psoriasis patienter behandlet med GLP-1 receptor agonister, understøtter GLP-1s immunregulatoriske handlinger.Hovedformålet med denne afhandling var at undersøge potentielle anti-inflammatoriske og immunregulatoriske effekter af GLP-1 på parametre relateret til immunsystemet, for at øge den mekanistiske forståelse for de effekter der er observeret klinisk og for at tilføre et nyt aspekt på samspillet mellem metabolisme, fedme og inflammation.In vitro studiet, et dyreforsøg og de tre manuskripter, der udgører denne afhandling beskriver forskellige vinkler på at studere GLP-1s effekter på immunsystemet. I Studie I blev funktionaliteten af humane ekspanderede Tregs, under tilstedeværelse af GLP-1, evalueret in vitro. I Studie II blev de antiinflammatoriske effekter af GLP-1 in vivo undersøgt i en PMA-induceret øre-inflammations model. Tre  humane studier blev gennemført, og danner grundlaget for de tre manuskripter i denne afhandling; to RYGB studier (Studie III, Manuskript I og Studie IV, Manuskript II) og et studie i overvægtige T2D patienter tilskrevet liraglutid behandling (Studie V, Manuskript III) for samlet set at evaluere immunologiske ændringer efter operation (1 uge, 3 måneder, og 1 år) eller efter 12 ugers GLP-1 behandling.Obesity-associated type 2 diabetes (T2D) is characterized by a state of chronic, low-grade inflammation with an excessive secretion of pro-inflammatory mediators, such as IL-6, TNF-α, and leptin from the adipose tissue and decrease in the anti-inflammatory adipokine adiponectin. T2D is accompanied with a set of metabolic abnormalities comprising the metabolic syndrome, such as hypertension, dyslipidemia, and insulin resistance. Although the exact causes for the onset of clinical disease remain largely unknown, emerging evidence seems to suggest that obesity-induced inflammation, especially in the adipose tissue, is involved in the metabolic dysregulation and therefore plays an important role in the pathogenesis of this deteriorating disease.Bariatric surgery, including the Roux-en Y gastric bypass (RYGB), is one of the most effective treatments for severe obesity. In addition to weight loss, the RYGB procedure is associated with immediate improvement in glycemic control and insulin secretion. The exact mechanisms for the immediate and long-term positive effect of RYGB on glucose metabolism and obesity related co-morbidities remain unclear. Changes in inflammatory cellular and molecular mediators have been found following RYGB, suggesting one potential mechanism by which bariatric surgery re-establishes insulin sensitivity.RYGB also enhances circulating levels of certain gastrointestinal-derived hormones, particularly the postprandial secretion of glucagon-like peptide 1 (GLP-1). A growing body of literature reports antiinflammatory and other immunological effects of GLP-1 in animals and in humans suggesting that GLP-1 acts beyond purely glucoregulatory mechanisms. The exaggerated postprandial GLP-1 secretion following RYGB may thus be involved in the beneficial metabolic effects both directly via the classical glucoregulatory pathways and indirectly via anti-inflammatory and immune-regulatory mechanisms.The findings of a direct GLP-1-mediated effect on lymphocyte subpopulations in vitro and in vivo and the few but interesting case reports on clinical improvements in psoriasis patients treated with GLP-1 receptor agonists have supported immune-regulatory actions of GLP-1.The main aim of this thesis was to explore potential anti-inflammatory and immunoregulatory effects of GLP-1 on immune system parameters to increase the mechanistic understanding of the effects observed in the clinic and to provide new aspect on the interplay between metabolism, obesity and inflammation.The in vitro work and animal study, and the three manuscripts constituting this thesis describe different approaches in studying GLP-1 effects on immune system parameters. In Study I, the functionality of human expanded Tregs in the presence of GLP-1 was examined in vitro. Study II investigated antiinflammatory effect of GLP-1 in vivo in the PMA-induced ear inflammation model. Three human studies  were conducted that generated the three manuscripts in the thesis; two RYGB studies (Study III, Manuscript I and Study IV, Manuscript II) and one study in obese T2D subjects commencing liraglutide therapy (Study V, Manuscript III), to evaluate immunological changes either after surgery (1 week, 3 months, and 1 year) or after 12 weeks of GLP-1 therapy

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Anti-inflammatory role of GLP-1 and the effect of gastric bypass on diabetes- and obesity-associated inflammation

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Anti-inflammatory role of GLP-1 and the effect of gastric bypass on diabetes- and obesity-associated inflammation

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