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

Abstract

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.