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

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