Short Term Glucagon‐Like Peptide‐1 Receptor Agonist Therapy Does Not Influence Hepatic De Novo Lipogenesis in Polycystic Ovary Syndrome

Abstract

Background PCOS is common and associated with obesity and the metabolic syndrome. Adolescents with PCOS and obesity are more likely to have hepatic steatosis (HS) which portends worsening metabolic disease. Glucagon like peptide -1 receptor agonist (GLP1RA) therapy has been shown to reduce HS, but its influence on mechanisms such as decreasing of de novo lipogenesis (DNL) or free fatty acid (FFA) concentrations are unknown. Methods Adolescents with obesity and PCOS (N=22), half with HS, were enrolled. Participants underwent an overnight metabolic study followed by a morning oral sugar tolerance test (OSTT; 76-78 g glucose +25 g fructose), with half treated with an evening and morning dose of GLP1RA. Serum for fasting and post-OSTT hormones and metabolic markers was collected. DNL rates were measured fasting and during the OSTT using an overnight intravenous stable isotope 13C2 acetate infusion with measurements of incorporation of the tracer into VLDL-triglyceride palmitate. Hepatic fat was measured with MRI utilizing the Dixon method. Groups were compared via t-test or Mann-Whitney U. Metabolic curves between groups were compared via linear mixed effects models. Results TheGLP1RA (N=10, age 15.3 ± 2.2 years, BMI 34.9 ± 7.7 kg/m2, 50% HS) and control groups (N=12, age 16.0 ± 2.2, BMI 36.3 ± 5.7, 50% HS) were similar at baseline in terms of hormonal and metabolic measures, although the fasting serum TG were significantly higher in GLP1RA (126 [95,169] vs 87 [75,106] mg/dL). In GLP1RA, OSTT glucose curveswere significantly lower (p<0.001 overall), as were time points 20, 60, 75, 90, 105, 120, 135, 150, 180, and 210 minutes. Although the OSTT response curves between the groups were not different for FFA, insulin, glycerol or glucagon, fasting glucagon was lower, and insulin at 60 min and glycerol at 300 min were higher in GLP1RA. No significant group differences were found between measures of fractional DNL, although the GLP1RA group was non-significantly lower for every individual time point during fasting and post-OSTT. The absolute DNL level was similar between groups. Conclusions Two doses of GLP1RA treatment impacted fasting and OSTT glucose, insulin and glucagon responses. Glycerol and FFA concentrations did not change and there was a trend for lower fractional DNL. Further study after a longer duration of GLP1RA treatment is needed to determine if decreased DNL is associated with decreases in hepatic steatosis following GLP1RA therapy.