PMON209 Ceramides Predict Metabolic Response to Metformin in Women with PCOS

: Polycystic ovarian syndrome (PCOS) is a complex disorder in which metabolic abnormalities are associated with reproductive dysfunction. Women with PCOS have been shown to have increased ceramide concentrations with the obese, insulin resistant phenotype having even higher levels. Ceramides modulate insulin signaling, promoting insulin resistance, and are markers of diabetes risk and cardiovascular mortality. Previous studies demonstrate that treating metabolic abnormalities of PCOS with metformin improved glucose effectiveness, caused weight loss, and restored ovulation in 61% of women after 12 weeks. However, these metabolic improvements did not explain improved ovulation experienced by some women. HYPOTHESIS: We hypothesized that in women with PCOS, baseline ceramide, diacylglycerol (DAG) and triacylyglycerol (TAG) concentrations are associated with an improved metabolic response to metformin.Subjects: Women (n=29), aged 29±5 years and diagnosed with PCOS by the NIH criteria were studied. METHODS: Individuals underwent an intravenous glucose tolerance test (IVGTT) and hCG-stimulation before and after 12-weeks of treatment with metformin (1500 mg per day). Metabolic responders were defined by improved glucose effectiveness after metformin treatment. RESULTS: Among predominantly white women with an average body mass index 29.4±6.1 kg/m(2), 12-weeks of metformin resulted in weight loss (-1.7±2.6 kg, p<0.01) and a reduction in BMI (-0.6±0.9 kg/m(2), p<0.01) with no change in HbA1c (5.5%±0.3 vs 5.5%±0.3, p=0.7). The concentrations of ceramides with acyl chain length at 22 and 24 (C22 and C24), total ceramides, dihydroceramides (C16: 0), C18: 2, DAG, dihydrosphingomyelin (DHSM), and TAG decreased after metformin treatment (p<0.05). Baseline total dihydroceramides (C16: 0) and DHSM were lower in metabolic responders compared to metabolic non-responders (C16: 0 172±11 vs 232±14 pmol/ml, p<0.01; DHSM 36650±2642 vs 48842±3379 pmol/ml, p<0.01). Total C16: 0 concentrations of <204 pmol/ml was 83% sensitive (AUC 0.79, p<0.01) and total DHSM concentrations of <51705 pmol/ml was 100% sensitive (AUC 0.73, p=0.02) in predicting improved metabolic response to metformin, as measured by IVGTT. After adjusting for multiple comparisons, baseline DAG and TAG concentrations were associated with baseline ß-cell function (DAG r(2)=0.47, p<0.01; TAG r(2)=0.32, p<0.01), basal insulin concentrations (DAG r(2)=0.48, p<0.01; TAG r(2)=0.33, p<0.01) and decreased insulin sensitivity (DAG r(2)= 0.45, p<0.01; TAG r(2)=0.3,p<0.01). Baseline ceramide concentrations were not associated with improved ovulation. CONCLUSION: Ceramide concentrations predict metabolic disruption and lower levels are associated with a beneficial metabolic response to metformin in women with PCOS. Based on the known association between higher ceramide levels and type 2 diabetes, the data suggest that metformin improves metabolic parameters in women with mild metabolic derangements but not in those with severe insulin resistance. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.