PMON244 Alterations in Nonesterified Free Fatty Acids (NEFA) Trafficking Rather Than Hyperandrogenism Contribute to Variations in Insulin Sensitivity Among Obese Women with Polycystic Ovary Syndrome

OBJECTIVES: To compare the metabolic and hormonal features of metabolically unhealthy obese PCOS women (MU-PCOS) vs. metabolically healthy obese PCOS women (MH-PCOS) and determine whether alterations in non-esterified free fatty acids (NEFA) response to hyperinsulinemia contribute to variations in insulin sensitivity between MU-PCOS and MH-PCOS. DESIGN: Prospective cross-sectional study. SETTING: Tertiary-care academic center. METHODS: Insulin resistance (IR) in the basal state was assessed by HOMA-IR in 125 consecutive obese oligo-ovulatory PCOS women (BMI≥ 30 kg/m(2); NIH 1990 or Rotterdam 2003 Phenotype A/B) undergoing an oral glucose tolerance test (oGTT); and IR in the dynamic state assessed by the modified frequently sampled intravenous glucose tolerance test (mFSIVGTT) in a subgroup of 16 non-diabetic obese PCOS women. Main Outcome Measures: Primary outcome measures were: 1) IR in AT was assessed in the basal state by the Adipose Insulin Resistance Index [Adipo-IR]) and dynamically by the mFSIVGTT-derived indices of insulin-mediated NEFA suppression [NEFAnadir, TIMEnadir, and %NEFAsupp]); 2) peak lipolysis rate [SNEFA]; and 3) peak NEFA uptake rate [KNEFA]. Secondary outcome measures were levels of insulin and glucose during oGTT, HOMA-β%, and degree of hyperandrogenism (i.e. mF-G score, free testosterone [T], total T, DHEAS). RESULTS: Eighty-five obese PCOS participants undergoing oGTT had a HOMA-IR index of ≥2.5 (MU-PCOS) and 40 had a HOMA-IR of <2.5 (MH-PCOS). MU-PCOS had higher mean HOMA-β%, levels of fasting, 1-hr and 2-hr. glucose and insulin, and peak insulin during the oGTT, and higher prevalence of prediabetes and elevated 1-hr. glucose and a trend towards higher prevalence of type 2 diabetes mellitus (T2DM), than MH-PCOS. Alternatively, measures of HA were similar between the groups. Assessing IR dynamically, subjects were subdivided into MU-PCOS by an insulin sensitivity index [Si] ≤1.7 [mU/L]−1·min−1 (n=8) or MH-PCOS by an Si ≥5.6 [mU/L]−1·min−1 (n=8), matched for age and BMI. MU-PCOS had lower Si and KNEFA, smaller %NEFAsupp, longer TIMEnidar, and higher NEFAnidar and Adipo-IR than MH-PCOS, although fasting plasma NEFA levels and SNEFA were similar. In bivalent analysis, Si correlated strongly and negatively with NEFAnadir, weakly and negatively with TIMEnadir, and positively and strongly with KNEFA and NEFAsupp, in MUO-PCOS only. CONCLUSION: Independent of age and BMI, metabolically unhealthy obese PCOS women, compared with metabolically healthy obese PCOS women, had lower rates of NEFA uptake and altered insulin-mediated plasma NEFA suppression in response to mFSIVGTT-determined endogenous insulin secretion, rather than disparities in HA and rate of lipolysis, mechanism that may contribute to variations in insulin sensitivity among obese PCOS women. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.