125-OR: New Lipid Biomarkers for Worsening Glucose Tolerance in Nondiabetic Relatives of People with Type 2 Diabetes

There is a growing need for early biomarkers for Type 2 diabetes (T2D). Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs) are bioactive lipids with 580 regioisomers in human tissues. Some FAHFAs such as Palmitic Acid Hydroxy Stearic Acids (PAHSAs) have anti-diabetic and anti-inflammatory effects. PAHSA levels are lower in serum and adipose tissue of insulin-resistant versus insulin-sensitive humans and strongly correlate with insulin sensitivity. Since PAHSAs and palmitic acid esters of hydroxy oleic acids (PAHOAs) are among the most abundant FAHFAs in human serum, we aimed to determine whether these FAHFAs predict worsening glucose tolerance in people with an increased T2D risk, i.e. first-degree relatives of people with T2D. All participants had normal glucose tolerance (NGT) at baseline. Throughout a rolling enrollment period, 27 participants remained NGT (NGT-NGT) and 21 developed impaired glucose tolerance (NGT-IGT). In the group that remained NGT, followup serum PAHSA regioisomers and total PAHSA levels were similar to baseline. In contrast, total serum PAHSA and most regioisomers concentrations decreased in participants who developed IGT. The change in total PAHSAs (R=-0.476; p=0.0006), 5-PAHSA (R=-0.506; p=0.0002), and 9-PAHSA (R=-0.356; p=0.013) correlated tightly with worsening glucose tolerance. Multivariate analysis showed the decrease in PAHSAs predicted worsening glucose tolerance independent of BMI and age. The levels of total PAHOAs and most PAHOA isomers were similar at enrollment and follow-up in the NGT-NGT group. In NGT-IGT, initial and followup PAHOA levels were higher than in participants who remained NGT. Initial total PAHOA levels were: NGT-NGT (15.63±0.79) vs NGT-IGT (28.19±2.27) p4.48E-07. Followup total PAHOA levels NGT-NGT (14.70±0.62) vs NGT-IGT (31.07±2.73) p2.88E-08. Conclusion: A fall in PAHSA levels serves as a biomarker for worsening glucose tolerance while high PAHOA levels predict worsening glucose tolerance and IGT. Disclosure I. Syed: None. K. Sluis: None. P. Aryal: Employee; Cellarity. Z. Solomon: None. R. Patel: Employee; Novo Nordisk. S. Konduri: None. D. Siegel: None. U. Smith: None. B.B. Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc. Consultant; Vida Ventures Advisors, Arrowhead Pharmaceuticals, Inc. Funding NIH K01 DK118041 (IS).Joslin Pilot & Feasibility Grant P30 DK046200 (IS).NIH R01 DK106210 (BBK).JPB Foundation (BBK).