Ketone monoester ingestion improves endothelial function during hyperglycemia in females with polycystic ovary syndrome

Postprandial hyperglycemia transiently impairs endothelial function. Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction and impaired glucose tolerance-both risk factors for cardiometabolic diseases-but the effects of hyperglycemia on endothelial function have yet to be assessed in PCOS. Exogenous ketone monoester (KME) supplementation lowers blood glucose and improves endothelial function in individuals predisposed to cardiometabolic diseases but has yet to be assessed in PCOS. Thus, we investigated whether oral glucose tolerance test (OGTT)-induced hyperglycemia impairs endothelial function in PCOS, and whether acute KME mitigates these impairments. Ten females with PCOS [age: 27 ± 5 yr, body mass index (BMI): 23.8 ± 2.7 kg/m 2] and 10 age- and BMI-matched controls (CTRL; age: 27 ± 4 yr, BMI: 23.7 ± 2.0 kg/m 2) completed a randomized, double-blind, placebo-controlled, crossover study. In the overnight postabsorptive state, participants consumed KME [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate; 482 mg/kg] or a taste-matched placebo 30 min before a 75-g OGTT. Endothelial function was assessed via flow-mediated dilation (%FMD) pre-OGTT and at 0-, 60-, and 120-min postbolus. Following placebo, %FMD was lower in PCOS than CTRL (effect of group, P < 0.01). %FMD declined from baseline to 60-min post-OGTT bolus in both groups (PCOS: 6.3 ± 0.4 vs. 4.2 ± 0.4%, P < 0.01; CTRL: 9.7 ± 0.9 vs. 6.6 ± 0.9%, P < 0.01), with sustained impairments at 120 min in PCOS only (6.3 ± 0.4 vs. 4.0 ± 0.5%, P < 0.01). In both groups, KME reduced plasma glucose area under the curve ( P < 0.01) and improved %FMD across the OGTT ( P < 0.01). These data indicate that OGTT-induced endothelial dysfunction is exacerbated in PCOS, and that acute KME improved endothelial function during the OGTT. Overall, these data KME supplementation as a potential means of reducing cardiometabolic risk in PCOS. NEW & NOTEWORTHY To the best of our knowledge, this is the first study to demonstrate that nonobese females with polycystic ovary syndrome (PCOS) exhibit prolonged impairments in endothelial function following glucose intake, indicating sustained hyperglycemia-driven vascular dysfunction. Notably, acute ketone monoester (KME) supplementation improved both glycemic control and endothelial function, highlighting KME as a promising nonpharmacological strategy to mitigate early cardiometabolic risk in this vulnerable population.