Amino acid and fatty acid metabolomic profile during fasting and hyperinsulinemia in girls with polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is associated with insulin resistance (IR) and altered muscle mitochondrial oxidative phosphorylation. IR in adults with obesity and diabetes is associated with changes in amino acid, free fatty acid (FFA), and mitochondrial acylcarnitine (AC) metabolism. We sought to determine whether these metabolites are associated with IR and/or androgens in youth-onset PCOS. We enrolled obese girls with PCOS [ n = 15, 14.5 yr (SD 1.6), %BMI 98.5 (SD 1.0)] and without PCOS [ n = 6, 13.2 yr (SD 1.2), %BMI 98.0 (SD 1.1)]. Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp. Untargeted metabolomics of plasma was performed while fasting and during hyperinsulinemia. Fasting arginine, glutamine, histidine, lysine, phenylalanine, and tyrosine were higher ( P < 0.04 for all but P < 0.001 for valine), as were glutamine and histidine during hyperinsulinemia ( P < 0.03). Higher valine during hyperinsulinemia was associated with IR ( r = 0.59, P = 0.006). Surprisingly, end-clamp AC C4 was lower in PCOS, and lower C4 was associated with IR ( r = -0.44, P = 0.04). End-clamp FFAs of C14:0, C16:1, and C18:1 were higher in PCOS girls, and C16:1 and C18:1 strongly associated with IR ( r = 0.73 and 0.53, P < 0.01). Free androgen index related negatively to short-, medium-, and long-chain AC ( r = -0.41 to -0.71, P < 0.01) but not FFA or amino acids. Obese girls with PCOS have a distinct metabolic signature during fasting and hyperinsulinemia. As in diabetes, IR related to valine and FFAs, with an unexpected relationship with AC C4, suggesting unique metabolism in obese girls with PCOS.