Metabolic Heterogeneity in Polycystic Ovary Syndrome Is Determined by Obesity: Plasma Metabolomic Approach Using GC-MS

Abstract

Abstract BACKGROUND Abdominal adiposity and obesity influence the association of polycystic ovary syndrome (PCOS) with insulin resistance and diabetes. We aimed to characterize the intermediate metabolism phenotypes associated with PCOS and obesity. METHODS We applied a nontargeted GC-MS metabolomic approach to plasma samples from 36 patients with PCOS and 39 control women without androgen excess, matched for age, body mass index, and frequency of obesity. RESULTS Patients with PCOS were hyperinsulinemic and insulin resistant compared with the controls. The increase in plasma long-chain fatty acids, such as linoleic and oleic acid, and glycerol in the obese patients with PCOS suggests increased lipolysis, possibly secondary to impaired insulin action at adipose tissue. Conversely, nonobese patients with PCOS showed a metabolic profile consisting of suppression of lipolysis and increased glucose utilization (increased lactic acid concentrations) in peripheral tissues, and PCOS patients as a whole showed decreased 2-ketoisocaproic and alanine concentrations, suggesting utilization of branched-chain amino acids for protein synthesis and not for gluconeogenesis. These metabolic processes required effective insulin signaling; therefore, insulin resistance was not universal in all tissues of these women, and different mechanisms possibly contributed to their hyperinsulinemia. PCOS was also associated with decreased α-tocopherol and cholesterol concentrations irrespective of obesity. CONCLUSIONS Substantial metabolic heterogeneity, strongly influenced by obesity, underlies PCOS. The possibility that hyperinsulinemia may occur in the absence of universal insulin resistance in nonobese women with PCOS should be considered when designing diagnostic and therapeutic strategies for the management of this prevalent disorder.