Metabolomics reveals impaired maturation of HDL particles in adolescents with hyperinsulinaemic androgen excess

Hyperinsulinaemic androgen excess (HIAE) in prepubertal and pubertal girls usually precedes a broader pathological phenotype in adulthood that is associated with anovulatory infertility, metabolic syndrome and type 2 diabetes. The metabolic derangements that determine these long-term health risks remain to be clarified. Here we use NMR and MS-based metabolomics to show that serum levels of methionine sulfoxide in HIAE girls are an indicator of the degree of oxidation of methionine-148 residue in apolipoprotein-A1. Oxidation of apo-A1 in methionine-148, in turn, leads to an impaired maturation of high-density lipoproteins (HDL) that is reflected in a decline of large HDL particles. Notably, such metabolic alterations occur in the absence of impaired glucose tolerance, hyperglycemia and hypertriglyceridemia, and were partially restored after 18 months of treatment with a low-dose combination of pioglitazone, metformin and flutamide.

青春期前与青春期女孩罹患的高胰岛素血症性雄激素过多症（Hyperinsulinaemic androgen excess, HIAE），通常会进展为成年后更为广泛的病理表型，该表型与无排卵性不孕、代谢综合征及2型糖尿病密切相关。目前，介导此类远期健康风险的代谢紊乱机制仍有待阐明。本研究借助核磁共振波谱法（Nuclear Magnetic Resonance, NMR）与基于质谱（Mass Spectrometry, MS）的代谢组学技术，证实高胰岛素血症性雄激素过多症女孩的血清甲硫氨酸亚砜水平，可作为载脂蛋白A1（apolipoprotein-A1）148位甲硫氨酸残基氧化程度的标志物。而载脂蛋白A1的148位甲硫氨酸氧化，会进一步导致高密度脂蛋白（HDL）成熟障碍，具体表现为大颗粒高密度脂蛋白数量减少。值得注意的是，此类代谢改变可在糖耐量受损、高血糖症及高甘油三酯血症尚未出现时发生，且经低剂量吡格列酮、二甲双胍与氟他胺联合治疗18个月后，部分异常可得到恢复。