Adipose tissue insulin resistance in peripubertal girls with first-degree family history of polycystic ovary syndrome

Abstract

Objective To assess metabolic and endocrine defects in girls genetically predisposed to polycystic ovary syndrome (PCOS). Design Controlled cross-sectional study. Setting University hospital. Patients Nine girls aged 8–14 years having a first-degree relative diagnosed with PCOS (PCOSr) and 10 age-matched girls unrelated to PCOS. Intervention None. Main outcome measure Insulin sensitivity determined by frequently sampled intravenous glucose tolerance testing (ISFSivGTT) and insulin-induced non-esterified fatty acid suppression (NEFAsupp), estimated by the log-linear slope of NEFA levels during the first 20 min of FSivGTT. Results In comparison to controls, PCOSr had higher body mass index Z-score (BMI-z), waist circumference and waist/height ratio. Levels of the androgen 17α-hydroxyprogesterone (17OHPg) were significantly increased in PCOSr, independently of adiposity, and inversely correlated with ISFSivGTT. ISFSivGTT was decreased and NEFAsupp was less steep in PCOSr as compared to controls, independently of BMI-z and 17OHPg. NEFAsupp was more pronounced with increasing ISFSivGTT, independently of adiposity. Conclusions Girls at high risk of developing PCOS display increased adiposity and 17OHPg levels, but are mainly characterized by global insulin resistance and resistance to insulin-induced suppression of lipolysis that were independent of adiposity and 17OHPg levels. Therefore, genetic predisposition to PCOS may be related to early insulin resistance and adipocyte dysfunction.

Translational Insight Into Polycystic Ovary Syndrome (PCOS) From Female Monkeys with PCOS-like Traits

“…Pancreatic decompensation [67, 68] and insulin resistance become obvious in PCOS daughters later in puberty [68, 69], but may have been undetected at a younger age due to the absence of dynamic testing.…”

“…In adulthood, T-exposed adult female monkeys exhibit preferential accumulation of visceral fat without differences in BMI [72, 73], DNA methylation changes in visceral fat gene promoter sites [41], and a defect in subcutaneous abdominal adipogenesis [74]. Taken together, these results suggest a diminished ability to safely store lipid in subcutaneous adipose depots, resulting in dyslipidemia from lipotoxicity with insulin resistance, pancreatic beta cell and islet morphology defects, as well as type 2 diabetes mellitus [66–68, 70]. Such adult female metabolic dysfunction may result from a combination of gestational hyperglycemia and T excess promoting postnatal insulin-driven fat storage, in parallel with T-constrained subcutaneous adipogenesis, leading to lipotoxocity and metabolic dysfunction.…”

“…2 illustrates this metabolically-related programming in our experimentally induced, T-exposed monkeys, with an emphasis on hyperinsulinemia and T excess as causal factors. The development of hyperinsulinemia from insulin resistance with reduced hypothalamic steroid negative feedback leading to LH hypersecretion would constrain through androgen excess the capacity of normal adipose to safely store fat, leading to lipotoxicity, metabolic dysfunction and reproductive PCOS-like traits, as has also been proposed for girls who will likely manifest PCOS [66, 68]. The combination of reproductive and metabolic developmental origins may thus comprise a more complete fetal origin for PCOS, since gestational diabetes, common among pregnant women with PCOS [77, 78], increases the incidence of obesity-related insulin resistance in offspring [79, 80], but not the full PCOS phenotype.…”

Ontogeny of polycystic ovary syndrome and insulin resistance in utero and early childhood

“…Metabolic evaluation reveals increased 2-hour insulin levels during the oral glucose tolerance test with similar levels of glucose, an indication of insulin resistance, compared to their Tanner and BMI matched controls (155). Three additional studies confirm this pre-adolescent or adolescent onset of hyperinsulinemic responses in daughters or sisters of women with PCOS that accompany insulin resistance (153, 159, 160). …”

Perinatal androgen exposure and adipose tissue programming: is there an impact on body weight fate?

“…However, daughters born to women with PCOS exhibit low circulating adiponectin and elevated triglyceride levels during prepubertal and pubertal age [123]. Of interest, pre-pubertal daughters of women with PCOS exhibit reduced lipolysis [124]. Moreover, their sons exhibit elevated BMI and cholesterol levels during childhood [125].…”