Hyperinsulinemia induces early and dyssynchronous puberty in lean female mice

Abstract

Girls with obesity are at increased risk of early puberty. Obesity is associated with insulin resistance and hyperinsulinemia. We hypothesized insulin plays a physiological role in pubertal transition, and super-imposed hyperinsulinemia due to childhood obesity promotes early initiation of puberty in girls. To isolate the effect of hyperinsulinemia from adiposity, we compared pre-pubertal and pubertal states in hyperinsulinemic, lean Muscle (M)-IGF-1R-lysine (K)-arginine (R) (MKR) mice to normoinsulinemic wild-type (WT), with puberty onset defined by vaginal opening (VO). Our results show MKR had greater insulin resistance and higher insulin levels (p< 0.05) than WT despite lower body weight (pɘ.0001) and similar IGF-1 levels (p=NS). Serum LH levels were higher in hyperinsulinemic MKR (p=0.005), and insulin stimulation induced an increase in LH levels in WT. VO was earlier in hyperinsulinemic MKR vs WT (pɘ.0001). When compared on the day of VO, kisspeptin expression was higher in hyperinsulinemic MKR vs WT (pɘ.05) and GnRH and IR isoform expression was similar (p=NS). Despite accelerated VO, MKR had delayed, disordered ovarian follicle and mammary gland development. In conclusion, we found that hyperinsulinemia alone without adiposity triggers earlier puberty. In our study, hyperinsulinemia also promoted dyssynchrony between pubertal initiation and progression, urging future studies in girls with obesity to assess alterations in transition to adulthood.

Early and precocious puberty during the COVID-19 pandemic

“…There is also a positive correlation between hyperinsulinemia, alone or in conjunction with adiposity, insulin resistance and precocious puberty ( 90 , 91 ). It has been suggested that insulin resistance, in particular, may lead to an increased bioavailability of sex hormones by reducing the levels of sex hormones binding proteins ( 92 ).…”