Lipids and glucose metabolism

Abstract

Subjects with Klinefelter syndrome (KS) develop several metabolic abnormalities more frequently than normal males, with a higher prevalence of obesity, type 2 diabetes (T2D), dyslipidemia, and metabolic syndrome. The etiology factors causing the increased prevalence of metabolic disorders have not been completely clarified and may involve several mechanisms, rather than simply the direct consequence of hypogonadism alone. While reduced levels of testosterone cause an unfavorable change in body composition, with higher fraction of body fat in KS compared to 46-XY peers, testosterone replacement therapy in hypogonadal KS subjects, even if associated with an improvement of body composition, is not totally effective in ameliorating lipid and glycemic abnormalities. Moreover, changes in body composition develop before puberty in KS subjects, suggesting a role of non-hormonal factors. Most genes on the redundant X chromosome(s) are subject to X inactivation, but there is a pseudo-autosomal region containing multiple genes that escape inactivation. The association of more severe karyotypes with higher prevalence of T2D suggests a role of the supernumerary X chromosomes in the onset of T2D in KS. Nevertheless, KS is associated with DNA methylation changes across the entire genome, which might be important in this context since the genetic basis of complex traits such as T2D is thought to be much related with subtle changes in the epigenome and transcriptome. Further research is needed to address this.