Sex-specific difference in intestinal glucose metabolism is associated with sexually dimorphic postprandial lactate shuttle and glucose homeostasis in mice.

Sexual dimorphism in glucose metabolism is increasingly recognized as a critical factor in metabolic homeostasis. Our prior study has highlighted the role of intestinal monocarboxylate transporter 1 (MCT1) in mediating lactate transport and its sex-specific effect on glucose metabolism in mice. Here, we investigated the sex-specific metabolic flux in the intestine and its impact on postprandial lactate shuttle and glucose homeostasis. Using a combination of isotopic tracing techniques and in vivo experiments, we discovered that intestinal epithelium exhibits sex-specific metabolic profiles, leading to differential glucose metabolism. Female mice displayed higher oxidative phosphorylation activity and greater utilization of lactate/pyruvate in the tricarboxylic acid (TCA) cycle than male mice, resulting in improved glucose tolerance. In contrast, male mice exhibited higher glycolytic activity with an increased postprandial lactate level, correlating with poorer glucose tolerance than female mice. Estrogen treatment in male mice reduced intestinal interstitial lactate level and improved glucose tolerance. Castration of male mice also improved glucose tolerance, whereas androgen replacement reversed this effect. Conversely, ovariectomy in female mice impaired glucose tolerance, which was restored by estrogen replacement. Our findings thus underscore the importance of sex-specific glucose metabolism in the intestine and its implications for metabolic health, laying a foundation for developing sex-specific therapeutic strategies for metabolic disorders. Sex dimorphic difference in glucose homeostasis has been well recognized; however, how glucose metabolism in the intestine contributes to this phenomenon is poorly known. We discovered that the male mice have an elevated rate of glycolysis in the intestine, whereas the female mice have an increased rate of oxidative phosphorylation, contributing to the sex difference in glucose tolerance. In addition, sex hormones are crucial in mediating such a difference between the two sexes.