Sex-Specific Metabolic Changes in Peripheral Organs of Diabetic Mice

Abstract

Diabetes mellitus (DM) can cause systemic metabolic disorders, but the impact of gender on DM-related metabolic changes is rarely reported. Herein, we analyzed metabolic alterations in the heart, liver, and kidney of male and female mice from normal to diabetes via a 1H NMR-based metabolomics method and aimed to investigate sex-specific metabolic mechanisms underlying the onset and development of diabetes and its complications. Our results demonstrate that male mice had more significant metabolic disorders from normal to diabetes than female mice. Moreover, the kidney was found as the major organ of metabolic disorders during the development of diabetes, followed by the liver and heart. These altered metabolites were mainly implicated in energy metabolism as well as amino acid, choline, and nucleotide metabolism. Therefore, this study suggests that the kidney is the primary organ affected by diabetes in a sex-specific manner, which provides a metabolic view on the pathogenesis of diabetic kidney diseases between genders.

Sex-specific metabolic alterations in the type 1 diabetic brain of mice revealed by an integrated method of metabolomics and mixed-model

“…More interestingly, we identified a significant interaction effect of gender and diabetes on the change of lactate in the cortex, as indicated by increased lactate level in male mice but decreased lactate level in female mice from normal to diabetes. A similar result was also obtained for the change of lactate in the kidney of mice during T1D development [34] . One possible explanation is that estrogens increase mitochondrial function and aerobic glycolysis [42] , [43] , resulting in the reduction of lactate production from anaerobic glycolysis in female mice.…”

“…Compared with female mice, the level of succinate, a key intermediate of the TCA cycle, was significantly increased in the hippocampus and cerebellum of male mice. Previously, we also detected a higher succinate level in the kidney of male mice relative to female mice [34] . Moreover, several energy-related biomolecules such as inosine and NAD+ were also increased in the cortex, hypothalamus, cerebellum and midbrain of male mice.…”

“…However, here we found that choline deficiency may already occur in the cortex and striatum of T1D mice at the 4th week after STZ injection. A decrease in choline was also detected in the kidney of mice from normal to diabetes, especially in male mice [34] . These results suggest that dietary choline supplementation may require to be considered for T1D patients.…”

“…Therefore, neurotransmitter metabolism in the brain is dependent on sex. Additionally, Zhang et al [34] found higher levels of hepatic glycine and renal aspartate in male mice relative to female mice.…”

“…Sex-and region-specific differences in glutamate and glutamine were reported in the human brain using MRS analysis [55] . In addition, using multi-tissue metabolomics analysis, we previously revealed that the levels of glutamate and glutamine were significantly reduced in the kidney of male mice during T1D development, but not in female mice [34] . Aspartate and glycine are two major amino acid neurotransmitters in multiple brain regions [56] and serve as a selective agonist for N-methyl- d -aspartate (NMDA) receptors, which has also been associated with cognitive functions [57] .…”