TOPLINE:Sex-specific differences in kidney metabolism may underlie differences in diabetic kidney disease (DKD) outcomes in men and women, new research suggests.
METHODOLOGY:To identify sex-based differences in kidney metabolism and in the blood metabolome of men and women with diabetes, researchers first conducted studies of proximal tubular epithelial cells (PTECs) from healthy male and female donors.They then studied mice with different combinations of sex chromosomes to identify any differences by gonadal sex.The team then conducted blood metabolomic analyses in one cohort of adolescents and two cohorts of adults with or without diabetes and kidney disease to investigate serum metabolites and links with all-cause mortality.TAKEAWAY:PTECs from healthy male donors showed increased mitochondrial respiration, oxidative stress, and apoptosis and greater injury when exposed to high glucose than PTECs from healthy female donors.Human male PTECs showed increased glucose and glutamine fluxes to the tricarboxylic acid (TCA [Krebs]) cycle, whereas human female PTECs showed increased pyruvate content.In a cohort of adolescents with or without diabetes, a blood metabolomic analysis showed increased TCA cycle metabolites in males.In a cohort of adults with diabetes, women without DKD had higher serum pyruvate concentrations than men with or without DKD; serum pyruvate concentrations positively correlated with the estimated glomerular filtration rate and negatively correlated with all-cause mortality in this cohort.In a cohort of adults with chronic kidney disease, male sex and diabetes were associated with increased plasma TCA cycle metabolites, which correlated with all-cause mortality.IN PRACTICE:”Strategies to favor pyruvate accumulation while preventing excessive TCA cycle activity should be investigated,” the authors wrote.
SOURCE:The study was led by Sergi Clotet-Freixas of University Health Network (UHN), Toronto, Ontario, Canada, and published online on March 6 in Science Translational Medicine.
LIMITATIONS:Lack of access to patient-specific PTECs was a limitation. The authors advised caution when relating the preclinical findings in PTECs to in vivo data because mouse models of diabetes more consistently exhibit glomerular, rather than tubular, injury. The different type of diabetes between the animals (type 1) and humans (type 2) in the study was also a limitation.
DISCLOSURES:This work was supported by a Canadian Institutes of Health Research (CIHR) Catalyst grant; Canada Foundation for Innovation grant; Kidney Research Scientist Core Education and National Training grants; UHN Foundation, University of Toronto, and the Schroeder Arthritis Institute at the UHN grants; funding from the Natural Sciences Research Council, Ontario Research Fund, IBM, and Ian Lawson van Toch Fund; the CIHR Strategy for Patient-Oriented Research Program and Can-SOLVE CKD; FONDO DE INVESTIGACIÓN SANITARIA-FEDER, ISCIII, and REDINREN; an NIH grant; and a German Research Foundation grant.
Several coauthors have received fees from industry. For all competing interests, see the paper.
Source : Medscape