ABSTRACT
Type 2 diabetes (T2D) is characterized by the malfunction of pancreatic β cells. Susceptibility and pathogenesis of T2D can be affected by multiple factors, including sex differences. However, the mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq), we demonstrate the presence of sexually dimorphic transcriptomes in mouse β cells. Using a high-fat diet-induced T2D mouse model, we identified sex-dependent T2D altered genes, suggesting sex-based differences in the pathological mechanisms of T2D. Furthermore, based on islet transplantation experiments, we found that compared to mice with sex-matched islet transplants, sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway of β cells. Moreover, the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance. These data suggest sexual dimorphism in T2D pathogenicity, indicating that sex should be considered when treating T2D. We hope that our findings could provide new insights for the development of precision medicine in T2D.
ABSTRACT
Aim: Sex-dependent differences in kidney histology have been observed in different species of the laboratory animals. The present study was conducted to evaluate the sex and strain-dependent changes in DBA/2CrSlc mouse kidney morphology by using light microscopy and immunohistochemistry. Methods: A total of 12 DBA/2CrSlc male and female mice of 2 months of age were used in this study. Mice were sacrificed by exsanguination under anesthesia using a mixture of Ketamine and Medetomidine. Both right and left kidneys were removed aseptically and central slices including hilum were cut perpendicular to the long axis of the organ and preserved in Zamboni solution. Paraffin blocks were made and tissue sections were stained with hematoxylin and eosin, and PAS stains to observe the general morphology of the kidney glomerulus. Immunohistochemistry was performed to detect renin positive sites, expression of Cyclooxygenase-2 (COX-2) and Nitric Oxide Synthase (nNOS). Number of renin, COX-2 and nNOS positive sites were counted and tabulated. The data were statistically analyzed for any significant differences between male and female mice. Results: Our results reveal that the glomerular capsule of male mouse kidney was consisted of a single layer of simple cuboidal epithelium whereas it was a single layer of simple squamous epithelium in the female kidney. PAS-positive granules (small and giant granules) were observed in PST epithelium and collecting ducts in female kidney, but this feature was absent in male kidneys. Strong nNOS positive reaction for PST epithelium and collecting ducts was observed in female, but this character was absent in male kidney. The total number of glomeruli, renin, COX-2, and nNOS positive sites was comparatively higher in female kidneys then that in male. However, statistical analysis revealed no significant differences of the areas of renin, nNOS and COX-2-positive sites between the male and female kidneys (P<0.05). Conclusion: Light microscopic and immunohistochemical study revealed sex-dependent histological morphology of the DBA/2CrSlc mouse kidney. DBA/2CrSlc female mouse kidney revealed renin, COX-2 and nNOS -positive reactions in the present study but male mice showed nNOS-negative reaction. The reason for nNOS-negative reaction in male is not clearly understood. It is suggested that this species can be experimentally used in the laboratory for investigating kidney function and related pathological studies.