(P41-18-26) Type 2 Diabetes Mellitus Induces Cell- and Sex-Specific Transcriptomic and Metabolomic Responses in the Aging Brain

Objectives: Type 2 diabetes mellitus (T2DM) can lead to microvascular dysfunction in the brain, characterized by disruption of endothelial cell–cell junctions, and metabolic changes, which contribute to increased risk of cognitive decline and dementia. We showed that T2DM induces sex-specific changes in the transcriptome of the hippocampal neurovascular unit (NVU; endothelial cells, astrocytes, microglia, and neurons) and brain metabolome of young adult mice. However, how T2DM-induced microvascular vulnerability and alterations in the brain metabolome present in the context of aging remains unresolved.

Methods: db/db< and wild-type (WT) male and female mice were aged to 9 months. The mice were fed a purified AIN-93M diet for the final 3 months. Cognitive and behavioral testing using Y-maze and open-field tests were performed at 6 and 9 months of age. Whole brain tissue samples were used for untargeted metabolomic analysis, The hippocampus was isolated and single-nuclei RNA sequencing (snRNA-seq) was performed.

Results: snRNA-seq revealed changes in transcriptome of NVU with aging and T2DM. Further, the response of NVU cells to T2DM during aging was cell-specific, highlighting the importance of simultaneous analyses of all cell types. Preliminary analysis revealed sex specificity in T2DM-induced changes in gene expression in cells of the NVU. Metabolomic analysis confirmed the sex-specific response, with 93 metabolites altered by T2DM in db/db mice compared with WT. These metabolites were predominantly fatty acyls (mainly fatty acids and fatty acylcarnitines) and carboxylic acids and derivatives. When sex was considered, a sex-dependent response to T2DM was observed; females had a larger metabolic response (157 metabolites) as compared to males (59 metabolites), with 22 metabolites shared between sexes.

Conclusions: These preliminary results provide novel information on cell- and sex-specific transcriptomic changes in the hippocampus, as well as brain metabolome in response to diabetes in aging, providing novel data for precision prevention and treatment strategies.

Funding Sources: This work was funded in part or in whole by the HEAL-HER (Heart, BrEast and BrAin Heath Equity Research) Program supported by residual class settlement funds in the matter of April Krueger v. Wyeth, Inc., Case No. 03-cv-2496 (US District Court, SD of Calif.)