Abstract Body: Background: Chronic inflammation associated with aberrant activation of monocytes and macrophages is a hallmark of type 2 diabetes (T2D) and associated diabetic vascular complications (DVCs). Patients with history of uncontrolled diabetes can experience sustained progression of DVCs despite subsequent glycemic control, a phenomenon termed “metabolic memory (MetM)”. It is unclear if currently available drugs for T2D are fully or partially effective against MetM of DVCs. Hence, in the present study we aimed to investigate T2D-associated changes in the monocyte transcriptome, and the extent to which an anti-diabetic drug can reverse these aberrant transcriptomic changes.
Methods: We treated diabetic db/db mice with the antidiabetic drug, dapagliflozin (db/dbDAPA) or vehicle (db/dbVeh), and non-diabetic control db/+ mice with vehicle for six-weeks, and key parameters of diabetes were routinely monitored. At the end of the treatment, RNA from bone marrow derived monocytes was subjected to RNA-sequencing (RNA-seq)/ unbiased transcriptomic profiling.
Results: DAPA treatment conferred glycemic control in diabetic db/db mice (significant reduction in blood glucose/HbA1c). RNA-seq of monocytes identified differentially expressed genes (DEGs) (including inflammatory genes) in diabetic mice groups versus control. Interestingly, we found around 48 percent shared DEGs in the diabetic db/dbVeh and db/dbDAPA groups versus db/+, including a few long non-coding RNA (lncRNA), suggesting persistent changes in gene expression despite glucose normalization with DAPA. Pathway analysis of DEGs showed persistent activation of inflammatory pathways, specifically TNF signaling via NF-kB, even after DAPA treatment, suggesting presence of MetM. Interestingly, DAPA treatment upregulated key biological processes related to metabolic homeostasis, glycolysis and oxidative phosphorylation suggesting DAPA treatment also has some protective effects via restoring these key metabolic processes.
Conclusion: Anti-diabetic drugs may not be fully effective against monocyte dysfunction related to inflammatory DVCs, underscoring the need for more effective therapies.