###### Abstract  
CD163, a scavenger receptor with anti-inflammatory function expressed exclusively on monocytes/macrophages, is dysregulated in cases of diabetes complications. This study aimed to characterize circulating CD163+ monocytes in the presence (D\({}^{+\text{Compos}}\)) or absence (D\({}^{-\text{Compos}}\)) of diabetes-related complications. RNA-sequencing and mass cytometry were conducted on CD163+ monocytes in adults with long-duration diabetes and D\({}^{+\text{Compos}}\) or D\({}^{-\text{Compos}}\). Out of 10,868 differentially expressed genes identified between D\({}^{+\text{Compos}}\) and D\({}^{-\text{Compos}}\), 885 were up-regulated and 190 were down-regulated with a \(\geq\) 1.5-fold change. In D\({}^{+\text{Compos}}\), regulation of centrosome cycle genes were enriched 6.7-fold compared to the reference genome. _MIR2/A, MIR3648-1_, and _MIR23A_, the most up-regulated and CD200_RI_, the most down-regulated gene, were detected in C\({}^{+\text{Compos}}\) from the list of 75 'genes of interest'. CD163+ monocytes in D\({}^{+\text{Compos}}\) had a low proportion of recruitment markers CCR5, CD11b, CD11c, CD31, and immune regulation markers CD39 and CD66. A gene-protein network identified down-regulated _TLR4_ and CD11b as 'hub-nodes'. In conclusion, this study reports novel insights into CD163+ monocyte dysregulation in diabetes-related complications. Enriched centrosome cycle genes and up-regulated _miRNA_/s linked to apoptosis, coupled with down-regulated monocyte activation, recruitment, and immune regulation, suggest functionally distinct CD163+ monocytes in cases of diabetes complications. Further investigation is needed to confirm their role in diabetes-related tissue damage.  
diabetes mellitus; complications; inflammation; monocytes; scavenger receptor; CD163 2024 25 10094 2024 25 10  
decreased in individuals with complications compared to those without complications [5]. CD163, the hemoglobin (Hb)-haptoglobin (Hp) scavenger receptor, clears free circulating toxic Hb via Hb-Hp complexes, thereby reducing the local oxidative stress caused by reactive oxygen species. The CD163+ monocyte acts as a scavenger with anti-inflammatory functions, resolving systemic or local inflammation and ultimately protecting the tissues from damage [6,7]. In the same study, it was observed that alterations of the CD163+ monocytes were associated with circulating levels of matrix metalloproteinases (MMPs) and cytokines, indicating a potential regulatory interaction between these proteins and CD163+ monocytes [5].  
Additionally, the tissue presence of CD163+ macrophages in various diabetes complications was examined in a recent systematic review and was found to differ between individuals with and without diabetes complications [8]. In individuals with diabetes and cardiovascular disease, CD163+ cells were decreased in the atherosclerotic plaques compared to individuals with cardiovascular disease without diabetes [9]. In renal complications, CD163+ cells in the glomeruli were reported to be positively correlated with the progression of nephropathy in individuals with diabetes [10].  
While CD163+ monocytes/macrophages have been studied across various diabetes complications, how CD163+ monocytes are dysregulated in diabetes complications is unclear. Therefore, we aimed to comprehensively characterize circulating CD163+ monocytes, focusing on their functional profile and regulatory mechanisms, in individuals with long-duration diabetes, with or without complications. We hypothesize that there exists a distinct profile of CD163+ monocytes between these two groups, particularly emphasizing the presence of dysfunctional circulating CD163+ monocytes in individuals with complications.