Search

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+Comps) or absence (D−Comps) of diabetes-related complications. RNA-sequencing and mass cytometry were conducted on CD163+ monocytes in adults with long-duration diabetes and D+Comps or D−Comps. Out of 10,868 differentially expressed genes identified between D+Comps and D−Comps, 885 were up-regulated and 190 were down-regulated with a ≥ 1.5-fold change. In D+Comps, 'regulation of centrosome cycle' genes were enriched 6.7-fold compared to the reference genome. MIR27A, MIR3648-1, and MIR23A, the most up-regulated and CD200R1, the most down-regulated gene, were detected in D+Comps from the list of 75 'genes of interest'. CD163+ monocytes in D+Comps had a low proportion of recruitment markers CCR5, CD11b, CD11c, CD31, and immune regulation markers CD39 and CD86. 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 miRNAs 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. [ABSTRACT FROM AUTHOR]

Infiltration of macrophages to the kidney is a feature of early diabetic nephropathy. For this to happen monocytes must become activated, migrate from the circulation, and infiltrate the mesangium. This process involves degradation of extracellular matrix, a process mediated by matrix metalloproteinases (MMPs). In the present study we investigate the expression of proinflammatory cytokines TNF-[alpha], IL-6, and MMP-9 in glomeruli of control and diabetic rodents and use an in vitro coculture system to examine whether factors secreted by mesangial cells in response to a diabetic milieu can induce monocyte MMP-9 expression and infiltration. After 8 wk of diabetes, the glomerular level of TNF-[alpha], IL-6, and macrophage number and colocalization of MMP-9 with macrophage were increased (P < 0.01). Coculture of THP1 monocytes and glomerular mesangial cells in 5 or 25 mM glucose increased MMP-9 (5 mM: 65% and 25 mM: 112%; P < 0.05) and conditioned media degradative activity (5 mM: 30.0% and 25 mM: 33.5%: P < 0.05). These effects were reproduced by addition of mesangial cell conditioned medium to THP1 cells. High glucose (25 mM) increased TNF-[alpha], IL-6, and monocyte chemoattractant protein-1 in mesangial cell conditioned medium. These cytokines all increased adhesion and differentiation of THP1 cells (P < 0.05), but only TNF-[alpha] and IL-6 increased MMP-9 expression (50- and 60-fold, respectively; P < 0.05). Our results show that mesangial cell-secreted factors increase monocyte adhesion, differentiation, MMP expression, and degradative capacity. High glucose could augment these effects by increasing mesangial cell proinflammatory cytokine secretion. This mesangial cell-monocyte interaction may be important in activating monocytes to migrate from the circulation to the kidney in the early stages of diabetic nephropathy. matrix metalloproteinases; matrix degradation; cell adhesion and infiltration; inflammation response doi: 10.1152/ajprenal.00074.2009.

Objectives: This study aimed to evaluate the effects of a novel, low-volume combined high-intensity interval training (HIIT) and progressive resistance training (PRT) in overweight/obese adults., Methods: This randomised control trial compared the effect of regular supervised HIIT combined with PRT (Exercise) with an unsupervised stretching intervention (Control), in previously inactive adults with either normal glucose (NG), pre-diabetes or type 2 diabetes (T2DM) with body mass index of >25 kg/m 2 . Participants were randomly allocated (1:1) to receive low-volume exercise or control by an online randomisation tool. The primary outcome was the difference in change of hepatic steatosis between Exercise and Control. A prespecified sensitivity analysis was undertaken for weight stable participants (<5% change in bodyweight from baseline). Secondary outcomes were change in hepatic steatosis within the glucose groups, glycaemic control, cardiorespiratory fitness, muscle strength and body composition., Results: Between June 2018 and May 2021, 162 participants were randomly assigned (NG: 76, pre-diabetes: 60, T2DM: 26) and 144 were included in the final analysis. Mean absolute change in hepatic steatosis was -1.4% (4.9) in Exercise (n=73) and -0.1% (7.2) in Control (n=71)(p=0.25). By preplanned sensitivity analysis, the mean change in hepatic steatosis with Exercise (n=70) was -1.5% (5) compared with 0.7% (4.6) with Control (n=61) (p=0.017). Subgroup analysis within the glucose groups showed that exercise reduced hepatic steatosis in those with pre-diabetes but not NG or T2DM (pre-diabetes: -1.2% (4.4) in Exercise and 1.75% (5.7) in Control, p=0.019)., Conclusion: These findings show that low-volume HIIT with PRT yields improvements in muscle strength and cardiorespiratory fitness and may have a small effect on hepatic steatosis., Trial Registration Number: The trial was prospectively registered with the ANZCTR (ACTRN12617000552381)., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Advanced glycation end products (AGEs) have been implicated in the tissue fibrosis and extracellular matrix (ECM) expansion in organ complications of diabetes mellitus and in other diseases. CCN2, also known as cellular communication factor 2 and earlier as connective tissue growth factor, is a matrix-associated protein that acts as a pro-fibrotic cytokine to cause fibrosis in tissues in many diseases. We were the first to report that AGEs regulate CCN2, which itself can then affect ECM synthesis. In this chapter, we describe the methods of preparation of soluble AGEs and matrix-bound AGEs that can be used to study AGE effect on CCN2 and ECM expansion., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Many studies have shown effects of members of the CCN family on matrix synthesis and accumulation but few have examined degradative pathways. This scarcity of information is in part due to the lack of suitable model systems. Here we describe methods for making rhCCN2 and also for the preparation of a biosynthetically labeled matrix substrate that can be used to measure the effect of CCN on cellular or secreted degradative pathways.

Aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor that binds to partners to mediate responses to environmental signals. To investigate its role in the innate immune system, floxed ARNT mice were bred with lysozyme M-Cre recombinase animals to generate lysozyme M-ARNT (LAR) mice with reduced ARNT expression. Myeloid cells of LAR mice had altered mRNA expression and delayed wound healing. Interestingly, when the animals were rendered diabetic, the difference in wound healing between the LAR mice and their littermate controls was no longer present, suggesting that decreased myeloid cell ARNT function may be an important factor in impaired wound healing in diabetes. Deferoxamine (DFO) improves wound healing by increasing hypoxia-inducible factors, which require ARNT for function. DFO was not effective in wounds of LAR mice, again suggesting that myeloid cells are important for normal wound healing and for the full benefit of DFO. These findings suggest that myeloid ARNT is important for immune function and wound healing. Increasing ARNT and, more specifically, myeloid ARNT may be a therapeutic strategy to improve wound healing., (Copyright © 2014 the American Physiological Society.)