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A high glycemic burden drives functional and metabolic alterations of human monocytes in patients with type 1 diabetes

ABSTRACT: A high glycemic burden drives functional and metabolic alterations of human monocytes in patients with type 1 diabetes

PROVIDER: PRJNA646775 | ENA |

REPOSITORIES: ENA

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A high glycemic burden drives functional and metabolic alterations of human monocytes in patients with type 1 diabetes

Project description:Diabetes mellitus is associated with serious long-term complications, including increased cardiovascular risk and a higher occurrence of infections. These diabetes-related complications are suggestive of altered responses of the innate immune system. Recent studies have shown that energy metabolism of monocytes is a crucial determinant of their functionality. Here we investigate whether metabolism and function of monocytes are changed in patients with diabetes and aim to identify diabetes-associated factors driving these alterations. Patients with type 1 diabetes (T1D) and healthy age-, sex- and BMI-matched nondiabetic controls were recruited and detailed characteristics related to disease status including diabetes duration and glycemic burden (HbA1c levels) were collected. Monocytes were isolated from peripheral blood to determine immune functionality, metabolic responses and to perform transcriptome analyses. Upon ex vivo stimulation with TLR-4 agonist LPS or TLR-2 agonist P3C, monocytes of patients with T1D secreted lower levels of various cytokines (TNFα, IL-1β and IL-1Ra) and had lower glycolytic rates in comparison to monocytes isolated from matched controls. Stratification based on HbA1c levels revealed that a lower cytokine secretion was coupled to a higher glycolytic rate of monocytes in patients with a higher glycemic burden. Gene expression signatures of circulating monocytes displayed an enhanced inflammatory expression pattern that was associated with this high glycemic burden. A high glycemic burden in patients with T1D promotes expression of inflammatory genes of monocytes in vivo and is coupled to an impaired relationship between metabolism and inflammatory function upon activation ex vivo.

2020-10-09 | GSE154609 | GEO

Transcription profiling of monocytes from patients with autoimmune diabetes

Project description:Identifying a discriminating expression pattern of inflammatory genes in monocytes of patients with autoimmune diabetes

2008-08-01 | E-MEXP-1516 | biostudies-arrayexpress

Monocytes release pro-cathepsin D to drive blood-to-brain transcytosis in diabetes

Project description:Microvascular complications are the major outcome of type 2 diabetes mellitus progression and the underlying mechanism remains to be determined. To explore the contribution of circulating monocytes to the microvascular lesions, high-throughput RNA sequencing was conducted and we found high-level expression of cathepsin D (CTSD) in the monocytes of type 2 diabetes mellitus patients. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied with cognitive deficit. Mechanistically, we found the monocytes release non-enzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low density lipoprotein receptor-related protein 1 (LRP1). Importantly, genetic ablation of CTSD in the monocytes exhibited protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. Our findings thus uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is thus a potential target for the intervention of microvascular complications in diabetes.

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Profiling of CD14+ monocytes from humans with Type diabetes and without diabetes [CHIRP-seq]

Project description:We identified a novel lncRNA DRAIR that is downregulated in CD14+ monocytes from type 2 diabetes relative to controls. Functional studies showed that DRAIR regulates anti-inflammatory genes and its knockdown enhances proinflammatoory phentype of monocytes. To examine mechanisms of DRAIR actions, we performed Chromatin isolation by RNA purification (ChIRP) assays using DRAIR biotinylated tiling oligonucleotides to identify chromatin inding sites in THP-1 monocytes.

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Profiling of CD14+ monocytes from humans with Type diabetes and without diabetes

Project description:Profiling of CD14+ monocytes from humans with Type diabetes and without diabetes

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RNA-sequencing of IRF5+ and IRF5- circulating monocytes from patients with Type-2 Diabetes

Project description:Purpose: To characterise the transcriptomic landscape in monocytes associated with IRF5 expression Methods: RNA sequencing from FACS sorted IRF5+ and IRF5- CD14+ monocytes Results: Differential expression based on IRF5 postiivity provides insight into its roles in monocyte function and in type-2 diabetes Conclusions: This study represents the first analyses of IRF5-dependent transcriptome in circulating monocytes from patients with Type-2 diabetes

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Profiling of CD14+ monocytes from humans with Type diabetes and without diabetes [RNA-Seq]

Project description:Monocyte activation by high glucose and free fatty acids promotes inflammation implicated in vascular complications associated with Type 2 diabetes (T2D). Emerging evidence shows that long non coding RNA (lncRNA)s regulate inflammation, but their role in T2D induced monocyte dysfunction is unclear. To examine this, we profiled the transcriptome of CD14+ monocytes from volunteers with T2D and without diabetes (n=5 each) using strand-specific RNA-seq on Illumina HiSeq 2500. Our study identified several differentially regulated lncRNAs along with coding genes involved in monocyte functions related to inflammation and monocytosis.

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Inhibition of 12/15-Lipoxygenase Protects Against β Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

Project description:Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-lipoxygenase (12/15-LOX) is induced in β cells and macrophages during T1D and produces pro-inflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling suggested reduced promiscuity of ML351 compared to ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of pro-inflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the non-obese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in the insulitis. Our data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.

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Profiling of CD14+ monocytes from humans with Type diabetes and without diabetes [RNA-Seq]

Project description:Profiling of CD14+ monocytes from humans with Type diabetes and without diabetes [RNA-Seq]

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Profiling of CD14+ monocytes from humans with Type diabetes and without diabetes [CHIRP-seq]

Project description:Profiling of CD14+ monocytes from humans with Type diabetes and without diabetes [CHIRP-seq]

| PRJNA656806 | ENA