Immune regulation of islet homeostasis and adaptation

Guo, Jinglong; Fu, Wenxian

doi:10.1093/jmcb/mjaa009

Cited by 15 publications

(10 citation statements)

References 114 publications

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“…performed an analysis of single-cell data on human pancreas and found that monocytes and CD8+ T cells are enriched in the T2D pancreas ( 97 ). Our results are consistent with previous reports that monocytes and macrophages are the primary immune cell subsets that contribute to islet inflammation during T2D development ( 98 ). We also found correlations between the 17 pyroptosis-related hub genes and 13 immune cell types.…”

Section: Discussionsupporting

confidence: 94%

Bulk and single-cell transcriptome analyses of islet tissue unravel gene signatures associated with pyroptosis and immune infiltration in type 2 diabetes

Song

Jiang

et al. 2023

Front. Endocrinol.

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IntroductionType 2 diabetes (T2D) is a common chronic heterogeneous metabolic disorder. However, the roles of pyroptosis and infiltrating immune cells in islet dysfunction of patients with T2D have yet to be explored. In this study, we aimed to explore potential crucial genes and pathways associated with pyroptosis and immune infiltration in T2D.MethodsTo achieve this, we performed a conjoint analysis of three bulk RNA-seq datasets of islets to identify T2D-related differentially expressed genes (DEGs). After grouping the islet samples according to their ESTIMATE immune scores, we identified immune- and T2D-related DEGs. A clinical prediction model based on pyroptosis-related genes for T2D was constructed. Weighted gene co-expression network analysis was performed to identify genes positively correlated with pyroptosis-related pathways. A protein–protein interaction network was established to identify pyroptosis-related hub genes. We constructed miRNA and transcriptional networks based on the pyroptosis-related hub genes and performed functional analyses. Single-cell RNA-seq (scRNA-seq) was conducted using the GSE153885 dataset. Dimensionality was reduced using principal component analysis and t-distributed statistical neighbor embedding, and cells were clustered using Seurat. Different cell types were subjected to differential gene expression analysis and gene set enrichment analysis (GSEA). Cell–cell communication and pseudotime trajectory analyses were conducted using the samples from patients with T2D.ResultsWe identified 17 pyroptosis-related hub genes. We determined the abundance of 13 immune cell types in the merged matrix and found that these cell types were correlated with the 17 pyroptosis-related hub genes. Analysis of the scRNA-seq dataset of 1892 islet samples from patients with T2D and controls revealed 11 clusters. INS and IAPP were determined to be pyroptosis-related and candidate hub genes among the 11 clusters. GSEA of the 11 clusters demonstrated that the myc, G2M checkpoint, and E2F pathways were significantly upregulated in clusters with several differentially enriched pathways.DiscussionThis study elucidates the gene signatures associated with pyroptosis and immune infiltration in T2D and provides a critical resource for understanding of islet dysfunction and T2D pathogenesis.

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Section: Discussionsupporting

confidence: 94%

Bulk and single-cell transcriptome analyses of islet tissue unravel gene signatures associated with pyroptosis and immune infiltration in type 2 diabetes

Song

Jiang

et al. 2023

Front. Endocrinol.

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“…It is known that function of pancreatic β cells is gradually impaired by excessive glucose (glucotoxicity) and fatty acids (lipotoxicity) under the context of obese T2DM (Shao et al 2014 ). Additionally, obesity-associated systemic low-grade inflammation could cause an elevation of inflammatory cytokines and chemokines in circulation together with the accumulation and impaired function of various immune cells including macrophages and B cells in pancreas, resulting in islet inflammation and β-cell dysfunction (Eguchi et al 2017 ; Guo et al 2020 ; Ying et al 2019 ). Consistently, our current study observed decreased HOMA-β and increased insulitis as the progress of diabetes in db/db mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Exenatide regulates Th17/Treg balance via PI3K/Akt/FoxO1 pathway in db/db mice

Shao

2022

Mol Med

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Background The T helper 17 (Th17)/T regulatory (Treg) cell imbalance is involved in the course of obesity and type 2 diabetes mellitus (T2DM). In the current study, the exact role of glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide on regulating the Th17/Treg balance and the underlying molecular mechanisms are investigated in obese diabetic mice model. Methods Metabolic parameters were monitored in db/db mice treated with/without exenatide during 8-week study period. The frequencies of Th17 and Treg cells from peripheral blood and pancreas in db/db mice were assessed. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box O1 (FoxO1) pathway in Th17 and Treg cells from the spleens of male C57BL/6J mice was detected by western blotting. In addition, the expression of glucagon-like peptide-1 receptor (GLP-1R) in peripheral blood mononuclear cells (PBMCs) of male C57BL/6J mice was analyzed. Results Exenatide treatment improved β-cell function and insulitis in addition to glucose, insulin sensitivity and weight. Increased Th17 and decreased Treg cells in peripheral blood were present as diabetes progressed while exenatide corrected this imbalance. Progressive IL-17 + T cell infiltration of pancreatic islets was alleviated by exenatide intervention. In vitro study showed no significant difference in the level of GLP-1R expression in PBMCs between control and palmitate (PA) groups. In addition, PA could promote Th17 but suppress Treg differentiation along with down-regulating the phosphorylation of PI3K/Akt/FoxO1, which was reversed by exenatide intervention. FoxO1 inhibitor AS1842856 could abrogate all these effects of exenatide against lipid stress. Conclusions Exenatide could restore systemic Th17/Treg balance via regulating FoxO1 pathway with the progression of diabetes in db/db mice. The protection of pancreatic β-cell function may be partially mediated by inhibiting Th17 cell infiltration into pancreatic islets, and the resultant alleviation of islet inflammation.

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“…It is also impaired in T2D [ 81 ]. Tissue-resident macrophages are known to play an important role in normal islets and in disease [ 82 ]. They can be important for beta cell proliferation, homeostasis, and function [ 83 ].…”

Section: Further Stepsmentioning

confidence: 99%

Overcoming the Limitations of Stem Cell-Derived Beta Cells

2022

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Great advances in type 1 diabetes (T1D) and type 2 diabetes (T2D) treatment have been made to this day. However, modern diabetes therapy based on insulin injections and cadaveric islets transplantation has many disadvantages. That is why researchers are developing new methods to regenerate the pancreatic hormone-producing cells in vitro. The most promising approach is the generation of stem cell-derived beta cells that could provide an unlimited source of insulin-secreting cells. Recent studies provide methods to produce beta-like cell clusters that display glucose-stimulated insulin secretion—one of the key characteristics of the beta cell. However, in comparison with native beta cells, stem cell-derived beta cells do not undergo full functional maturation. In this paper we review the development and current state of various protocols, consider advantages, and propose ways to improve them. We examine molecular pathways, epigenetic modifications, intracellular components, and the microenvironment as a possible leverage to promote beta cell functional maturation. A possibility to create islet organoids from stem cell-derived components, as well as their encapsulation and further transplantation, is also examined. We try to combine modern research on beta cells and their crosstalk to create a holistic overview of developing insulin-secreting systems.

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Immune regulation of islet homeostasis and adaptation

Cited by 15 publications

References 114 publications

Bulk and single-cell transcriptome analyses of islet tissue unravel gene signatures associated with pyroptosis and immune infiltration in type 2 diabetes

Bulk and single-cell transcriptome analyses of islet tissue unravel gene signatures associated with pyroptosis and immune infiltration in type 2 diabetes

Exenatide regulates Th17/Treg balance via PI3K/Akt/FoxO1 pathway in db/db mice

Overcoming the Limitations of Stem Cell-Derived Beta Cells

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