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Senescent beta-cells exhibit a unique secretory phenotype that promotes inflammation and remodeling of the extracellular environment

ABSTRACT: Type 2 Diabetes (T2D) patients have higher proportions of senescent beta-cells than their non-diabetic counterparts (Aguayo-Mazzucato et al., 2019). Senescent beta-cells may propagate dysfunction in neighboring cells through the paracrine effects of the senescence-associated secretory phenotype (SASP). To address the heterogeneity in beta-cell SASP expression and its role in T2D, we measured expression levels of beta-cell SASP signature genes in a mouse model of acute insulin resistance using the insulin receptor antagonist, S961. We have previously shown that this model induces hyperglycemia and accelerates beta-cell senescence (Aguayo-Mazzucato et al., 2019). Pancreatic islets were isolated from 3 groups of mice: a control group, a treated group of mice with surgically installed osmotic pumps secreting S961 for 2 weeks, and a third group in which mice recovered from S961 treatment for two weeks. During treatment, mice developed marked hyperglycemia and hyperinsulinemia which was completely reversed during the two-week recovery period. Islets were dispersed into single cells and scRNASeq was performed using the 10x Genomics Chromium Single Cell Gene Expression Assay.

ORGANISM(S): Mus musculus

PROVIDER: GSE149984 | GEO | 2021/04/06

REPOSITORIES: GEO

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Project description:Relative beta cell deficit and increased beta cell apoptosis are hallmarks of type 2 diabetes (T2D). The Insulin/Insulin Growth Factor (Igf) signaling pathway is an established regulator of beta cell survival and is found downregulated in human T2D islets. The Insulin Receptor Substrate 2 (Irs2) plays a central role in the coordination of this pathway in beta cells. Thus, Irs2 knockout mice (Irs2 -/-) exhibit increased beta cell apoptosis that leads to a progressive decline of beta cell mass and hyperglycaemia. In this study, we sought to determine whether the anti-diabetic compound sodium tungstate could prevent the onset of diabetes in Irs2 -/- mice. Oral administration of tungstate resulted in an overall improvement in whole-body glucose tolerance in Irs2 -/- mice which correlated with increased beta cell mass. Enhanced beta cell mass was due to a dramatic reduction of beta cell apoptosis without changes in proliferation. Whole genome gene profiling analysis of islets isolated from treated Irs2 -/- mice confirmed a broad impact of tungstate on cell death pathways. Mechanistically, tungstate induced Erk1/2 phosphorylation in islets in vitro and, in agreement, treated Irs2 -/- islets exhibited increased basal Erk1/2 phosphorylation. Tungstate also downregulated expression of apoptosis-related genes in Irs2-/- islets in vitro, uncovering a direct effect of this compound in islets. All together, our data demonstrate that tungstate can restore beta cell mass and glucose homeostasis in a context of deficient Insulin/Igf signaling. This study underscores the importance of developing strategies specifically designed to arrest beta cell apoptosis as a means to prevent progressive beta cell failure in diabetes. 10-week old WT and Irs2 -/- mice were randomly divided into two treatment group, in a total of 4 experimental groups. For 21 days one group received distilled water as drinking water (untreated group) whilst the other received ad libitum a solution of 2mg/ml of sodium tungstate in distilled water (treated group). For each experimental group 2 independent samples were analysed, in a total of 8 samples.

Project description:Recent advances in the understanding of the genetics of type 2 diabetes (T2D) susceptibility have focused attention on the regulation of transcriptional activity within the pancreatic beta-cell. MicroRNAs (miRNAs) represent an important component of regulatory control, and have proven roles in the development of human disease and control of glucose homeostasis. We set out to establish the miRNA profile of human pancreatic islets and of enriched beta-cell populations, and to explore their potential involvement in T2D susceptibility. We used Illumina small RNA sequencing to profile the miRNA fraction in three preparations each of primary human islets and of enriched beta-cells generated by fluorescence-activated cell sorting. In total, 366 miRNAs were found to be expressed (i.e. >100 cumulative reads) in islets and 346 in beta-cells; of the total of 384 unique miRNAs, 328 were shared. A comparison of the islet-cell miRNA profile with those of 15 other human tissues identified 40 miRNAs predominantly expressed (i.e. >50% of all reads seen across the tissues) in islets. Several highly-expressed islet miRNAs, such as miR-375, have established roles in the regulation of islet function, but others (e.g. miR-27b-3p, miR-192-5p) have not previously been described in the context of islet biology. As a first step towards exploring the role of islet-expressed miRNAs and their predicted mRNA targets in T2D pathogenesis, we looked at published T2D association signals across these sites. We found evidence that predicted mRNA targets of islet-expressed miRNAs were globally enriched for signals of T2D association (p-values <0.01, q-values <0.1). At six loci with genome-wide evidence for T2D association (AP3S2, KCNK16, NOTCH2, SCL30A8, VPS26A, and WFS1) predicted mRNA target sites for islet-expressed miRNAs overlapped potentially causal variants. In conclusion, we have described the miRNA profile of human islets and beta-cells and provide evidence linking islet miRNAs to T2D pathogenesis. Examination of the miRNA profiles in 3 preparations of isolated pancreatic islets and 3 preparations of FACS-enriched pancreatic beta-cells

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Senescent beta-cells exhibit a unique secretory phenotype that promotes inflammation and remodeling of the extracellular environment

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