Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Single-Cell RNAseq Reveals That Pancreatic Î²-Cells From Very Old Male Mice Have a Young Gene Signature

ABSTRACT: Aging improves pancreatic Î²-cell function in mice. This is a surprising finding since aging is typically associated with functional decline. We performed single-cell RNA sequencing of Î²-cells from 3 and 26 month old mice to explore how changes in gene expression contribute to improved function with age. The old mice were healthy, had reduced blood glucose levels and increased Î²-cell mass, which correlated to their body weight. Î²-cells from young and old mice had similar transcriptome profiles. In fact, only 193 genes (0.89% of all detected genes) were significantly regulated (â¥ 2-fold; false discovery rate < 0.01; normalized counts > 5). Of these, 183 were downregulated and mainly associated with pathways regulating gene expression, cell cycle, cell death and survival as well as cellular movement, function and maintenance. Collectively, our data show that Î²-cells from very old mice have transcriptome profiles similar to those of young mice. These data support previous findings that aging is not associated with reduced Î²-cell mass or functional Î²-cell decline in mice. Single-cell RNA sequencing of mouse pancreatic islet beta cells

ORGANISM(S): Mus musculus

SUBMITTER: Yurong Xin

PROVIDER: E-GEOD-83146 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:GLP-1 analogues, such as exendin-4, preserve functional Î²-cell mass in various model systems and are revolutionising management of type 2 diabetes. Yet, comparatively little is known about effectiveness in the face of severe Î²-cell depletion. Moreover, direct and sequential effects of exendin-4 on islet-specific gene expression over time in vivo are not well characterised. To address these issues and others, we have examined the time-dependent effects of exendin-4 treatment on Î²-cell mass regulation alongside accompanying changes in islet gene expression in vivo. Context-dependent actions were assessed by comparing effects on normal islets and also following massive toxigenetic Î²-cell ablation in pIns-MYCERTAM transgenic mice in vivo. Despite over 90% loss of Î²-cell mass, exendin-4 treatment normalised blood glucose and insulin levels in hyperglycaemic mice, though benefits rapidly waned on withdrawal of treatment. As exendin-4 did not arrest the decline in Î²-cell mass or turnover in this study, we could directly isolate effects on function of surviving Î²-cells. Improved glucose homeostasis was associated with dynamic changes in multiple islet genes and pathways in vivo favouring glucose-stimulated insulin secretion, such as Irs2, Pdx1, Sox4, glucokinase, and glycolysis pathway. Several key growth pathways and epigenetic regulators were also differentially expressed. Thus, even in the face of extensive Î²-cell loss exendin-4 can markedly improve hyperglycaemia by differential gene expression in surviving islet cells. Activation of MYCERTAM was achieved through administration of 1mg of 4 hydroxytamoxifen (4OHT; Sigma-Aldrich, St. Louis, MO) by daily intraperitoneal injection. To assess the effect of exendin-4 on MYCER-induced hyperglycaemia, mice were given either twice-daily subcutaneous (sc) injections of exendin-4 (50ug/kg dissolved in 5mls water), or equivalent volumes of water vehicle, starting 2 days prior to 4OHT injections. For microarray analyses parallel mouse experiments were set up using 8-12 week old pIns-MYCERTAM male mice either treated with 4OHT or vehicle (peanut oil) and exendin-4 or vehicle, as described, for 4, 8, 16, 32 and 72 hours (n=3 for each time point and for each of four conditions; 4OHT and exendin-4 treated, peanut oil and exendin-4 treated, 4OHT and water treated, peanut oil and water treated). !Sample_data_processing = After the quality control step, the following 8 samples out of 60 showing poor reproducibility were excluded from our further study: GSM930242, GSM930247, GSM930251, GSM930263, GSM930264, GSM930289, GSM930291, GSM930298.

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Single-Cell RNAseq Reveals That Pancreatic Î²-Cells From Very Old Male Mice Have a Young Gene Signature

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