Title: | Context-dependent actions of Exendin-4 on β-cell function and dynamic changes in islet gene expression over time in vivo
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dateReleased: |
04-11-2014
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description: |
GLP-1 analogues, such as exendin-4, preserve functional β-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 β-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 β-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 β-cell ablation in pIns-MYCERTAM transgenic mice in vivo. Despite over 90% loss of β-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 β-cell mass or turnover in this study, we could directly isolate effects on function of surviving β-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 β-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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privacy: |
not applicable
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aggregation: |
instance of dataset
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ID: |
E-GEOD-37936
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refinement: |
raw
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alternateIdentifiers: |
37936
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keywords: |
functional genomics
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dateModified: |
06-02-2014
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availability: |
available
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types: |
gene expression
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name: |
Mus musculus
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ID: |
A-AFFY-45
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name: |
Affymetrix GeneChip Mouse Genome 430 2.0 [Mouse430_2]
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accessURL: | https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-37936/E-GEOD-37936.raw.1.zip |
storedIn: |
ArrayExpress
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gzip compressed
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format: |
TXT
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accessType: |
download
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authentication: |
none
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authorization: |
none
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accessURL: | https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-37936/E-GEOD-37936.processed.1.zip |
storedIn: |
ArrayExpress
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qualifier: |
gzip compressed
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format: |
TXT
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accessType: |
download
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authentication: |
none
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authorization: |
none
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accessURL: | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE37936 |
storedIn: |
Gene Expression Omnibus
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qualifier: |
not compressed
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format: |
HTML
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accessType: |
landing page
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primary: |
true
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authentication: |
none
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authorization: |
none
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abbreviation: |
EBI
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homePage: | http://www.ebi.ac.uk/ |
ID: |
SCR:004727
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name: |
European Bioinformatics Institute
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homePage: | https://www.ebi.ac.uk/arrayexpress/ |
ID: |
SCR:002964
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name: |
ArrayExpress
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