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Series GSE37936 Query DataSets for GSE37936
Status Public on Apr 11, 2014
Title Context-dependent actions of Exendin-4 on β-cell function and dynamic changes in islet gene expression over time in vivo
Organism Mus musculus
Experiment type Expression profiling by array
Summary 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.
 
Overall design 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.
 
Contributor(s) Young J, Wang Y, Robson S, Abouna S, Laiho A, Gyenesei A, Kytömäki L, Hermann R, Weickert M, Barberà A, Pelengaris S, Khan M
Citation missing Has this study been published? Please login to update or notify GEO.
Submission date May 11, 2012
Last update date Feb 11, 2019
Contact name Michael Khan
E-mail Michael.Khan@warwick.ac.uk
Organization name University of Warwick
Department Life Sciences
Street address Gibbet Hill Road
City Coventry
ZIP/Postal code CV4 7AL
Country United Kingdom
 
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (60)
GSM930240 MycON treated with exenatide at 4 hours, biological rep1
GSM930241 MycON treated with exenatide at 4 hours, biological rep2
GSM930242 MycON treated with exenatide at 4 hours, biological rep3
Relations
BioProject PRJNA165653

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Supplementary file Size Download File type/resource
GSE37936_RAW.tar 193.9 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

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