Unknown,Transcriptomics,Genomics,Proteomics

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Effects of exendin-4 in Brunner's glands of male GLP-1R-/- and wild-type control mice

ABSTRACT: To gain insight into the biological functions of the highly expressed GLP-1R in Brunnerâs glands, transcriptome analyses were conducted in male GLP-1R-/- and wild-type control mice. Analyses were performed 6 hours after a single s.c. dose of exendin-4 (1.0mg/kg s.c.), following 18 hours of two doses of exendin-4 (1.0 mg/kg s.c., administered at 0 and 9 hours), and in untreated controls. Brunnerâs glands were isolated by laser capture micro dissection and extracted total RNA was used for microarray profiling. A total of 18 samples consisting of laser captured microdissected Brunner's glands from individual male GLP-1R-/- and wild-type (CD-1) mice. Before the isolation of Brunner's glands, mice were dosed with exendin-4 for 6 and 18 hours. The extracted total RNA from Brunner's glands were compared by full transcriptome profiling.

ORGANISM(S): Mus musculus

SUBMITTER: Klaus Stensgaard Frederiksen

PROVIDER: E-GEOD-80119 | 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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Effects of exendin-4 in Brunner's glands of male GLP-1R-/- and wild-type control mice

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