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Accession IconGSE37936

Context-dependent actions of Exendin-4 on -cell function and dynamic changes in islet gene expression over time in vivo

Organism Icon Mus musculus
Sample Icon 60 Downloadable Samples
Technology Badge Icon Affymetrix Mouse Genome 430 2.0 Array (mouse4302)

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Description
GLP-1 analogues, such as exendin-4, preserve functional -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 -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 -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 -cell ablation in pIns-MYCERTAM transgenic mice in vivo. Despite over 90% loss of -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 -cell mass or turnover in this study, we could directly isolate effects on function of surviving -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 -cell loss exendin-4 can markedly improve hyperglycaemia by differential gene expression in surviving islet cells.
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