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

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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