Translational Programming of Beta-cells in Response to Glucose Toxicity

ABSTRACT Control of insulin biosynthesis in beta-cells occurs primarily at the level of translation of the insulin mRNA. An acute rise in glucose levels stimulates insulin translation by a process that involves binding of proteins to the 5' untranslated region of the insulin mRNA. Simultaneous translational upregulation of other secretory granule

proteins also contributes to glucose-stimulated insulin secretion and provides evidence that beta-cells coordinately regulate translation of functionally related mRNAs. By contrast, exposure of beta-cells to sustained high glucose suppresses glucose-stimulated insulin translation and secretion. The mechanisms responsible for

dysregulation of insulin translation and whether the deleterious effect of chronic high glucose impacts translation of other proteins are not known. This project will test the hypothesis that glucose toxicity leads to early alterations in mRNA-specific beta-cell translation that are mediated by intrinsic properties of mRNAs and by dynamic

remodeling of the ribosome itself. Furthermore, we propose this programmatic translational dysregulation contributes to impaired glucose-stimulated insulin secretion. Knowledge gained from this study has the potential to identify novel therapeutic targets for prevention of progressive beta-cell failure in diabetes and for optimizing

functionality of ex vivo generated beta-cells for cell replacement therapy.