3112-LB: Sustained High Glucose Perturbs mRNA-Specific Translation in Pancreatic Beta-Cells

Introduction and Objective: Pancreatic β-cells are highly specialized insulin-secreting cells, and their loss or dysfunction causes diabetes. Acute physiological glucose exposure robustly increases mRNA translation of insulin and secretory granule proteins that support insulin release. By contrast, chronic exposure to high glucose decreases insulin translation and secretion and is an important contributor to β-cell dysfunction during the development of diabetes. The mechanism by which chronic hyperglycemia impairs insulin translation is not well understood. Methods: We used ribosome profiling and proteomics to analyze impact of sustained high glucose on mRNA translation in pancreatic β-cells. Results: We found that prior to induction of endoplasmic reticulum stress or decreased global protein synthesis, chronic high glucose suppressed glucose stimulated insulin secretion (GSIS) and specifically downregulated translation of insulin and proteins related to insulin secretory granule formation/function and exocytosis. Intriguingly, chronic high glucose altered the stoichiometry of β-cell ribosomal proteins by decreasing the abundance of ribosomal protein RPLP1 on translating ribosomes, consistent with nutrient-induced ribosome heterogeneity. In MIN6 and primary islets, knockdown of RPLP1 did not have an impact on global protein synthesis, but it decreased both GSIS and translation of insulin. Moreover, streptozotocin-induced diabetic mice transplanted with RPLP1-depleted islets had decreased function during glucose tolerance test, underscoring the physiological relevance of our findings. Conclusion: Our studies show that sustained high glucose remodels β-cell ribosome structure and function in ways that contribute to β-cell failure. Targeting the β-cell ribosome could provide a novel strategy for preventing progressive β-cell failure in diabetes and for optimizing functionality of ex vivo generated β-cells for cell-replacement therapy. Disclosure A. Cheruiyot Harvey: None. J. Hollister-Lock: None. K. Iwasaki: None. J.S. Navarro Arriola: None. O. Akintola: None. L. Nguyen: None. S. Bonner-Weir: None. C. Aguayo-Mazzucato: Consultant; Ended; Novo Nordisk, Sanofi. J. Schaffer: Advisory Panel; Current; Novo Nordisk Foundation. Funding National Institutes of Health, NIDDK (K99DK140526), National Institutes of Health, NIDDK (R01DK138605)