Ribosome remodeling under glucotoxic conditions impairs beta-cell function
Diabetes develops when pancreatic beta-cells fail to secrete sufficient insulin to meet metabolic demand. Chronic hyperglycemia accelerates beta-cell failure and dysregulates mRNA translation before the onset of endoplasmic reticulum stress, but the underlying mechanisms remain unknown. Here, quantitative mass spectrometry of translating ribosomes isolated from MIN6 cells under control and glucotoxic conditions revealed that sustained high glucose remodels ribosome composition by selectively decreasing Ribosomal Protein Lateral Stalk Subunit P1 (RPLP1) on actively translating ribosomes. Knockdown of RPLP1 in MIN6 cells and in primary islets reduced translation of insulin and impaired glucose-stimulated insulin secretion. Depletion of RPLP1 in vivo led to glucose intolerance. Together, our findings indicate that glucotoxicity remodels beta-cell ribosomes, leading to selective mRNA translation impairment and decreased insulin secretion. This previously unrecognized mechanism linking metabolic overload to beta-cell dysfunction suggests that preserving RPLP1 association with ribosomes could represent a therapeutic strategy for maintaining beta-cell function in diabetes.