Ornithine decarboxylase 1 modulation regulates plasma membrane integrity and associated gene networks under glucotoxicity and lipotoxicity stress: An in vitro study

Hyperglycemia marks the onset of type 2 diabetes, and its pathogenesis involves glucotoxicity and lipotoxicity that compromise pancreatic β-cell function and plasma membrane integrity. While plasma membrane disruption is recognized as a critical factor in diabetic complications, the molecular mechanisms protecting membrane structure under metabolic stress remain poorly understood. Despite ornithine decarboxylase 1 (ODC1) being identified as a key enzyme in polyamine biosynthesis with roles in cellular growth and stress response, its specific contribution to plasma membrane protection during glucotoxicity and lipotoxicity conditions has not been systematically investigated. Despite being the most responsive and abundantly expressed in the pancreas, the lack of insight into its role restricts our understanding of membrane-protective mechanisms that could serve as therapeutic targets for diabetes management. To address this gap, we examined how ODC1 modulation affects plasma membrane structure and associated gene expression networks under metabolic stress conditions. Differential gene expression analysis of human pancreatic islet datasets from the GEO database identified plasma membrane-associated genes co-expressed with ODC1 in type 2 diabetes. Using HEK293T cells, we established in vitro models of glucotoxicity and lipotoxicity and manipulated ODC1 expression through overexpression and small interfering (siRNA)-mediated knockdown. Gene expression validation revealed that ODC1 regulates plasma membrane genes, including JUN, RHOA, CAV1, PRNP, SGK1, ATP5B, CLIC4, and CCND1, while ODC1 knockdown impaired membrane damage and apoptotic features. These findings establish ODC1 as a critical protective factor maintaining plasma membrane structure during metabolic stress, revealing novel therapeutic targets for preserving β-cell function in type 2 diabetes.