Abstract
Type 2 diabetes mellitus (T2DM) is a significant global health concern, affecting approximately 537 million people worldwide. In T2DM, pancreatic β-cells fail to secrete adequate insulin in response to insulin resistance, a dysfunction often linked to metabolic abnormalities that can lead to increased cell death. The mechanistic target of rapamycin (mTOR) is a pivotal protein kinase involved in metabolic signalling, existing in two distinct complexes: mTORC1 and mTORC2. Both complexes are known to be dysregulated in T2DM. The DEP domain-containing mTOR-interacting protein (DEPTOR) serves as a natural inhibitor of mTOR, modulating its activity and playing a critical role in cellular processes such as growth, proliferation, and survival. DEPTOR’s dysregulation has been implicated in various cancers through enhanced autophagy, yet its specific role in T2DM remains largely unexplored. This study aims to elucidate the regulation of DEPTOR in the pancreas of db/db mice, a widely used model for T2DM.
Our findings indicate that DEPTOR protein expression is significantly reduced in the pancreatic tissue of obese db/db mice at 16 weeks of age compared to lean controls, suggesting a potential link between DEPTOR levels and metabolic dysregulation in T2DM. Interestingly, this reduction is not observed at 26 weeks, implying that the regulatory mechanisms governing DEPTOR may shift as the disease progresses. Further investigation through immunoprecipitation studies suggests that the decrease in DEPTOR protein levels is not due to post-translational modifications, such as ubiquitination, which typically signal proteins for degradation. This suggests that DEPTOR stability is likely preserved during this timeframe, pointing to alternative regulatory mechanisms at play. In contrast, RT-qPCR analyses reveal a corresponding decrease in DEPTOR mRNA levels in the pancreatic tissue of obese db/db mice. This finding implies that the reduction in DEPTOR protein may be primarily driven by decreased transcription or potential post-transcriptional regulation.
This research represents one of the first investigations into the role of DEPTOR in T2DM, providing valuable insights into its potential involvement in pancreatic β-cell function and overall metabolic dysregulation. Understanding the regulation of DEPTOR could open new avenues for therapeutic strategies targeting mTOR signalling pathways in T2DM.