Publication
Autophagy is an essential quality control mechanism for maintaining organellar functions in eukaryotic cells. Defective autophagy in pancreatic beta cells has been shown to be involved in the progression of diabetes through impaired insulin secretion under glucolipotoxic stress. The underlying mechanism reveals the pathologic role of the hyperactivation of mechanistic target of rapamycin (mTOR), which inhibits lysosomal biogenesis and autophagic processes. Moreover, accumulating evidence suggests that oxidative stress induces Ca2+ depletion in the endoplasmic reticulum (ER) and cytosolic Ca2+ overload, which may contribute to mTOR activation in perilysosomal microdomains, leading to autophagic defects and beta-cell failure due to lipotoxicity. This review delineates the antagonistic regulation of autophagic flux by mTOR and AMP-dependent protein kinase (AMPK) at the lysosomal membrane, and both of these molecules could be activated by perilysosomal calcium signaling. However, aberrant and persistent Ca2+ elevation upon lipotoxic stress increases mTOR activity and suppresses autophagy. Therefore, normalization of autophagy is an attractive therapeutic strategy for patients with beta-cell failure and diabetes.|Excessive intake of fatty acids can result in a condition known as lipotoxicity (harmful effect of fats on cells), which can harm pancreatic beta cells (cells that produce insulin) and contribute to type 2 diabetes. Researchers have found that this harm is due to a disturbance in the cells' autophagy process (a system used by cells to eliminate unnecessary or dysfunctional parts). Specifically, the research revealed that the autophagy process is hindered by the activation of a protein complex called mTORC1 and the suppression of a protein named AMPK. These proteins control the autophagy process and their disturbance leads to the buildup of harmful substances in the cell, causing cell death. The researchers propose that future treatment strategies could focus on restoring the balance of these proteins to safeguard pancreatic beta cells from lipotoxicity. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.