Nutrient Sensor mTOR and OGT: Orchestrators of Organelle Homeostasis in Pancreatic β-Cells

Figure 1

The pathology of β-cell dysfunction and failure during chronic nutrient excess: schematic summary of organelle dysfunction driven by dysregulated activity of mTORC1 and OGT. Type 2 diabetes (T2D) and obesity are characterized by chronically elevated hyperglycemia, hyperlipidemia, and elevations in branched-chain amino acids (BCAAs) and inflammation. These conditions activate two key intracellular nutrient sensors in β-cells: mechanistic target of rapamycin complex 1 (mTORC1) and O-linked N-acetylglucosamine transferase (OGT). Sustained activity of either of these nutrient sensors leads to comprehensive organelle dysfunction in β-cells. mTORC1 activity induces mitochondrial oxidative stress, impairs ATP production, and induces morphological and networking changes that disrupt mitochondrial health and function. In the endoplasmic reticulum (ER), mTORC1 hyperactivity causes ER stress, which can reinforce mTORC1 activity in positive feedback. mTORC1 suppresses autophagosome formation and fusion with lysosomes, which can impact the homeostasis of other organelles such as the mitochondria and ER. mTORC1 hyperactivity also induces lysosomal membrane damage, reduces biogenesis, and impairs the activity of lysosomal enzymes. mTORC1 also has a bidirectional relationship with inflammation that can strengthen these upstream signals. Published studies of increased OGT activity in β-cells during T2D have been more limited, but OGT generally follows similar patterns to mTORC1 in terms of its effects on organelle function. As the mitochondria, ER, autophagy, and lysosomes are each critical to the activities within β-cells, disruption of mTORC1 and OGT signaling leads to β-cell dysfunction and, if sustained, β-cell apoptosis. Black arrow: promotes indicated organelle dysfunction; dotted arrow: appears to promote indicated organelle dysfunction in some but not all contexts.