Fig. 2

TDP-43 aggregation and defective neuronal glucose metabolism. Loss of TDP-43 function, caused by its abnormal aggregation in neurons, can potentially lead to defective glycolysis and to defects in the TCA cycle or electron transport chain, leading to decreased ATP levels. Additionally, TDP-43 loss of function might induce a Warburg effect in neurons, increasing their reliance on glycolysis for ATP production. Finally, TDP-43 aggregation can lead to increased production of reactive oxygen species (ROS). Type 2 diabetes mellitus (T2DM) can be beneficial in each of these pathogenic mechanisms; hyperglycemia in T2DM provides readily available fuel for glucose metabolism and can also meet the increased requirement of glucose in neurons as a result of the Warburg effect, and it can counter ROS by replenishing levels of the anti-oxidant glutathione