We have been interested in how glucose is sensed and regulates metabolic homeostasis. We have identified a glucose sensing pathway at the lysosome, in that the glycolytic enzyme aldolase is the sensor and transmits the signal of glucose availability to v-ATPase that serves as a central node for either activating AMPK or maintaining the activity of mTORC1. We have also identifed PEN2 as the target of metformin, revealing that the PEN2-metformin complex inhibits v-ATPase to activate AMPK for the various clinical benefits of the drug. Meanwhile, we have used aldolase as a target to screen for compounds that block aldolase from binding to its substrate FBP, and found Aldometanib as such a compound. We have shown that Aldometanib lowers blood glucose levels, allevates fatty liver, and extends lifespan.