Figure 7: Schematic Detailing the Proposed Mechanism for HIF-1α Suppression in Diabetes

In control cells, hypoxia drives increased anaerobic glycolysis, malate-aspartate shuttle (MAS) activity, and reverse Krebs cycle activity. The increased succinate concentrations promote HIF-1α protein stabilization (via inhibition of the HIF hydroxylase enzymes), driving optimal adaptation to hypoxia. In diabetic cells, increased fatty acids in hypoxia inhibits anaerobic glycolysis, resulting in suppressed succinate concentrations and decreased HIF-1α protein stabilization, blunting the adaptation to hypoxia.