Figure 4.

Hyperglycemia causes cellular stress via the polyol pathway

(A) Glucose concentrations (mM) of commonly used basal media are significantly higher compared to those in the brain (Brain, in vivo). BME, basal medium Eagle. BP, BrainPhys medium. DMEM, Dulbecco’s modified Eagle medium. HG, high glucose. LG, low glucose. GMEM, Glasgow minimum essential medium. Nb, Neurobasal medium. IMDM, Isocove’s modified Dulbecco’s medium. IMEM, improved minimum essential medium.

(B) Under normoglycemia, glucose is phosphorylated to produce glucose 6-phosphate to initiate glycolysis, which feeds pyruvate into the tricarboxylic acid (TCA) cycle.

(C) Under chronic hyperglycemia, the enzyme that converts glucose into glucose 6-phosphate, hexokinase, becomes saturated. As glucose builds up, aldose reductase converts glucose into sorbitol, which is then converted into fructose. Fructose accumulation increases advanced glycation end products (AGEs) which cause ER stress. In addition, the conversion of glucose to sorbitol depletes the nicotinamide adenine dinucleotide phosphate (NADPH) required for the antioxidant system, thereby increasing oxidative stress. Hyperglycemia also leads to an increase in the overall rate of glycolysis with a concurrent decrease in the rate of oxidative phosphorylation, termed a glycolytic shift, which is associated with numerous disease phenotypes across tissue types.