Figure 2: Mitochondria are the main source of free radicals in neurodegenerative diseases, which is particularly true in the Alzheimer brain. The tripeptide GSH is formed in the cytosol from cysteine, glutamate, and glycine as substrates (glutamate reacts with cysteine in the presence of γ-glutamylcysteine ligase to produce γ-glutamylcysteine, which in turn reacts in a second step catalyzed by the enzyme GSH synthetase with glycine, to produce GSH). From the cytosol, GSH is distributed to the nucleus, endoplasmic reticulum (ER), and mitochondria. GSH is a key, abundant antioxidant system to control free radical overproduction in the central nervous system. As long as GSH can be replenished, a reducing intracellular environment prevails, depending on the amount of substrates for its synthesis and the proper functioning of the antiporter system, X. In T2D, the polyol pathway consumes NADPH to transform glucose into sorbitol, affecting the GSH system. Conversely, the two important substrates for GSH replenishment, cysteine and glycine, are reportedly diminished in T2D. SOD: superoxide dismutase; GR: glutathione reductase; GPx: glutathione peroxidase; GSH: γ-l-glutamyl-l-cysteinyl-glycine; GSSG: oxidized glutathione; NADPH: reduced form of NADP+ nicotinamide adenine dinucleotide phosphate; AR: aldose reductase; SDH: sorbitol dehydrogenase.