Mechanism of action of β-cell glucose toxicity. In our hypothesis, hyperglycemia presents such excessively high concentrations
of glucose to islet glycolytic enzymes that glucose is shunted to the alternative pathway of enolization, with subsequent
formation of superoxide, H2O2, and eventually hydroxyl radicals (see text). Hydroxyl radicals interfere with normal processing of PDX-1 mRNA, a necessary
transcription factor for insulin gene expression and glucose-induced insulin secretion. The two major defense mechanisms against
H2O2 formation are catalase, which metabolizes H2O2 into water and oxygen, and GPx, which depends on islet GSH to convert H2O2 into water and GSSG. GSH is regenerated by islet NADPH and GSH reductase. The enzymes responsible for de novo GSH synthesis
are GCL and GSH synthetase (see text).