INS and Hyperglycemia: Additionally, we discuss hyperglycemia-activated pathways such as polyol flux, AGE–RAGE interactions, protein kinase C/nicotinamide adenine dinucleotide phosphate (PKC/NADPH) oxidase activation, and poly (ADP-ribose) polymerase 1 (PARP-1)-mediated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibition, which contribute to inflammation, endothelial dysfunction, β-cell failure, insulin resistance, and micro/macrovascular injury.