However, several underlying causes have been proposed including insulin resistance, fuel preference, mitochondrial dysfunction, calcium overload and mishandling, reactive oxygen species generation, inflammation, cell death pathways, neurohormonal mechanisms, advanced glycated end-products accumulation, lipotoxicity, glucotoxicity, transcriptional changes, and post-translational modifications in diabetes (as recently reviewed in [15,16]). The gene discussed is INS; the disease is diabetes mellitus.