However, some pathways appeared in only 1 or 2 periods, and the differences in the pathway enrichment at each stage may due to the alterations of in vivo environments, such as chronic hyperglycaemia (Supplemental Material Figure S1A), β-cell mass loss, dysfunction-induced decrease in insulin secretion (Supplemental Material Figure S1B), peripheral organism inflammation, insulin resistance and oxidative stress7. Here, INS is linked to Hyperglycemia.