It is known that the progression of prediabetes to T2D shows stage-dependent features: (1) HOMA insulin sensitivity decreases steeply 5 years prior to T2D occurrence; (2) FG undergoes abrupt increase 2-3 years before T2D onset; (3) significant elevation of A1c is not observed until 1 year before the diagnosis of T2D (Supplemental Figure  1) [24–26]. This evidence concerns the gene INS and type 2 diabetes mellitus.