In line with our findings, Cruickshank et al. previously found a U-shaped relationship between insulin and IGFBP-1 during the natural course from normoglycemia to frank type 2 diabetes in a cross-sectional study among Europeans and Pakistanis: IGFBP-1 concentrations were lower in those with impaired compared with normal glucose tolerance, whereas IGFBP-1 rose again in those with diabetes, probably reflecting insulin arriving at the liver, the principal site of IGFBP-1 synthesis (Figure 2C) [81]. This evidence concerns the gene INS and type 2 diabetes mellitus.