In the present study, we aimed to characterize the role of HBP1 in T2DM through its regulation of the IGFBP1 gene, and found that the insulin/HBP1/IGFBP1/IGF-1/PI3K/AKT axis is critical for blood glucose regulation, because the deletion of HBP1 disrupts glucose homeostasis and induces T2DM. This evidence concerns the gene IGFBP1 and type 2 diabetes mellitus.