We next tested the effect of IGFBP3/TMEM219 pharmacological blockade in the aforementioned preclinical T2D model and demonstrated that administration of the newly generated ecto-TMEM219 significantly reduced blood glucose levels and body weight when given to HFD-treated mice as compared to untreated controls (Fig. 4i, j), and also showed reduced peripheral IGFBP3 levels (Fig. 4k) and increased insulin level, while IGF-I level remained unaltered (Supplementary Fig. 5c, d). This evidence concerns the gene IGFBP3 and type 2 diabetes mellitus.