These results: (i) highlight PITPNA-dependent PtdIns-4-P synthesis on TGN membranes as critical for sustaining insulin granule biogenesis and maturation, (ii) indicate compromise of this activity is a powerful marker of beta-cell failure during T2D, and (iii) identify new prospects for T2D therapy. This evidence concerns the gene PITPNA and type 2 diabetes mellitus.