Defects in insulin processing and granule maturation are linked to pancreatic beta-cell failure during type 2 diabetes (T2D). Phosphatidylinositol transfer protein alpha (PITPNA) stimulates activity of phosphatidylinositol (PtdIns) 4-OH kinase to produce sufficient PtdIns-4-phosphate (PtdIns-4-P) in the trans-Golgi network to promote insulin granule maturation. PITPNA in beta-cells of T2D human subjects is markedly reduced suggesting its depletion accompanies beta-cell dysfunction. Conditional deletion of Pitpna in the beta-cells of Ins-Cre, Pitpna^flox/flox mice leads to hyperglycemia resulting from decreasing glucose-stimulated insulin secretion (GSIS) and reducing pancreatic beta-cell mass. Furthermore, PITPNA silencing in human islets confirms its role in PtdIns-4-P synthesis and leads to impaired insulin granule maturation and docking, GSIS, and proinsulin processing with evidence of ER stress. Restoration of PITPNA in islets of T2D human subjects reverses these beta-cell defects and identify PITPNA as a critical target linked to beta-cell failure in T2D.

胰岛素加工和颗粒成熟的缺陷与 2 型糖尿病 (T2D) 期间胰腺 β 细胞衰竭有关。磷脂酰肌醇转移蛋白 α (PITPNA) 刺激磷脂酰肌醇 (PtdIns) 4-OH 激酶的活性，在反式高尔基体网络中产生足够的 PtdIns-4-磷酸 (PtdIns-4-P)，从而促进胰岛素颗粒成熟。 T2D 人类受试者 β 细胞中的PITPNA显着减少，表明其消耗伴随着 β 细胞功能障碍。在Ins -Cre 的 β 细胞中条件性删除Pitpna ，Pitpna ^flox/flox小鼠会因葡萄糖刺激的胰岛素分泌 (GSIS) 减少和胰腺 β 细胞质量减少而导致高血糖。此外，人类胰岛中的PITPNA沉默证实了其在 PtdIns-4-P 合成中的作用，并导致胰岛素颗粒成熟和对接、GSIS 和胰岛素原加工受损，并有 ER 应激的证据。在 T2D 人类受试者的胰岛中恢复PITPNA可逆转这些 β 细胞缺陷，并将PITPNA确定为与 T2D 中 β 细胞衰竭相关的关键靶点。