Dipeptidyl peptidase-4 (DPP-4), a ubiquitous proteolytic enzyme, inhibits insulin secretion from pancreatic beta cells by inactivating circulating incretin hormones GLP-1 and GIP. High circulating levels of DPP-4 is presumed to compromise insulin secretion in people with type 2 diabetes (T2D). Our group recently reported lipid induced DPP-4 expression in pancreatic beta cells, mediated by the TLR4-NFkB pathway. In the present study, we looked at the role of Vildagliptin on pancreatic DPP-4 inhibition, preservation of islet mass and restoration of insulin secretion. MIN6 mouse insulinoma cells incubated with palmitate and fetuin-A, a proinflammatory organokine associated with insulin resistance, showed activation of TLR4-NFkB pathway, which was rescued on Vildagliptin treatment. In addition, Vildagliptin, by suppressing palmitate-fetuin-A mediated DPP-4 expression in MIN6, prevented the secretion of IL-1beta and fetuin-A in the culture media. DPP-4 siRNA abrogated TLR4-NFkB pathway mediated islet cell inflammation. Vildagliptin also reduced palmitate-fetuin-A mediated intracellular lipid accumulation in MIN6 and isolated islets from high fat fed (HFD) mice as observed by Oil O Red staining with downregulation of CD36 and PPARgamma. Vildagliptin also preserved islet mass and rescued insulin secretory defect in HFD mice. Our results suggest that inhibition of DPP-4 by Vildagliptin protects pancreatic beta cells from the deleterious effects of lipid and fetuin-A, preserves insulin secretory functions and improves hyperglycemia.

二肽基肽酶-4 (DPP-4) 是一种普遍存在的蛋白水解酶，通过灭活循环肠促胰岛素激素 GLP-1 和 GIP 来抑制胰腺 β 细胞的胰岛素分泌。据推测，DPP-4 的高循环水平会损害 2 型糖尿病 (T2D) 患者的胰岛素分泌。我们的小组最近报道了由 TLR4-NFkB 通路介导的脂质诱导的胰腺 β 细胞中的 DPP-4 表达。在本研究中，我们研究了维格列汀对胰腺 DPP-4 抑制、胰岛质量保存和胰岛素分泌恢复的作用。 MIN6小鼠胰岛素瘤细胞与棕榈酸酯和胎球蛋白-A（一种与胰岛素抵抗相关的促炎性器官因子）一起培养，显示出TLR4-NFkB通路的激活，维格列汀治疗可挽救该通路。此外，维格列汀通过抑制 MIN6 中棕榈酸酯-胎球蛋白-A 介导的 DPP-4 表达，阻止培养基中 IL-1β 和胎球蛋白-A 的分泌。 DPP-4 siRNA消除了 TLR4-NFkB 通路介导的胰岛细胞炎症。通过油 O 红染色观察到，维格列汀还减少了 MIN6 中棕榈酸胎球蛋白 A 介导的细胞内脂质积累，并从高脂喂养 (HFD) 小鼠中分离出胰岛，并下调了 CD36和PPARgamma。维格列汀还保留了 HFD 小鼠的胰岛质量并挽救了胰岛素分泌缺陷。我们的结果表明，维格列汀抑制 DPP-4 可保护胰腺 β 细胞免受脂质和胎球蛋白 A 的有害影响，保留胰岛素分泌功能并改善高血糖。