Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Center for Metabolic Origins of Disease, Orlando, FL 32827, USA.
Cell Metab. 2017 Jan 10;25(1):152-165. doi: 10.1016/j.cmet.2016.10.007. Epub 2016 Nov 10.
Pharmacological inhibition of the dipeptidyl peptidase-4 (DPP4) enzyme potentiates incretin action and is widely used to treat type 2 diabetes. Nevertheless, the precise cells and tissues critical for incretin degradation and glucose homeostasis remain unknown. Here, we use mouse genetics and pharmacologic DPP4 inhibition to identify DPP4 cell types essential for incretin action. Although enterocyte DPP4 accounted for substantial intestinal DPP4 activity, ablation of enterocyte DPP4 in Dpp4 mice did not produce alterations in plasma DPP4 activity, incretin hormone levels, and glucose tolerance. In contrast, endothelial cell (EC)-derived DPP4 contributed substantially to levels of soluble plasma DPP4 activity, incretin degradation, and glucose control. Surprisingly, DPP4 cells of bone marrow origin mediated the selective degradation of fasting GIP, but not GLP-1. Collectively, these findings identify distinct roles for DPP4 in the EC versus the bone marrow compartment for selective incretin degradation and DPP4i-mediated glucoregulation.
二肽基肽酶-4（DPP4）酶的药理学抑制增强了肠促胰岛素的作用，被广泛用于治疗 2 型糖尿病。然而，对于肠促胰岛素降解和葡萄糖稳态至关重要的确切细胞和组织仍不清楚。在这里，我们使用小鼠遗传学和药理学 DPP4 抑制来鉴定肠促胰岛素作用所必需的 DPP4 细胞类型。尽管肠细胞 DPP4 占肠道 DPP4 活性的很大一部分，但在 Dpp4 小鼠中敲除肠细胞 DPP4 并没有改变血浆 DPP4 活性、肠促胰岛素激素水平和葡萄糖耐量。相比之下，内皮细胞（EC）衍生的 DPP4 对可溶性血浆 DPP4 活性、肠促胰岛素降解和葡萄糖控制水平有很大贡献。令人惊讶的是，骨髓来源的 DPP4 细胞介导了空腹 GIP 的选择性降解，但不是 GLP-1。总之，这些发现确定了 DPP4 在 EC 与骨髓隔室中对选择性肠促胰岛素降解和 DPP4i 介导的糖调节的不同作用。
