Khan Dawood, Vasu Srividya, Moffett R Charlotte, Irwin Nigel, Flatt Peter R
From the SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK.
Pancreas. 2018 Feb;47(2):190-199. doi: 10.1097/MPA.0000000000000983.
Modulation of cholecystokinin (CCK) receptors has been shown to influence pancreatic endocrine function.
We assessed the impact of the CCKA and CCKB receptor modulators, (pGlu-Gln)-CCK-8 and gastrin-17, respectively, on β-cell secretory function, proliferation and apoptosis and glucose tolerance, and investigating alterations of CCK and gastrin islet expression in diabetes.
Initially, the presence of CCK and gastrin, and expression of their receptors were evidenced in β-cell lines and mouse islets. (pGlu-Gln)-CCK-8 and gastrin-17 stimulated insulin secretion from BRIN-BD11 and 1.1B4 β-cells, associated with no effect on membrane potential or [Ca]i. Only (pGlu-Gln)-CCK-8 possessed insulin secretory actions in isolated islets. In agreement, (pGlu-Gln)-CCK-8 improved glucose disposal and glucose-induced insulin release in mice. In addition, (pGlu-Gln)-CCK-8 evoked clear satiety effects. Interestingly, islet colocalization of CCK with glucagon was elevated in streptozotocin- and hydrocortisone-induced diabetic mice, whereas gastrin coexpression in α cells was reduced. In contrast, gastrin colocalization within β-cells was higher in diabetic mice, while CCK coexpression with insulin was decreased in insulin-deficient mice. (pGlu-Gln)-CCK-8 and gastrin-17 also augmented human and rodent β-cell proliferation and offered protection against streptozotocin-induced β-cell cytotoxicity.
We highlight the direct involvement of CCKA and CCKB receptors in pancreatic β-cell function and survival.
胆囊收缩素（CCK）受体的调节已被证明会影响胰腺内分泌功能。
我们分别评估了CCKA和CCKB受体调节剂（pGlu-Gln）-CCK-8和胃泌素-17对β细胞分泌功能、增殖和凋亡以及葡萄糖耐量的影响，并研究糖尿病中CCK和胃泌素胰岛表达的变化。
最初，在β细胞系和小鼠胰岛中证实了CCK和胃泌素的存在及其受体的表达。（pGlu-Gln）-CCK-8和胃泌素-17刺激BRIN-BD11和1.1B4β细胞分泌胰岛素，且对膜电位或细胞内钙浓度无影响。只有（pGlu-Gln）-CCK-8在分离的胰岛中具有胰岛素分泌作用。同样，（pGlu-Gln）-CCK-8改善了小鼠的葡萄糖代谢和葡萄糖诱导的胰岛素释放。此外，（pGlu-Gln）-CCK-8引起明显的饱腹感。有趣的是，在链脲佐菌素和氢化可的松诱导的糖尿病小鼠中，CCK与胰高血糖素在胰岛中的共定位升高，而α细胞中胃泌素的共表达降低。相反，糖尿病小鼠β细胞内胃泌素的共定位较高，而胰岛素缺乏小鼠中CCK与胰岛素的共表达降低。（pGlu-Gln）-CCK-8和胃泌素-17还增强了人和啮齿动物β细胞的增殖，并提供了对链脲佐菌素诱导的β细胞细胞毒性的保护作用。
我们强调CCKA和CCKB受体直接参与胰腺β细胞的功能和存活。
