SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
Diabetologia. 2012 Oct;55(10):2747-2758. doi: 10.1007/s00125-012-2654-6. Epub 2012 Jul 20.
AIMS/HYPOTHESIS: Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8.
The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice.
(pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p < 0.05 to p < 0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p < 0.01 to p < 0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p < 0.05 to p < 0.001), accumulated food intake (p < 0.05 to p < 0.001), non-fasting glucose (p < 0.05) and triacylglycerol deposition in pancreatic (p < 0.01), adipose (p < 0.05) and liver (p < 0.001) tissue, and improved oral (p < 0.05) and i.p. (p < 0.05) glucose tolerance and insulin sensitivity (p < 0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology.
CONCLUSIONS/INTERPRETATION: These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.
目的/假设：胆囊收缩素（CCK）是一种快速降解的胃肠道肽，可刺激饱腹感和胰岛素分泌。我们旨在研究新型 N 端修饰的 CCK 类似物（pGlu-Gln）-CCK-8 的有益减肥和代谢作用。
在胰腺克隆 BRIN BD11 细胞中和高脂肪喂养和 ob/ob 小鼠体内全面评估（pGlu-Gln）-CCK-8 的生物学作用。
（pGlu-Gln）-CCK-8 完全抵抗酶降解，其饱腹感作用明显（p < 0.05 至 p < 0.001）比 CCK-8 更有效。在 BRIN-BD11 细胞中，（pGlu-Gln）-CCK-8 与 CCK-8 相比，胰岛素促分泌作用增强（p < 0.01 至 p < 0.001）。当急性给予高脂肪喂养或 ob/ob 小鼠时，（pGlu-Gln）-CCK-8 改善了葡萄糖稳态。在高脂肪喂养的小鼠中，每天两次皮下注射（pGlu-Gln）-CCK-8 28 天，可显著降低体重（p < 0.05 至 p < 0.001）、积累的食物摄入量（p < 0.05 至 p < 0.001）、非禁食血糖（p < 0.05）以及胰腺（p < 0.01）、脂肪（p < 0.05）和肝脏（p < 0.001）组织中的三酰甘油沉积，并改善口服（p < 0.05）和腹腔内（p < 0.05）葡萄糖耐量和胰岛素敏感性（p < 0.001）。在给予（pGlu-Gln）-CCK-8 的 ob/ob 小鼠中也观察到类似的观察结果。此外，这些有益作用不能通过简单的饮食限制来复制，也与能量消耗的变化无关。（pGlu-Gln）-CCK-8 没有产生耐药性的证据，对接受（pGlu-Gln）-CCK-8 治疗的小鼠的胰腺、肝脏和肾功能的组织学或血液标志物分析表明，几乎没有异常病理学。
结论/解释：这些研究强调了（pGlu-Gln）-CCK-8 缓解肥胖和胰岛素抵抗的潜力。
