O'Harte Finbarr P M, Parthsarathy Vadivel, Hogg Christopher, Flatt Peter R
School of Biomedical Sciences, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine BT52 1SA, UK.
School of Biomedical Sciences, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine BT52 1SA, UK.
Biochem Pharmacol. 2017 Dec 15;146:165-173. doi: 10.1016/j.bcp.2017.10.002. Epub 2017 Oct 4.
The adipokine, apelin has many biological functions but its activity is curtailed by rapid plasma degradation. Fatty acid derived apelin analogues represent a new and exciting avenue for the treatment of obesity-diabetes. This study explores four novel fatty acid modified apelin-13 analogues, namely, (LysGluPAL)apelin-13 amide, pGlu(LysGluPAL)apelin-13 amide, LysGluPAL(Tyr)apelin-13 and LysGluPAL(Val)apelin-13. Fatty acid modification extended the half-life of native apelin-13 to >24 h in vitro. pGlu(LysGluPAL)apelin-13 amide was the most potent insulinotropic analogue in BRIN-BD11 cells and isolated islets with maximal stimulatory effects of up to 2.7-fold (p < .001). (LysGluPAL)apelin-13 amide (1.9-fold) and LysGluPAL(Tyr)apelin-13 (1.7-fold) were less effective, whereas LysGluPAL(Val)apelin-13 had an inhibitory effect on insulin secretion. Similarly, pGlu(LysGluPAL)apelin-13 amide was most potent in increasing beta-cell intracellular Ca concentrations (1.8-fold, p < .001) and increasing glucose uptake in 3T3-L1 adipocytes (2.3-fold, p < .01). Persistent biological action was observed with both pGlu(LysGluPAL)apelin-13 amide and (LysGluPAL)apelin-13 amide significantly reducing blood glucose (39-43%, p < .01) and enhancing insulin secretion (43-56%, p < .001) during glucose tolerance tests in diet-induced obese mice. pGlu(LysGluPAL)apelin-13 amide and (LysGluPAL)apelin-13 amide also inhibited feeding (28-40%, p < .001), whereas LysGluPAL(Val)apelin-13 increased food intake (8%, p < .05) in mice. These data indicate that novel enzymatically stable analogues of apelin-13 may be suitable for future development as therapeutic agents for obesity-diabetes.
脂肪因子Apelin具有多种生物学功能，但其活性会因血浆快速降解而受到限制。脂肪酸衍生的Apelin类似物为肥胖-糖尿病的治疗提供了一条新的、令人兴奋的途径。本研究探索了四种新型脂肪酸修饰的Apelin-13类似物，即（LysGluPAL）Apelin-13酰胺、pGlu（LysGluPAL）Apelin-13酰胺、LysGluPAL（Tyr）Apelin-13和LysGluPAL（Val）Apelin-13。脂肪酸修饰使天然Apelin-13在体外的半衰期延长至>24小时。pGlu（LysGluPAL）Apelin-13酰胺是BRIN-BD11细胞和分离胰岛中最有效的促胰岛素类似物，最大刺激作用高达2.7倍（p<0.001）。（LysGluPAL）Apelin-13酰胺（1.9倍）和LysGluPAL（Tyr）Apelin-13（1.7倍）效果较差，而LysGluPAL（Val）Apelin-13对胰岛素分泌有抑制作用。同样，pGlu（LysGluPAL）Apelin-13酰胺在增加β细胞内钙浓度（1.8倍，p<0.001）和增加3T3-L1脂肪细胞葡萄糖摄取（2.3倍，p<0.01）方面最有效。在饮食诱导的肥胖小鼠的葡萄糖耐量试验中，观察到pGlu（LysGluPAL）Apelin-13酰胺和（LysGluPAL）Apelin-13酰胺都具有持续的生物学作用，显著降低血糖（39-43%，p<0.01）并增强胰岛素分泌（43-56%，p<0.001）。pGlu（LysGluPAL）Apelin-13酰胺和（LysGluPAL）Apelin-13酰胺也抑制进食（28-40%，p<0.001），而LysGluPAL（Val）Apelin-13增加小鼠食物摄入量（8%，p<0.05）。这些数据表明，新型酶稳定的Apelin-13类似物可能适合未来作为肥胖-糖尿病治疗药物进行开发。
