The SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, UK.
The SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, UK.
Peptides. 2018 Feb;100:219-228. doi: 10.1016/j.peptides.2017.12.004.
Nine structurally modified apelin-13 analogues were assessed for their in vitro and acute in vivo antidiabetic potential. Stability was assessed in mouse plasma and insulinotropic efficacy tested in cultured pancreatic BRIN-BD11 cells and isolated mouse pancreatic islets. Intracellular Ca and cAMP production in BRIN-BD11 cells was determined, as was glucose uptake in 3T3-L1 adipocytes. Acute antihyperglycemic effects of apelin analogues were assessed following i.p. glucose tolerance tests (ipGGT, 18 mmol/kg) in normal and diet-induced-obese (DIO) mice and on food intake in normal mice. Apelin analogues all showed enhanced in vitro stability (up to 5.8-fold, t½ = 12.8 h) in mouse plasma compared to native apelin-13 (t½ = 2.1 h). Compared to glucose controls, stable analogues exhibited enhanced insulinotropic responses from BRIN-BD11 cells (up to 4.7-fold, p < 0.001) and isolated mouse islets (up to 5.3-fold) for 10 M apelin-13 amide (versus 7.6-fold for 10 M GLP-1). Activation of APJ receptors on BRIN-BD11 cells increased intracellular Ca (up to 3.0-fold, p < 0.001) and cAMP (up to 1.7-fold, p < 0.01). Acute ipGTT showed improved insulinotropic and glucose disposal responses in normal and DIO mice (p < 0.05 and p < 0.01, respectively). Apelin-13 amide and (pGlu)apelin-13 amide were the most effective analogues exhibiting acute, dose-dependent and persistent biological actions. Both analogues stimulated insulin-independent glucose uptake by differentiated adipocytes (2.9-3.3-fold, p < 0.05) and inhibited food intake (26-33%, p < 0.001), up to 180 min in mice, versus saline. In contrast, (Ala)apelin-13 and (Val)apelin-13 inhibited insulin secretion, suppressed beta-cell signal transduction and stimulated food intake in mice. Thus, stable analogues of apelin-13 have potential for diabetes/obesity therapy.
评估了 9 种结构修饰的 apelin-13 类似物的体外和急性体内抗糖尿病潜力。在小鼠血浆中评估了稳定性，并在培养的胰腺 BRIN-BD11 细胞和分离的小鼠胰岛中测试了胰岛素促分泌作用。测定了 BRIN-BD11 细胞中的细胞内 Ca 和 cAMP 产生，以及 3T3-L1 脂肪细胞中的葡萄糖摄取。在正常和饮食诱导肥胖 (DIO) 小鼠的腹腔葡萄糖耐量试验 (ipGGT，18mmol/kg) 后，以及在正常小鼠的食物摄入中，评估了 apelin 类似物的急性降血糖作用。与天然 apelin-13 (t1/2=2.1h) 相比，类似物在小鼠血浆中的体外稳定性均得到增强（高达 5.8 倍，t1/2=12.8h）。与葡萄糖对照相比，稳定类似物对 BRIN-BD11 细胞（高达 4.7 倍，p<0.001）和分离的小鼠胰岛（高达 5.3 倍）的胰岛素促分泌作用增强，而 10μM apelin-13 酰胺（10μM GLP-1 的 7.6 倍）。APJ 受体在 BRIN-BD11 细胞中的激活增加了细胞内 Ca（高达 3.0 倍，p<0.001）和 cAMP（高达 1.7 倍，p<0.01）。急性 ipGTT 显示在正常和 DIO 小鼠中胰岛素促分泌和葡萄糖处置反应得到改善（分别为 p<0.05 和 p<0.01）。apelin-13 酰胺和（pGlu）apelin-13 酰胺是最有效的类似物，具有急性、剂量依赖性和持续的生物学作用。两种类似物均刺激分化脂肪细胞的胰岛素非依赖性葡萄糖摄取（2.9-3.3 倍，p<0.05），并抑制食物摄入（26-33%，p<0.001），在小鼠中持续 180min，而盐水无作用。相比之下，（Ala）apelin-13 和（Val）apelin-13 抑制胰岛素分泌，抑制β细胞信号转导并刺激小鼠食物摄入。因此，apelin-13 的稳定类似物具有治疗糖尿病/肥胖症的潜力。
