Exendin-4 is a 39-amino-acid polypeptide (48-86) and a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist with an IC50 of 3.22 nM[1]. The mechanism of action of Exendin-4 is by binding to the GLP-1 receptor, activating adenylyl cyclase, increasing intracellular cAMP levels, and ultimately promoting insulin secretion while inhibiting glucagon secretion [2]. Exendin-4 has the effect of lowering blood pressure and inducing aortic vasodilation [3].
In vitro, Exendin-4 (0-20nM) incubated HUVEC cells for 15 minutes, which induced a dose-dependent increase in intracellular cAMP concentration, and Exendin-4 (20nM) increased the production of NO in HUVEC cells and increased p-eNOS and GTPCH1 levels [4]. Exendin-4 (0-10μM) treated MCF-7 cells for 48 hours, which had a significant cytotoxic effect with an IC50 of 5μM and reduced the expression of caspase-9, Akt and MMP2 in the cells [5].
In vivo, exendin-4 (10μg/kg or 20μg/kg) was used to treat obese mice via subcutaneous injection for 60 days, which improved serum ALT, reduced serum glucose and insulin levels, and mice in the low-dose group lost weight. 7%, and the body weight of mice in the high-dose group decreased by 14%[6]. Exendin-4 (10 μg/kg) treated SD rats by subcutaneous injection for 75 days, reduced body weight by approximately 30%, significantly reduced insulin, adiponectin, and leptin levels, but caused pancreatic acinar inflammation and pus toxicosis[7].
References:
[1] Doyle M E, Theodorakis M J, Holloway H W, et al. The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity[J]. Regulatory peptides, 2003, 114(2-3): 153-158.
[2] Doyle M E, Egan J M. Mechanisms of action of glucagon-like peptide 1 in the pancreas[J]. Pharmacology & therapeutics, 2007, 113(3): 546-593.
[3] Sélley E, Kun S, Szijártó I A, et al. Exenatide induces aortic vasodilation increasing hydrogen sulphide, carbon monoxide and nitric oxide production[J]. Cardiovascular Diabetology, 2014, 13: 1-9.
[4]Wei R, Ma S, Wang C, et al. Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner[J]. American Journal of Physiology-Endocrinology and Metabolism, 2016, 310(11): E947-E957.
[5]Fidan-Yaylalı G, Dodurga Y, Seçme M, et al. Antidiabetic exendin-4 activates apoptotic pathway and inhibits growth of breast cancer cells[J]. Tumor Biology, 2016, 37: 2647-2653.
[6]Ding X, Saxena N K, Lin S, et al. Exendin‐4, a glucagon‐like protein‐1 (GLP‐1) receptor agonist, reverses hepatic steatosis in ob/ob mice[J]. Hepatology, 2006, 43(1): 173-181.
[7]Nachnani J S, Bulchandani D G, Nookala A, et al. Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas[J]. Diabetologia, 2010, 53: 153-159.
Exendin-4是由39个氨基酸（48-86）组成的多肽，是一种长效的胰高血糖素样肽-1（GLP-1）受体激动剂，IC50为3.22 nM[1]。Exendin-4的作用机制是通过与GLP-1受体结合，激活腺苷酸环化酶，增加细胞内cAMP水平，最终促进胰岛素的分泌，同时抑制胰高血糖素的分泌[2]。Exendin-4具有降低血压，诱导主动脉血管舒张的作用[3]。
在体外，Exendin-4（0-20nM）孵育HUVEC细胞15分钟，诱导了细胞内cAMP浓度呈剂量依赖性增加，且Exendin-4（20nM）增加了HUVEC细胞内NO的产生，升高了p-eNOS和GTPCH1水平[4]。Exendin-4（0-10μM）处理MCF-7细胞48 h，具有显著的细胞毒性作用，IC50为5μM，且降低了细胞中caspase-9、Akt和MMP2的表达[5]。
在体内，Exendin-4（10 μg/kg或20 μg/kg）通过皮下注射治疗肥胖小鼠，持续60天，均改善了血清ALT，降低了血清葡萄糖和胰岛素水平，低剂量组小鼠体重减少7%，高剂量组小鼠体重减少14%[6]。Exendin-4（10μg/kg）通过皮下注射处理SD大鼠，持续75天，体重减轻了约30%，显著降低了胰岛素、脂联素和瘦素水平，但会导致胰腺腺泡炎症和脓毒症[7]。