Adomeglivant (LY2409021) is a potent, selective, orally administered, competitive, small-molecule antagonist of the glucagon receptor, with a Ki value of 6.66nM [1]. Adomeglivant blocks the glucagon signalling to cause a reduction of fasting and postprandial glucose[2]. Adomeglivant has been widely used to improve lipid levels and insulin resistance in mouse models of diabetes[3].
In vitro, Adomeglivant pretreatment for 20min blocked the effect of enhancing cAMP levels of glucagon (1nM) in HEK293-GLP-1R cells transfected with H188 plasmid, with an IC50 value of 1.2µM[4]. Treatment with 50μM Adomeglivant for 24h significantly inhibited the glucagon pathway in Japanese flounder liver cells, reduced glucose production in the cells, and resulted in a significant increase in the concentrations of lactate and pyruvate [5]. Adomeglivant treatment at 2μM for 24h significantly reduced ceramide levels and inhibited glucagon-stimulated lipotoxic apoptosis in H9c2 cells overexpressing glucagon receptor, as indicated by reduced cleaved caspase-3 levels[6].
In vivo, a single dose of Adomeglivant (5mg/kg) administered intraperitoneally for 30min inhibited the increase in blood glucose induced by clozapine N-oxide (3mg/kg; i.p.) [7]. Intraperitoneal administration of Adomeglivant at a dose of 2mg/kg/week for two consecutive weeks significantly reduced AMPK pathway activation and promoted p21Cip1 and p16Ink4a expression in islets of treadmill-trained mice[8].
References:
[1] Kelly R P, Garhyan P, Raddad E, et al. Short‐term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes[J]. Diabetes, Obesity and Metabolism, 2015, 17(4): 414-422.
[2] Kelly R P, Garhyan P, Raddad E, et al. Short‐term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes[J]. Diabetes, Obesity and Metabolism, 2015, 17(4): 414-422.
[3] Honzawa N, Fujimoto K, Kitamura T. Cell autonomous dysfunction and insulin resistance in pancreatic α cells[J]. International Journal of Molecular Sciences, 2019, 20(15): 3699.
[4] Chepurny O G, Matsoukas M T, Liapakis G, et al. Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP[J]. Journal of Biological Chemistry, 2019, 294(10): 3514-3531.
[5] Yang M, Pan M, Huang D, et al. Glucagon promotes gluconeogenesis through the GCGR/PKA/CREB/PGC-1α pathway in hepatocytes of the Japanese flounder Paralichthys olivaceus[J]. Cells, 2023, 12(7): 1098.
[6] Li L, Huang K, Wang D, et al. Chlorogenic acid and ferulic acid in SMYAD alleviate diabetic cardiomyopathy by inhibiting cardiac lipotoxicity via GCGR/PPARα and GCGR/AMPK pathways[J]. Phytomedicine, 2025: 156906.
[7] Kim A, Knudsen J G, Madara J C, et al. Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes[J]. Elife, 2021, 10: e72919.
[8] Carapeto P, Iwasaki K, Hela F, et al. Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence[J]. Nature metabolism, 2024, 6(10): 1976-1990.
Adomeglivant (LY2409021)是一种强效、选择性、口服给药的竞争性小分子胰高血糖素受体拮抗剂，Ki值为6.66nM[1]。Adomeglivant通过阻断胰高血糖素信号传导，有效降低空腹及餐后血糖水平[2]。Adomeglivant已广泛应用于糖尿病小鼠模型中改善血脂水平和胰岛素抵抗[3]。
在体外，使用Adomeglivant预处理转染H188质粒的HEK293-GLP-1R细胞20分钟，可阻断1nM的胰高血糖素提高cAMP水平的作用，IC50值为1.2µM[4]。用50μM的Adomeglivant处理Japanese flounder肝细胞24小时，能显著抑制胰高血糖素通路，减少细胞葡萄糖生成，并显著提高乳酸和丙酮酸浓度[5]。以2μM的Adomeglivant处理过表达胰高血糖素受体的H9c2细胞24小时，可降低神经酰胺水平，并通过减少裂解型caspase-3抑制胰高血糖素刺激的脂毒性凋亡[6]。
在体内，单次腹腔注射5mg/kg剂量的Adomeglivant 30分钟，能抑制clozapine N-oxide(3mg/kg; i.p.)诱导的小鼠血糖升高[7]。连续两周每周腹腔注射2mg/kg/week剂量的Adomeglivant，可降低跑步机训练小鼠胰岛中AMPK通路的活化，并促进p21Cip1和p16Ink4a的表达[8]。