Dulaglutide (LY2189265)

Dulaglutide (LY-2189265) is a novel, long-acting glucagon-like peptide 1 (GLP-1) analog for the treatment of type 2 diabetes mellitus (T2DM) ^[1].

Dulaglutide (LY2189265) significantly decreased hepatic lipid accumulation and reduced the expression of genes associated with lipid droplet binding proteins, de novo lipogenesis, and TG synthesis in PA-treated HepG2 cells. Dulaglutide (LY2189265) also increased the expression of proteins associated with lipolysis and fatty acid oxidation and FAM3A in PA-treated cells^[8].Dulaglutide (LY2189265) significantly promoted microglia to phagocytose and get rid of the Aβ plague. Additionally, Dulaglutide (LY2189265) treatment inhibited the production of pro-inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin -1β, and IL-6, whereas increased the load of anti-inflammatory molecules such as IL-10 affected by Aβ1-42 exposure^[9].

Dulaglutide (LY2189265) administration attenuated muscle wasting and restored muscle strength by reducing inflammation through the OPA-1-TLR-9 signaling pathway in the tibialis anterior (TA) and quadriceps (QD) muscles of aged mice^[3]. Dulaglutide (LY2189265) may reduce the hyperandrogenemia of PCOS rats by regulating the content of serum SHBG and the expression of 3βHSD, CYP19α1, and StAR related genes and proteins, thereby inhibiting the excessive development of small follicles and the formation of cystic follicles in the ovaries of PCOS rats, thereby improving polycystic ovary in PCOS rats^[4]. Dulaglutide (LY2189265) improves learning and memory ability in 9-week-old male wild-type C57/BL6 mice (AD mice)^[2].

After subcutaneous injection, Dulaglutide (LY2189265) was slowly absorbed and tmax at steady state ranged from 24 to 72 h (median = 48 h) ^[5，6]. The absolute bioavailability was 47% and the half-life was estimated at 4.7 days. Steady state was achieved between 2 and 4 weeks of dosing and the accumulation ratio was approximately 1.56^[7].

References:
[1]:Jimenez-Solem E, Rasmussen MH, et,al. Dulaglutide, a long-acting GLP-1 analog fused with an Fc antibody fragment for the potential treatment of type 2 diabetes. Curr Opin Mol Ther. 2010 Dec;12(6):790-7. PMID: 21154170.
[2]: Jiang Guo-Jing, ZHOU Mei, et,al. Protective effects of dura glycopeptide on learning and memory loss and synaptic degeneration in AD mice [J]. Medical theory & practice,2021,34(14):2365-2368.
[3]: Khin PP, Hong Y, et,al. Dulaglutide improves muscle function by attenuating inflammation through OPA-1-TLR-9 signaling in aged mice. Aging (Albany NY). 2021 Sep 19;13(18):21962-21974. doi: 10.18632/aging.203546. Epub 2021 Sep 19. PMID: 34537761; PMCID: PMC8507261.
[4]: Wu LM, Wang YX, et,al. Dulaglutide, a long-acting GLP-1 receptor agonist, can improve hyperandrogenemia and ovarian function in DHEA-induced PCOS rats. Peptides. 2021 Nov;145:170624. doi: 10.1016/j.peptides.2021.170624. Epub 2021 Aug 8. PMID: 34375684.
[5]: Barrington P, Chien JY, et,al. A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes. Diabetes Obes Metab. 2011 May;13(5):426-33. doi: 10.1111/j.1463-1326.2011.01364.x. Epub 2011 Jan 19. PMID: 21251178.
[6]: Barrington P, Chien JY, et,al. LY2189265, a long-acting glucagon-like peptide-1 analogue, showed a dose-dependent effect on insulin secretion in healthy subjects. Diabetes Obes Metab. 2011 May;13(5):434-8. doi: 10.1111/j.1463-1326.2011.01365.x. Epub 2011 Jan 19. PMID: 21251179.
[7]: Scheen AJ. Dulaglutide (LY-2189265) for the treatment of type 2 diabetes. Expert Rev Clin Pharmacol. 2016;9(3):385-99. doi: 10.1586/17512433.2016.1141046. Epub 2016 Feb 6. PMID: 26761217.
[8]: Lee J, Hong SW, et,al. Dulaglutide Ameliorates Palmitic Acid-Induced Hepatic Steatosis by Activating FAM3A Signaling Pathway. Endocrinol Metab (Seoul). 2022 Feb;37(1):74-83. doi: 10.3803/EnM.2021.1293. Epub 2022 Feb 9. PMID: 35144334; PMCID: PMC8901965.
[9]: Wang Y, Han B. Dulaglutide Alleviates Alzheimer's Disease by Regulating Microglial Polarization and Neurogenic Activity. Comb Chem High Throughput Screen. 2022 Jul 26. doi: 10.2174/1386207325666220726163514. Epub ahead of print. PMID: 35894460.

Dulaglutide (LY-2189265) 是一种新型长效胰高血糖素样肽 1 (GLP-1) 类似物,用于治疗 2 型糖尿病 (T2DM) ^[1]。\n

Dulaglutide (LY2189265) 在 PA 处理的 HepG2 细胞中显着降低肝脏脂质积累并降低与脂滴结合蛋白、从头脂肪生成和 TG 合成相关的基因表达。 Dulaglutide (LY2189265) 还增加了 PA 处理的细胞中与脂肪分解和脂肪酸氧化相关的蛋白质和 FAM3A 的表达^[8]。Dulaglutide (LY2189265) 显着促进小胶质细胞吞噬并清除 Aβ瘟疫。此外,Dulaglutide (LY2189265) 治疗抑制了促炎因子的产生,包括肿瘤坏死因子 (TNF)-α、白细胞介素 -1β 和 IL-6,同时增加了抗炎分子的负荷,例如受到影响的 IL-10通过 Aβ1-42 暴露^[9].

Dulaglutide (LY2189265) 通过 OPA-1-TLR-9 信号通路减少老年小鼠胫骨前肌 (TA) 和股四头肌 (QD) 肌肉中的炎症,从而减轻肌肉萎缩并恢复肌肉力量^{[3 ]}。 Dulaglutide (LY2189265)可能通过调节血清SHBG的含量和3βHSD、CYP19α1、StAR相关基因和蛋白的表达来减轻PCOS大鼠的高雄激素血症,从而抑制卵巢小卵泡的过度发育和囊性卵泡的形成PCOS大鼠,从而改善PCOS大鼠多囊卵巢^[4]。 Dulaglutide (LY2189265) 改善 9 周龄雄性野生型 C57/BL6 小鼠（AD 小鼠）的学习和记忆能力^[2]。

Dulaglutide (LY2189265) 皮下注射后吸收缓慢,稳态 tmax 为 24 至 72 h（中位数 = 48 h）^[5,6]。绝对生物利用度为 47%,半衰期估计为 4.7 天。给药2-4周达到稳态,蓄积率约为1.56^[7]。

Dulaglutide (LY2189265) 在 PA 处理的 HepG2 细胞中显着降低肝脏脂质积累并降低与脂滴结合蛋白、从头脂肪生成和 TG 合成相关的基因表达。 Dulaglutide (LY2189265) 还增加了 PA 处理的细胞中与脂肪分解和脂肪酸氧化相关的蛋白质和 FAM3A 的表达^[8]。Dulaglutide (LY2189265) 显着促进小胶质细胞吞噬并清除 Aβ瘟疫。此外,Dulaglutide (LY2189265) 治疗抑制了促炎因子的产生,包括肿瘤坏死因子 (TNF)-α、白细胞介素 -1β 和 IL-6,同时增加了抗炎分子的负荷,例如受到影响的 IL-10通过 Aβ1-42 暴露^[9].

Dulaglutide (LY2189265) 通过 OPA-1-TLR-9 信号通路减少老年小鼠胫骨前肌 (TA) 和股四头肌 (QD) 肌肉中的炎症,从而减轻肌肉萎缩并恢复肌肉力量^{[3 ]}。 Dulaglutide (LY2189265)可能通过调节血清SHBG的含量和3βHSD、CYP19α1、StAR相关基因和蛋白的表达来减轻PCOS大鼠的高雄激素血症,从而抑制卵巢小卵泡的过度发育和囊性卵泡的形成PCOS大鼠,从而改善PCOS大鼠多囊卵巢^[4]。 Dulaglutide (LY2189265) 改善 9 周龄雄性野生型 C57/BL6 小鼠（AD 小鼠）的学习和记忆能力^[2]。

Dulaglutide (LY2189265) 皮下注射后吸收缓慢,稳态 tmax 为 24 至 72 h（中位数 = 48 h）^[5,6]。绝对生物利用度为 47%,半衰期估计为 4.7 天。给药2-4周达到稳态,蓄积率约为1.56^[7]。