Taspoglutide (ITM077) is a novel analog of human glucagon-like peptide-1 [hGLP-1(7-36)NH2] in clinical development for the treatment of type 2 diabetes. Taspoglutide inhibits VEGFR2 in CHO cells with an IC50 value of 4.6±0.6nM[1,2]. Taspoglutide is a structural derivative of hGLP-1 with α-aminoisobutyric acid (Aib) substitutions replacing Ala8 and Gly35[1].
In vitro, Taspoglutide (0.001-100nM) stimulates insulin secretion in a glucose-dependent manner, enhancing secretion at high glucose (16.7mM) even at very low concentrations (0.001nM) in INS-1E rat insulinoma cells[1].
In vivo, Taspoglutide (0.4mg; s.c.; once-monthly for 12 weeks) significantly decreased food intake and body weight in hyperglycemic ApoE-/- mice[3]. Taspoglutide (0.4mg; s.c.; once-monthly for 12 weeks) treatment significantly increased levels of mRNA transcripts for the transcription factor liver X receptor (Lxr) as well as multiple LXR target genes, Abca1, Abcg5, Abcg1, and Abcg8, involved in cholesterol shuttling and clearance. Taspoglutide (0.4mg; s.c.; once-monthly for 12wk) also increased mRNA levels for hepatic lipase (Hl), a key enzyme in the regulation of triglyceride storage and clearance, as well as Cpt1a, a ratelimiting mitochondrial fatty acid carrier regulating the rate of free fatty acid β-oxidation in hyperglycemic ApoE-/- mice[3]. Taspoglutide Treatment (1mg; s.c.; once) significantly reduced proliferating pancreatic β-cells per islet cross-section in ZDF rats[4].
References:
[1]. Sebokova, Elena, et al. "Taspoglutide, an analog of human glucagon-like peptide-1 with enhanced stability and in vivo potency." Endocrinology 151.6 (2010): 2474-2482.
[2]. Rosenstock, Julio, et al. "The fate of taspoglutide, a weekly GLP-1 receptor agonist, versus twice-daily exenatide for type 2 diabetes: the T-emerge 2 trial." Diabetes care 36.3 (2013): 498-504.
[3]. Panjwani, Naim, et al. "GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE−/− mice." Endocrinology 154.1 (2013): 127-139.
[4]. Uhles, S., et al. "Taspoglutide, a novel human once‐weekly GLP‐1 analogue, protects pancreatic β‐cells in vitro and preserves islet structure and function in the Zucker diabetic fatty rat in vivo." Diabetes, Obesity and Metabolism 13.4 (2011): 326-336.
Taspoglutide (ITM077)是一种新型人胰高血糖素样肽-1类似物 [hGLP-1(7–36)NH₂]，目前正在用于2型糖尿病的临床开发。Taspoglutide是hGLP-1的结构衍生物，在Ala8和Gly35位点引入α-氨基异丁酸（Aib）取代[1]。在CHO 细胞中，Taspoglutide可抑制VEGFR2，其IC₅₀值为4.6±0.6nM[1]。
在体外实验中，Taspoglutide（0.001–100 nM）可呈葡萄糖依赖性地促进胰岛素分泌，在INS-1E大鼠胰岛瘤细胞中，即使在极低浓度（0.001nM）时，在高糖（16.7mM）条件下仍可显著增强胰岛素分泌[1]。
在体内实验中，Taspoglutide（0.4mg，皮下注射，每月一次，持续12周）可显著降低高血糖ApoE⁻/⁻小鼠的食物摄入量和体重[3]。给予Taspoglutide（0.4mg，皮下注射，每月一次，持续12周）可显著上调转录因子肝X受体（Lxr）以及多个参与胆固醇转运和清除的 LXR 靶基因（Abca1、Abcg1、Abcg5 和 Abcg8）的mRNA表达水平。此外，Taspoglutide 还可上调肝脂肪酶（Hl）（调控甘油三酯代谢的关键酶）以及肉碱棕榈酰转移酶1A（Cpt1a）（参与脂肪酸β-氧化的线粒体限速转运蛋白）的 mRNA 表达水平[3]。在ZDF大鼠中，Taspoglutide（1mg，皮下注射，单次给药）可显著减少每个胰岛横截面中处于增殖状态的胰腺β细胞数量[4]。