Sitagliptin (MK0431) is an oral and highly selective Dipeptidyl peptidase-4 (DPP-4) inhibitor with an IC50 of 18nM[1]. DPP-4 is a serine protease that rapidly degrades the incretin hormones GLP-1 and GIP, making it a key therapeutic target for type 2 diabetes[2]. Sitagliptin is mainly used in type 2 diabetes research[3].
In vitro, Sitagliptin (100μM; 1h) abolished porcine DPP-IV–stimulated CD4⁺ T-cell migration and intracellular cAMP accumulation without altering basal PKA activity or GLP-1/GIP-mediated signaling[4]. In isolated human islets cultured for 10 weeks, Sitagliptin (1µM) increased functional β-cell number, raised insulin content, elevated PDX-1+/insulin+ and Nkx6.1+/insulin+ cells, increased Ki67+ β-cells, and lowered TUNEL+ apoptotic β-cells without changing α-cell mass[5].
In vivo, Sitagliptin (100mg/kg; i.p.; 1h before SAP induction) alleviated oxidative stress and excessive autophagy in lung tissue of WT mice with SAP-ALI, activated the p62–Keap1–Nrf2 pathway, and promoted Nrf2 nuclear translocation[6]. Sitagliptin (90mg/kg/day; orally; 180 days) reversed obesity-induced increases in visceral fat ratio, adipocyte size, macrophage infiltration, and serum IL-6, IL-1β, and TNF-α levels in high-fat-diet-fed immature mice[7].
References:
[1] Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F, Mark M. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther. 2008;325(1):175-182.
[2] Ahrén B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab. 2007;21(4):517-533.
[3] Scott LJ. Sitagliptin: A Review in Type 2 Diabetes. Drugs. 2017;77(2):209-224.
[4] Kim SJ, Nian C, Doudet DJ, McIntosh CH. Dipeptidyl peptidase IV inhibition with MK0431 improves islet graft survival in diabetic NOD mice partially via T-cell modulation. Diabetes. 2009;58(3):641-651.
[5] Liu W, Lau HK, Son DO, et al. Combined use of GABA and sitagliptin promotes human β-cell proliferation and reduces apoptosis. J Endocrinol. 2021;248(2):133-143.
[6] Kong L, Deng J, Zhou X, et al. Sitagliptin activates the p62-Keap1-Nrf2 signalling pathway to alleviate oxidative stress and excessive autophagy in severe acute pancreatitis-related acute lung injury. Cell Death Dis. 2021;12(10):928.
[7] Wang X, Weng W, Cui Y, Zou C. Sitagliptin Alleviates Obesity in Immature Mice by Inhibiting Oxidative Stress and Inflammation. Reprod Sci. 2024;31(11):3549-3559.
Sitagliptin (MK0431) 是一种口服、高选择性的二肽基肽酶-4（DPP-4）抑制剂，IC50为18nM[1]。DPP-4是一种丝氨酸蛋白酶，可快速降解肠促胰岛素GLP-1和GIP，因此成为2型糖尿病治疗的关键靶点[2]。Sitagliptin主要用于2型糖尿病的研究[3]。
在体外，Sitagliptin（100μM；1小时）可消除猪DPP-IV诱导的CD4⁺ T细胞迁移和细胞内cAMP积聚，而不影响基础PKA活性或GLP-1/GIP介导的信号传导[4]。在培养10周的分离人胰岛中，Sitagliptin（1μM）可增加功能性β细胞数量，提高胰岛素含量，增加PDX-1⁺/insulin⁺和Nkx6.1⁺/insulin⁺细胞比例，增加Ki67⁺ β细胞数量，并降低TUNEL⁺凋亡β细胞数量，但不改变α细胞质量[5]。
在体内，Sitagliptin（100mg/kg；腹腔注射；SAP诱导前1小时）可减轻WT小鼠SAP相关急性肺损伤（SAP-ALI）肺组织中的氧化应激和过度自噬，激活p62–Keap1–Nrf2通路，并促进Nrf2核转位[6]。Sitagliptin（90mg/kg/day；口服；180天）可逆转高脂饮食诱导的幼龄肥胖小鼠中内脏脂肪比例、脂肪细胞大小、巨噬细胞浸润以及血清IL-6、IL-1β和TNF-α水平的升高[7]。