Shahbazian Mohammad, Jafarynezhad Faezeh, Yadeghari Maryam, Farhadi Zeinab, Samani Sanaz Lotfi, Esmailidehaj Mansour, Safari Fatemeh, Azizian Hossein
Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Department of Anatomy and Cell Biology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
J Basic Clin Physiol Pharmacol. 2022 Feb 15;34(2):205-213. doi: 10.1515/jbcpp-2021-0374. eCollection 2023 Mar 1.
Diabetic cardiometabolic disorders are characterized by significant changes in cardiac metabolism and are increased in postmenopausal women, which emphasize the role of 17-estradiol (E2). Despite this, there are few safe and effective pharmacological treatments for these disorders. The role of G protein-coupled estrogen receptor (GPR30), which mediates the non-genomic effects of E2, is mostly unexplored.
In this study, we used ovariectomy (menopausal model) and type 2 diabetic (T2D) rats' models to evaluate the preclinical action of G-1 (GPR30 agonist) against cardiometabolic disorders. T2D was induced by a high-fat diet and a low dose of streptozotocin. G-1 was administrated for six weeks after the establishment of T2D.
We found that G-1 counteracts the effects of T2D and ovariectomy by increasing the body weight, reducing fasting blood sugar, heart weight, and heart weight to body weight ratio. Also, both ovariectomy and T2D led to decreases in the cardiac protein levels of hexokinase 2 (HK2) and GLUT4, while G-1-treated female rats reversed these changes and only increased HK2 protein level. In addition, T2D and ovariectomy increased glucose and glycogen content in the heart, but G-1 treatment significantly reduced them.
In conclusion, our work demonstrates that G-1 as a selective GPR30 agonist is a viable therapeutic approach against T2D and cardiometabolic diseases in multiple preclinical female models.
糖尿病心脏代谢紊乱的特征是心脏代谢发生显著变化，且在绝经后女性中更为常见，这凸显了17-β-雌二醇（E2）的作用。尽管如此，针对这些紊乱的安全有效的药物治疗却很少。介导E2非基因组效应的G蛋白偶联雌激素受体（GPR30）的作用大多尚未得到探索。
在本研究中，我们使用卵巢切除术（绝经模型）和2型糖尿病（T2D）大鼠模型来评估G-1（GPR30激动剂）对心脏代谢紊乱的临床前作用。通过高脂饮食和低剂量链脲佐菌素诱导T2D。在T2D建立后给予G-1六周。
我们发现G-1通过增加体重、降低空腹血糖、心脏重量以及心脏重量与体重比来抵消T2D和卵巢切除术的影响。此外，卵巢切除术和T2D均导致心脏中己糖激酶2（HK2）和葡萄糖转运蛋白4（GLUT4）的蛋白水平降低，而经G-1处理的雌性大鼠逆转了这些变化，且仅增加了HK2蛋白水平。另外，T2D和卵巢切除术增加了心脏中的葡萄糖和糖原含量，但G-1治疗显著降低了它们。
总之，我们的研究表明，作为一种选择性GPR30激动剂，G-1在多种临床前雌性模型中是对抗T2D和心脏代谢疾病的一种可行的治疗方法。
