Background Diabetic cardiometabolic disorders are characterized by significant changes in cardiac metabolism and are increased in postmenopausal women, which emphasize the role of 17β-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. Methods 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. Results 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. Conclusions 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.

Background: Type 2 diabetes mellitus (T2DM) is associated with cardiometabolic changes, and menopause exacerbates these conditions, leading to a greater risk of cardiovascular diseases (CVDs). The G protein-coupled estrogen receptor (GPER), which mediates the rapid effects of estrogen, has beneficial cardiac effects in both T2DM and menopause, but its mechanism of action is not well understood. Objectives: This study aimed to determine whether G1 as a selective GPER-agonist has beneficial effects on cardiac lipid metabolism in ovariectomized rats with T2DM. Methods: Female Wistar rats were divided into 5 groups (n = 7 in each group): Sham-control (Sh-Ctl), T2DM, ovariectomized-T2DM (OVX-T2DM), OVX-T2DM-G1 (GPER-agonist), and OVX-T2DM-vehicle (OVX-T2DM-Veh). After stabilization of T2DM, G1 (200 μg/Kg) was administrated for 6 weeks. Then, the levels of free fatty acids (FFAs), CD36, peroxisome proliferator-activated receptor α (PPARα), and lipid accumulation in the cardiac tissue were determined. Results: Compared with the Sh-Ctl group, cardiac FFAs (P < 0.001), CD36 (P < 0.05), and lipid accumulation (P < 0.001) increased, and cardiac PPARα (P < 0.01) decreased in T2DM animals; ovariectomy intensified these changes. Also, cardiac FFAs, PPARα, and lipid accumulation (P < 0.05) significantly decreased in the OVX-T2DM-G1 group compared to the OVX-T2DM-Veh group. However, cardiac CD36 levels did not change. Conclusions: G1 as a selective GPER-agonist affects lipid metabolism in T2DM animals. It also plays a vital role in improving cardiac metabolism during postmenopausal diabetic conditions.

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