The effects of G protein-coupled receptor 30 (GPR30) on cardiac glucose metabolism in diabetic ovariectomized female rats
-
Mohammad Shahbazian
Abstract
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.
Acknowledgments
The authors are grateful to Ms. Zeinab Hafizi for technical assistance. All authors read and approved the final manuscript.
-
Research funding: None declared.
-
Author contribution: All authors have accepted responsibility for the entire content of this manuscript and approved its submission
-
Competing interests: The authors declare that there is no conflict of interests.
-
Informed consent: Informed consent was obtained from all individuals included in this study.
-
Ethical approval: All the experimental procedures were performed according to the committee for the purpose of control and supervision of experiments on animals, norms and approved by the Shahid Sadoughi University of Medical Sciences, Animal Ethical Committee with an approval number 1400.005
References
1. Yoshimura, M, Anzawa, R, Mochizuki, S. Cardiac metabolism in diabetes mellitus. Curr Pharmaceut Des 2008;14:2521–6, https://doi.org/10.2174/138161208786071263.Search in Google Scholar PubMed
2. Piché, M-E, Poirier, P. Obesity, ectopic fat and cardiac metabolism. Expet Rev Endocrinol Metabol 2018;13:213–21.10.1080/17446651.2018.1500894Search in Google Scholar PubMed
3. Kota, SK, Kota, SK, Jammula, S, Panda, S, Modi, KD. Effect of diabetes on alteration of metabolism in cardiac myocytes: therapeutic implications. Diabetes Technol Therapeut 2011;13:1155–60, https://doi.org/10.1089/dia.2011.0120.Search in Google Scholar PubMed
4. An, D, Rodrigues, B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 2006;291:H1489-H1506, https://doi.org/10.1152/ajpheart.00278.2006.Search in Google Scholar PubMed
5. Azizian, H, Khaksari, M, Esmailidehaj, M, Farhadi, Z. Cardioprotective and anti-inflammatory effects of G-protein coupled receptor 30 (GPR30) on postmenopausal type 2 diabetic rats. Biomed Pharmacother 2018;108:153–64, https://doi.org/10.1016/j.biopha.2018.09.028.Search in Google Scholar PubMed
6. Farhadi, Z, Khaksari, M, Azizian, H, Mortazaeizadeh, A, Shabani, M, Shahrokhi, N. Beneficial effects of tamoxifen on leptin sensitivity in young mice fed a high fat diet: role of estrogen receptor alpha and cytokines. Life Sci 2020;246:117384, https://doi.org/10.1016/j.lfs.2020.117384.Search in Google Scholar PubMed
7. Farhadi, Z, Khaksari, M, Azizian, H, Dabiri, S, Fallah, H, Nozari, M. Aging is associated with loss of beneficial effects of estrogen on leptin responsiveness in mice fed high fat diet: role of estrogen receptor α and cytokines. Mech Ageing Dev 2020;186:111198, https://doi.org/10.1016/j.mad.2019.111198.Search in Google Scholar PubMed
8. Salpeter, S, Walsh, J, Ormiston, T, Greyber, E, Buckley, N, Salpeter, E. Meta‐analysis: effect of hormone‐replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metabol 2006;8:538-54, https://doi.org/10.1111/j.1463-1326.2005.00545.x.Search in Google Scholar PubMed
9. Sharma, G, Hu, C, Staquicini, DI, Brigman, JL, Liu, M, Mauvais-Jarvis, F, et al.. Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes. Sci Transl Med 2020;12:12. https://doi.org/10.1126/scitranslmed.aau5956.Search in Google Scholar PubMed PubMed Central
10. Sharma, G, Hu, C, Brigman, JL, Zhu, G, Hathaway, HJ, Prossnitz, ER. GPER deficiency in male mice results in insulin resistance, dyslipidemia, and a proinflammatory state. Endocrinology 2013;154:4136–45, https://doi.org/10.1210/en.2013-1357.Search in Google Scholar PubMed PubMed Central
11. Azizian, H, Khaksari, M, Asadikaram, G, Esmailidehaj, M, Shahrokhi, N. Progesterone eliminates 17β-estradiol-mediated cardioprotection against diabetic cardiovascular dysfunction in ovariectomized rats. Biomed J 2021;44:461–70, https://doi.org/10.1016/j.bj.2020.03.002.Search in Google Scholar PubMed PubMed Central
12. Farhadi, Z, Khaksari, M, Azizian, H, Dabiri, S. The brain neuropeptides and STAT3 mediate the inhibitory effect of 17-β Estradiol on central leptin resistance in young but not aged female high-fat diet mice. Metab Brain Dis 2022. https://doi.org/10.1007/s11011-021-00884-4. 35031929.Search in Google Scholar PubMed
13. Dean, M, Hunt, J, McDougall, L, Rose, J. Uterine glycogen metabolism in mink during estrus, embryonic diapause and pregnancy. J Reprod Dev 2014;60:438–46, https://doi.org/10.1262/jrd.2014-013.Search in Google Scholar PubMed PubMed Central
14. Gregorio, KCR, Laurindo, CP, Machado, UF. Estrogen and glycemic homeostasis: the fundamental role of nuclear estrogen receptors ESR1/ESR2 in glucose transporter GLUT4 regulation. Cells 2021;10:99, https://doi.org/10.3390/cells10010099.Search in Google Scholar PubMed PubMed Central
15. Ebrahimi, MN, Khaksari, M, Sepehri, G, Karam, GA, Raji-Amirhasani, A, Azizian, H. The effects of alone and combination tamoxifen, raloxifene and estrogen on lipid profile and atherogenic index of ovariectomized type 2 diabetic rats. Life Sci 2020;263:118573, https://doi.org/10.1016/j.lfs.2020.118573.Search in Google Scholar PubMed
16. Li, Z-l, Liu, J-c, Liu, S-b, Li, X-q, Yi, D-h, Zhao, M-g. Improvement of vascular function by acute and chronic treatment with the GPR30 agonist G1 in experimental diabetes mellitus. PLoS One 2012;7:e38787.https://doi.org/10.1371/journal.pone.0038787.Search in Google Scholar PubMed PubMed Central
17. Litwak, SA, Wilson, JL, Chen, W, Garcia-Rudaz, C, Khaksari, M, Cowley, MA, et al.. Estradiol prevents fat accumulation and overcomes leptin resistance in female high-fat diet mice. Endocrinology 2014;155:4447–60, https://doi.org/10.1210/en.2014-1342.Search in Google Scholar PubMed
18. Reichelt, ME, Mellor, KM, Bell, JR, Chandramouli, C, Headrick, JP, Delbridge, LM. Sex, sex steroids, and diabetic cardiomyopathy: making the case for experimental focus. Am J Physiol Heart Circ Physiol 2013;305:H779–92, https://doi.org/10.1152/ajpheart.00141.2013.Search in Google Scholar PubMed
19. Fielitz, J, Leuschner, M, Zurbrügg, HR, Hannack, B, Pregla, R, Hetzer, R, et al.. Regulation of matrix metalloproteinases and their inhibitors in the left ventricular myocardium of patients with aortic stenosis. J Mol Med 2004;82:809–20, https://doi.org/10.1007/s00109-004-0606-4.Search in Google Scholar PubMed
20. Apaijai, N, Charoenphandhu, N, Ittichaichareon, J, Suntornsaratoon, P, Krishnamra, N, Aeimlapa, R, et al.. Estrogen deprivation aggravates cardiac hypertrophy in nonobese type 2 diabetic Goto–Kakizaki (GK) rats. Biosci Rep 2017;37:BSR20170886, https://doi.org/10.1042/BSR20170886.Search in Google Scholar PubMed PubMed Central
21. Xu, Y, Arenas, IA, Armstrong, SJ, Davidge, ST. Estrogen modulation of left ventricular remodeling in the aged heart. Cardiovasc Res 2003;57:388–94, https://doi.org/10.1016/s0008-6363(02)00705-8.Search in Google Scholar PubMed
22. Mahmoodzadeh, S, Dworatzek, E, Fritschka, S, Pham, TH, Regitz-Zagrosek, V. 17β-estradiol inhibits matrix metalloproteinase-2 transcription via MAP kinase in fibroblasts. Cardiovasc Res 2010;85:719–28, https://doi.org/10.1093/cvr/cvp350.Search in Google Scholar PubMed PubMed Central
23. Bansal, S, Chopra, K. Distinct role of estrogen receptor-alpha and beta on postmenopausal diabetes-induced vascular dysfunction. Gen Comp Endocrinol 2014;206:51–9, https://doi.org/10.1016/j.ygcen.2014.06.013.Search in Google Scholar PubMed
24. Ye, G, Donthi, RV, Metreveli, NS, Epstein, PN. Overexpression of hexokinase protects hypoxic and diabetic cardiomyocytes by increasing ATP generation. Cardiovasc Toxicol 2005;5:293–300, https://doi.org/10.1385/ct:5:3:293.10.1385/CT:5:3:293Search in Google Scholar
25. Malfitano, C, de Souza Junior, AL, Carbonaro, M, Bolsoni-Lopes, A, Figueroa, D, de Souza, LE, et al.. Glucose and fatty acid metabolism in infarcted heart from streptozotocin-induced diabetic rats after 2 weeks of tissue remodeling. Cardiovasc Diabetol 2015;14:1–10, https://doi.org/10.1186/s12933-015-0308-y.Search in Google Scholar PubMed PubMed Central
26. Frank, SK, Fromm, HJ. Effect of streptozotocin-induced diabetes and insulin treatment on the synthesis of hexokinase II in the skeletal muscle of the rat. Arch Biochem Biophys 1986;249:61–9, https://doi.org/10.1016/0003-9861(86)90560-6.Search in Google Scholar PubMed
27. Da Silva, D, Ausina, P, Alencar, EM, Coelho, WS, Zancan, P, Sola‐Penna, M. Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice. IUBMB Life 2012;64:766–74, https://doi.org/10.1002/iub.1063.Search in Google Scholar PubMed
28. Ding, F, Yao, J, Zhao, L, Mao, Z, Chen, S, Brinton, RD. Ovariectomy induces a shift in fuel availability and metabolism in the hippocampus of the female transgenic model of familial Alzheimer’s. PLoS One 2013;8:e59825, https://doi.org/10.1371/journal.pone.0059825.Search in Google Scholar PubMed PubMed Central
29. Bian, C, Bai, B, Gao, Q, Li, S, Zhao, Y. 17β-estradiol regulates glucose metabolism and insulin secretion in rat islet β cells through GPER and Akt/mTOR/GLUT2 pathway. Front Endocrinol 2019;10:531, https://doi.org/10.3389/fendo.2019.00531.Search in Google Scholar PubMed PubMed Central
30. Hsu, JT, Kan, WH, Hsieh, YC, Choudhry, MA, Schwacha, MG, Bland, KI, Chaudry, IH. Mechanism of estrogen-mediated improvement in cardiac function after trauma-hemorrhage: p38-dependent normalization of cardiac Akt phosphorylation and glycogen levels. Shock 2008;30:372–8. https://doi.org/10.1097/SHK.0b013e318164f25c. 18277950.Search in Google Scholar PubMed
31. Montanari, D, Yin, H, Dobrzynski, E, Agata, J, Yoshida, H, Chao, J, et al.. Kallikrein gene delivery improves serum glucose and lipid profiles and cardiac function in streptozotocin-induced diabetic rats. Diabetes 2005;54:1573-80.https://doi.org/10.2337/diabetes.54.5.1573.Search in Google Scholar PubMed
32. Kampmann, U, Christensen, B, Nielsen, TS, Pedersen, SB, Ørskov, L, Lund, S, et al.. GLUT4 and UBC9 protein expression is reduced in muscle from type 2 diabetic patients with severe insulin resistance. PLoS One 2011,6:e27854, https://doi.org/10.1371/journal.pone.0027854.Search in Google Scholar PubMed PubMed Central
33. Giacometti, J, Muhvić, D, Grubić-Kezele, T, Nikolić, M, Šoić-Vranić, T, Bajek, S. Olive leaf polyphenols (OLPs) stimulate GLUT4 expression and translocation in the skeletal muscle of diabetic rats. Int J Mol Sci 2020;21:8981, https://doi.org/10.3390/ijms21238981.Search in Google Scholar PubMed PubMed Central
34. Al-Nakkash, L, Markus, B, Batia, L, Prozialeck, WC, Broderick, TL. Genistein induces estrogen-like effects in ovariectomized rats but fails to increase cardiac GLUT4 and oxidative stress. J Med Food 2010;13:1369–75, https://doi.org/10.1089/jmf.2009.0271.Search in Google Scholar PubMed PubMed Central
35. Barsotti, A, Giannoni, A, Di Napoli, P, Emdin, M. Energy metabolism in the normal and in the diabetic heart. Curr Pharmaceut Des 2009;15:836–40, https://doi.org/10.2174/138161209787582066.Search in Google Scholar PubMed
36. Campbell, SE, Febbraio, MA. Effects of ovarian hormones on exercise metabolism. Curr Opin Clin Nutr Metab Care 2001;4:515–20, https://doi.org/10.1097/00075197-200111000-00009.Search in Google Scholar PubMed
37. Barreto-Andrade, JN, de Fátima, LA, Campello, RS, Guedes, JAC, de Freitas, HS, MOU Fabres Machado, M. Estrogen receptor 1 (ESR1) enhances Slc2a4/GLUT4 expression by a SP1 cooperative mechanism. Int J Med Sci 2018;15:1320, https://doi.org/10.7150/ijms.26774.Search in Google Scholar PubMed PubMed Central
38. Yan, H, Yang, W, Zhou, F, Li, X, Pan, Q, Shen, Z, et al.. Estrogen improves insulin sensitivity and suppresses gluconeogenesis via the transcription factor Foxo1. Diabetes 2019;68:291–304, https://doi.org/10.2337/db18-0638.Search in Google Scholar PubMed PubMed Central
39. Model, JFA, Lima, MV, Ohlweiler, R, Vogt, ÉL, Rocha, DS, de Souza, SK, et al.. Liraglutide improves lipid and carbohydrate metabolism of ovariectomized rats. Mol Cell Endocrinol 2021;524:111158, https://doi.org/10.1016/j.mce.2021.111158.Search in Google Scholar PubMed
40. Ibrahim, MM, Bheemanapally, K, Sylvester, PW, Briski, KP. Sex differences in glucoprivic regulation of glycogen metabolism in hypothalamic primary astrocyte cultures: role of estrogen receptor signaling. Mol Cell Endocrinol 2020;518:111000, https://doi.org/10.1016/j.mce.2020.111000.Search in Google Scholar PubMed PubMed Central
41. Young, ME, McNulty, P, Taegtmeyer, H. Adaptation and maladaptation of the heart in diabetes: part II: potential mechanisms. Circulation 2002,105:1861–70, https://doi.org/10.1161/01.cir.0000012467.61045.87.Search in Google Scholar PubMed
42. de los Ángeles Carrasco-Ruiz, M, Hernández-Aragón, LG, Chávez-Ríos, JR, Rodríguez-Antolín, J, Pacheco, P, Martínez-Gómez, M, et al.. High estradiol differentially affects the expression of the glucose transporter type 4 in pelvic floor muscles of rats. Int Neurourol J 2018;22:161, https://doi.org/10.5213/inj.1836116.058.Search in Google Scholar PubMed PubMed Central
© 2022 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- The clinical potential of flavonoids in Peyronie’s disease
- Reviews
- Emphasizing roles of BDNF promoters and inducers in Alzheimer's disease for improving impaired cognition and memory
- Diabetic wound healing approaches: an update
- Metformin: new applications for an old drug
- Bispecific antibodies and its applications: a novel approach for targeting SARS-Cov-2
- A review on pulmonary and mediastinal synovial sarcoma
- Original Articles
- Cytokine release by human bone marrow stromal cells isolated from osteoarthritic and diabetic osteoarthritic patients in vitro
- Antioxidant and anti-inflammatory effect of olive leaf extract treatment in diabetic rat brain
- Implication of nitrergic system in the anticonvulsant effects of ferulic acid in pentylenetetrazole-induced seizures in male mice
- The effects of G protein-coupled receptor 30 (GPR30) on cardiac glucose metabolism in diabetic ovariectomized female rats
- Effects of weight-bearing vs. non-weight-bearing endurance exercise on reducing body fat and inflammatory markers in obese females
- [Lys5,MeLeu9,Nle10]-NKA(4–10) induces neurokinin 2 receptor mediated urination and defecation and neurokinin 1 receptor mediated flushing in rats: measured using the rapid detection voiding assay
- Single 30 min treadmill exercise session suppresses the production of pro-inflammatory cytokines and oxidative stress in obese female adolescents
- Letter to the Editor
- Effect of tirzepatide on prediabetics and blood pressure with implications for future research
Articles in the same Issue
- Frontmatter
- Editorial
- The clinical potential of flavonoids in Peyronie’s disease
- Reviews
- Emphasizing roles of BDNF promoters and inducers in Alzheimer's disease for improving impaired cognition and memory
- Diabetic wound healing approaches: an update
- Metformin: new applications for an old drug
- Bispecific antibodies and its applications: a novel approach for targeting SARS-Cov-2
- A review on pulmonary and mediastinal synovial sarcoma
- Original Articles
- Cytokine release by human bone marrow stromal cells isolated from osteoarthritic and diabetic osteoarthritic patients in vitro
- Antioxidant and anti-inflammatory effect of olive leaf extract treatment in diabetic rat brain
- Implication of nitrergic system in the anticonvulsant effects of ferulic acid in pentylenetetrazole-induced seizures in male mice
- The effects of G protein-coupled receptor 30 (GPR30) on cardiac glucose metabolism in diabetic ovariectomized female rats
- Effects of weight-bearing vs. non-weight-bearing endurance exercise on reducing body fat and inflammatory markers in obese females
- [Lys5,MeLeu9,Nle10]-NKA(4–10) induces neurokinin 2 receptor mediated urination and defecation and neurokinin 1 receptor mediated flushing in rats: measured using the rapid detection voiding assay
- Single 30 min treadmill exercise session suppresses the production of pro-inflammatory cytokines and oxidative stress in obese female adolescents
- Letter to the Editor
- Effect of tirzepatide on prediabetics and blood pressure with implications for future research