Intervening effects of progesterone combined with estradiol on streptozotocin-induced diabetes in ovariectomized mice and the underlying mechanisms
Main Article Content
Abstract
Background: Estrogen and progesterone are closely related to the occurrence of diabetes, and the progestogenic and estrogenic effects in the development of diabetes are related to their blood levels and the organism state, and it is not clear what effect their combination will be. The present study was to investigate the interaction between estrogen and progesterone in the development of diabetes mellitus.
Methods: A model of type 1 diabetes mellitus（T1DM）was established in ovariectomized (OVX) mice by intraperitoneal injection of streptozotocin (STZ), and the levels of plasma glucose, insulin, C-peptide, progesterone, and estradiol, the changes of islet cells, the expressions of glucose transporter 4 (GLUT4), Glucokinase (Gck), Glucose-6-phosphatase (G-6-P) and phosphoenolpyruvate carboxylase (PCK) were detected after chronically injected different doses of progesterone and 17β-estradiol subcutaneously for 4 weeks.
Results: Progesterone and 17β-estradiol could delay the occurrence of T1DM induced by STZ in ovariectomized mice, but there was no dose-response relationship; progesterone (2mg/kg) and 17β-estradiol (0.1mg/kg) injected separately or jointly could make the plasma concentration of estradiol and progesterone reaches the physiological dose range, which markedly inhibited the increase of the blood glucose induced by STZ, improved the glucose tolerance, protected islet cells, promoted C-peptide and insulin secretion, up-regulated skeletal muscle GLUT4 and liver Gck expressions, but significantly down-regulated the expressions of liver PCK and G-6-P mRNA.
Conclusions: The physiological dose of progesterone combined with estradiol has certain synergistic effects in delaying the occurrence of diabetes, the mechanisms are probably related to the protection of islet cells, the promotion of insulin release, skeletal muscle glucose transport, and liver glucose metabolism.
Keywords:
progesterone, estradiol, diabetes, pancreatic islet, glucose metabolism, GLUT4
Article Details
How to Cite
YAN, Yuan et al.
Intervening effects of progesterone combined with estradiol on streptozotocin-induced diabetes in ovariectomized mice and the underlying mechanisms.
Medical Research Archives, [S.l.], v. 12, n. 6, june 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5395>. Date accessed: 02 july 2024.
doi: https://doi.org/10.18103/mra.v12i6.5395.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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10. Millette K, Rodriguez K, Sheng X, Finley SD, Georgia S. Exogenous Lactogenic Signaling Stimulates Beta Cell Replication In Vivo and In Vitro. Biomolecules. 2022;12(2):21 5. doi: 10.3390/biom12020215
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13. Wong WP, Tiano JP, Liu S, Hewitt SC, Le May C, Dalle S, et al. Extranuclear estrogen receptor-α stimulates NeuroD binding to the insulin promoter and favors insulin synthesis. Proc Natl Acad Sci USA. 2010; 107(29): 1305 7–13062. doi: 10.1073/pnas.0914501107
14. Babiloni-Chust I, Dos Santos RS, Medina-Gali RM, Perez-Serna AA, Encinar JA, Martinez-Pinna J, et al. G protein coupled estrogen receptor activation by bisphenol-A disrupts the protection from apoptosis conferred by the estrogen receptors ERalpha and ERbeta in pancreatic beta cells. Environ Int. 2022;164:107250. doi: 10.1016/j.envint.2022
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20. Lin P, Zhang X, Zhu B, Gao J, Yin D, Zeng J, et al. Naringenin protects pancreatic beta cells in diabetic rat through activation of estrogen receptor beta. Eur J Pharmacol. 2023; 960:176115. doi: 10.1016/j.ejphar.20 23.176115
21. Medina RA, Meneses AM, Vera JC, Guzman C, Nualart F, Astuya A, et al. Estrogen and progesterone up-regulate glucose transporter expression in ZR-75-1 human breast cancer cells. Endocrinology. 2003; 144(10): 4527-4535. doi: 10.1210/en.20 03-029
22. Handgraaf S, Philippe J. The Role of Sexual Hormones on the Enteroinsular Axis. Endocr Rev. 2019 Aug 1;40(4):1152-1162. doi: 10.1210/er.2019-00004
23. Picard F, Wanatabe M, Schoonjans K, Lydon J, O'Malley BW, Auwerx J. Nonlinear partial differential equations and applications: Progesterone receptor knockout mice have an improved glucose homeostasis secondary to β-cell proliferation. Proc Natl Acad Sci. 200 2;99(24):15644-15648. doi: 10.1073/pnas.202612199
24. Lee SR, Choi WY, Heo JH, Huh J, Kim G, Lee KP et al. Progesterone increases blood glucose via hepatic progesterone receptor membrane component 1 under limited or impaired action of insulin. Sci Rep. 2020;10 (1):16316. doi: 10.1038/s41598-020-73330-7
25. Masuyama H, Hiramatsu Y. Potential role of estradiol and progesterone in insulin resistance through constitutive androstane receptor. J Mol Endocrinol. 2011;47(2):229-39. doi: 10.1530/JME-11-0046.
26. Bone HG, Lindsay R, McClung MR, Perez AT, Raanan MG, Spanheimer RG. Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2013;98(12):4691-701.
27. Furman BL. Streptozotocin-Induced Diabetic Models in Mice and Rats. Curr Protoc. 2021;1(4):e78.
28. Yi B, Huang G, Zhou Z. Different Role of Zinc Transporter 8 between Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus. J Diabetes Investig. 2016;7(4):459-65. doi: 10.1111/jdi.12441
29. Kampmann U, Knorr S, Fuglsang J, Ovesen P. Determinants of Maternal Insulin Resistance during Pregnancy: An Updated Overview. J Diabetes Res. 2019;2019:53 20156. doi: 10.1155/2019/5320156
30. Nunes VA, Portioli-Sanches EP, Rosim MP, Araujo MS, Praxedes-Garcia P, Valle MM, et al. Progesterone induces apoptosis of insulin-secreting cells: insights into the molecular mechanism. J Endocrinol. 2014;221 (2):273-84.
31. Candolfi M, Jaita G, Zaldivar V, Zárate S, Ferrari L, Pisera D, et al. Progesterone antagonizes the permissive action of estradiol on tumor necrosis factor-a-induced apoptosis of anterior pituitary cells. Endocrinology. 2005 ;146(2):736-43. doi: 10.1210/en.2004-1276
32. Cheng X, Shimizu I, Yuan Y, Wei M, Shen M, Huang H, et al. Effects of estradiol and progesterone on tumor necrosis factor a-induced apoptosis in human hepatoma HuH-7 cells. Life Sci. 2006;79(21):1988-94.
33. 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(4):46 1-470. doi: 10.1016/j.bj.2020.03.002
34. Ordóñez P, Moreno M, Alonso A, Llaneza P, Díaz F, González C. 17beta-Estradiol and/or progesterone protect from insulin resistance in STZ-induced diabetic rats. J Steroid Biochem Mol Biol. 2008;111(3-5):287-94.
35. Merino B, García-Arévalo M. Sexual hormones and diabetes: The impact of estradiol in pancreatic β cell. Int Rev Cell Mol Biol. 2021;359:81-138.
36. Le May C, Chu K, Hu M, Ortega CS, Simpson ER, Korach KS, et al. Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Natl Acad Sci U S A. 2006;103(24): 9232-7. doi: 10.1073/pnas.0602956103
37. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068-83. doi: 10.1016/S0140-6736(13)62154-6
38. Thorens B. GLUT2, glucose sensing and glucose homeostasis. Diabetologia. 2015;58 (2):221-32.
39. Wright EM. Glucose transport families SLC5 and SLC50. Mol Aspects Med. 2013;34(2-3):183-96.
40. Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch. 2020;472(9):1273-1298. doi: 10.1007/s00424-020-02417-x
41. Huang CF, Yang CY, Chan DC, Wang CC, Huang KH, Wu CC, et al. Arsenic Exposure and Glucose Intolerance/Insulin Resistance in Estrogen-Deficient Female Mice. Environ Health Perspect. 2015;123(11):1138-44. doi: 10.1289/ehp.1408663
42. Seyer P, Vallois D, Poitry-Yamate C, Schütz F, Metref S, Tarussio D, et al. Hepatic glucose sensing is required to preserve P cell glucose competence. J Clin Invest. 2013;123(4):1662-76. doi: 10.1172/JCI65538
43. Rudland VL. Diagnosis and management of glucokinase monogenic diabetes in pregnancy: current perspectives. Diabetes Metab Syndr Obes. 2019;12:1081-1089. doi: 10.2147/DMSO.S186610
44. Westermeier F, Holyoak T, Asenjo JL, Gatica R, Nualart F, Burbulis I, et al. Gluconeogenic Enzymes in β-Cells: Pharmacological Targets for Improving Insulin Secretion. Trends Endocrinol Metab. 2019;30 (8):520-531.
45. Chen SH, Liu XN, Peng Y. MicroRNA-351 eases insulin resistance and liver gluconeogenesis via the PI3K/AKT pathway by inhibiting FLOT2 in mice of gestational diabetes mellitus. J Cell Mol Med. 2019;23(9): 5895-5906. doi: 10.1111/jcmm.14079
46. Azboy İ, Özkaya M, Demir T, Demirtaş A, Kağan Arslan A, Özkul E, et al. Biomechanical properties of osteoporotic rat femurs after different hormonal treatments: genistein, estradiol, and estradiol/progesterone. SICOT J. 2016;2:24. doi: 10.1051/sicotj/2016016
47. Getoff N, Schittl H, Hartmann J, Gerschpacher M, Ying S, Danielova I, et al. Mutual Interaction of 17β-Estradiol and Progesterone: Electron Emission. Free Radical Effect Studied by Experiments in vitro. In Vivo. 2010;24(4):535-41.
2. Li Y, Huang J, Yan Y, Liang J, Liang Q, Lu Y, et al. Preventative effects of resveratrol and estradiol on streptozotocin-induced diabetes in ovariectomized mice and the related mechanisms. PLoS One. 2018;13(10):e020449 9. doi: 10.1371/journal.pone.0204499
3. Saadeh NA, Hammouri HM, Zahran DJ. Diabetic Ketoacidosis in Northern Jordan: Seasonal Morbidity and Characteristics of Patients. Diabetes Metab Syndr Obes. 2023; 16: 3057–3064. doi: 10.2147/DMSO.S413405
4. Elian V, Popovici V, Ozon EA, Musuc AM, Fița AC, Rusu E, et al. Current Technologies for Managing Type 1 Diabetes Mellitus and Their Impact on Quality of Life—A Narrative Review. Life (Basel) 2023;13(8): 1663. doi: 10.3390/life13081663
5. Salonia A, Lanzi R, Scavini M, Pontillo M, Gatti E, Petrella G, et al. Sexual function and endocrine profile in fertile women with type 1 diabetes. Diabetes Care. 2006; 29: 312–316.
6. Paschou SA, Athanasiadou KI, Papanas N. Menopausal Hormone Therapy in Women with Type 2 Diabetes Mellitus: An Updated Review. Diabetes Ther. 2024; 15(4): 741–748. doi: 10.1007/s13300-024-01546-1
7. Tiano JP, Mauvais-Jarvis F. Importance of oestrogen receptors to preserve functional β-cell mass in diabetes. Nat Rev Endocrinol. 2012; 8: 342–351.
8. Mauvais-Jarvis F. Role of Sex Steroids in β Cell Function, Growth, and Survival.Trends Endocrinol Metab. 2016; 27(12):844-855. doi: 10.1016/j.tem.2016.08.008
9. Taraborrelli S. Physiology, production and action of progesterone. Acta Obstetricia Et Gynecologica Scandinavica. 2015; 94 Suppl 161: 8-16. doi: 10.1111/aogs.12771
10. Millette K, Rodriguez K, Sheng X, Finley SD, Georgia S. Exogenous Lactogenic Signaling Stimulates Beta Cell Replication In Vivo and In Vitro. Biomolecules. 2022;12(2):21 5. doi: 10.3390/biom12020215
11. Pasanen S, Ylikomi T, Syvl H, Tuohimaa PJM, Endocrinology C. Distribution of progesterone receptor in chicken: novel target organs for progesterone and estrogen action. 1997; 135(1): 79-91. doi: 10.1016/s030 3-7207(97)00192-5
12. Tiano JP, Mauvais-Jarvis F. Importance of oestrogen receptors to preserve functional β-cell mass in diabetes. Nat Rev Endocrinol. 2012; 8(6): 342–351. doi: 10.1038/nrendo.2011.242
13. Wong WP, Tiano JP, Liu S, Hewitt SC, Le May C, Dalle S, et al. Extranuclear estrogen receptor-α stimulates NeuroD binding to the insulin promoter and favors insulin synthesis. Proc Natl Acad Sci USA. 2010; 107(29): 1305 7–13062. doi: 10.1073/pnas.0914501107
14. Babiloni-Chust I, Dos Santos RS, Medina-Gali RM, Perez-Serna AA, Encinar JA, Martinez-Pinna J, et al. G protein coupled estrogen receptor activation by bisphenol-A disrupts the protection from apoptosis conferred by the estrogen receptors ERalpha and ERbeta in pancreatic beta cells. Environ Int. 2022;164:107250. doi: 10.1016/j.envint.2022
15. Tiano JP, Mauvais-Jarvis F. Molecular mechanisms of estrogen receptors' suppression )of lipogenesis in pancreatic β-cells. Endocrinology. 2012; 153(7): 2997–3005. doi: 10.1210/en.2011-1980
16. Kilic G, Alvarez-Mercado AI, Zarrouki B, Opland D, Liew CW, Alonso LC, et al. The islet estrogen receptor-alpha is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes. PLoS One. 2014;9(2):e87941. doi: 10.1371/jo urnal.pone.0087941
17. Alonso-Magdalena P, Ropero AB, Carrera MP, Cederroth CR, Baquié M, Gauthier BR, et al. Pancreatic insulin content regulation by the estrogen receptor ER α. Plos One. 2008; 3(4): e2069. doi: 10.1371/journal.pone.0002069
18. Soriano S, Ropero AB, Alonso-Magdalena P, Ripoll C, Quesada I, Gassner B, et al. Rapid regulation of K(ATP) channel activity by 17β-estradiol in pancreatic β-cells involves the estrogen receptor β and the atrial natriuretic peptide receptor. Mol Endocrinol. 2009; 23(12): 1973–1982. doi: 10.1210/me.20 09-0287
19. Mauvais-Jarvis F, Le May C, Tiano JP, Liu S, Kilic-Berkmen G, Kim JH. The Role of Estrogens in Pancreatic Islet Physiopathology .Adv Exp Med Biol. 2017;1043:385-399. doi: 10.1007/978-3-319-70178-3_18
20. Lin P, Zhang X, Zhu B, Gao J, Yin D, Zeng J, et al. Naringenin protects pancreatic beta cells in diabetic rat through activation of estrogen receptor beta. Eur J Pharmacol. 2023; 960:176115. doi: 10.1016/j.ejphar.20 23.176115
21. Medina RA, Meneses AM, Vera JC, Guzman C, Nualart F, Astuya A, et al. Estrogen and progesterone up-regulate glucose transporter expression in ZR-75-1 human breast cancer cells. Endocrinology. 2003; 144(10): 4527-4535. doi: 10.1210/en.20 03-029
22. Handgraaf S, Philippe J. The Role of Sexual Hormones on the Enteroinsular Axis. Endocr Rev. 2019 Aug 1;40(4):1152-1162. doi: 10.1210/er.2019-00004
23. Picard F, Wanatabe M, Schoonjans K, Lydon J, O'Malley BW, Auwerx J. Nonlinear partial differential equations and applications: Progesterone receptor knockout mice have an improved glucose homeostasis secondary to β-cell proliferation. Proc Natl Acad Sci. 200 2;99(24):15644-15648. doi: 10.1073/pnas.202612199
24. Lee SR, Choi WY, Heo JH, Huh J, Kim G, Lee KP et al. Progesterone increases blood glucose via hepatic progesterone receptor membrane component 1 under limited or impaired action of insulin. Sci Rep. 2020;10 (1):16316. doi: 10.1038/s41598-020-73330-7
25. Masuyama H, Hiramatsu Y. Potential role of estradiol and progesterone in insulin resistance through constitutive androstane receptor. J Mol Endocrinol. 2011;47(2):229-39. doi: 10.1530/JME-11-0046.
26. Bone HG, Lindsay R, McClung MR, Perez AT, Raanan MG, Spanheimer RG. Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2013;98(12):4691-701.
27. Furman BL. Streptozotocin-Induced Diabetic Models in Mice and Rats. Curr Protoc. 2021;1(4):e78.
28. Yi B, Huang G, Zhou Z. Different Role of Zinc Transporter 8 between Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus. J Diabetes Investig. 2016;7(4):459-65. doi: 10.1111/jdi.12441
29. Kampmann U, Knorr S, Fuglsang J, Ovesen P. Determinants of Maternal Insulin Resistance during Pregnancy: An Updated Overview. J Diabetes Res. 2019;2019:53 20156. doi: 10.1155/2019/5320156
30. Nunes VA, Portioli-Sanches EP, Rosim MP, Araujo MS, Praxedes-Garcia P, Valle MM, et al. Progesterone induces apoptosis of insulin-secreting cells: insights into the molecular mechanism. J Endocrinol. 2014;221 (2):273-84.
31. Candolfi M, Jaita G, Zaldivar V, Zárate S, Ferrari L, Pisera D, et al. Progesterone antagonizes the permissive action of estradiol on tumor necrosis factor-a-induced apoptosis of anterior pituitary cells. Endocrinology. 2005 ;146(2):736-43. doi: 10.1210/en.2004-1276
32. Cheng X, Shimizu I, Yuan Y, Wei M, Shen M, Huang H, et al. Effects of estradiol and progesterone on tumor necrosis factor a-induced apoptosis in human hepatoma HuH-7 cells. Life Sci. 2006;79(21):1988-94.
33. 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(4):46 1-470. doi: 10.1016/j.bj.2020.03.002
34. Ordóñez P, Moreno M, Alonso A, Llaneza P, Díaz F, González C. 17beta-Estradiol and/or progesterone protect from insulin resistance in STZ-induced diabetic rats. J Steroid Biochem Mol Biol. 2008;111(3-5):287-94.
35. Merino B, García-Arévalo M. Sexual hormones and diabetes: The impact of estradiol in pancreatic β cell. Int Rev Cell Mol Biol. 2021;359:81-138.
36. Le May C, Chu K, Hu M, Ortega CS, Simpson ER, Korach KS, et al. Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Natl Acad Sci U S A. 2006;103(24): 9232-7. doi: 10.1073/pnas.0602956103
37. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068-83. doi: 10.1016/S0140-6736(13)62154-6
38. Thorens B. GLUT2, glucose sensing and glucose homeostasis. Diabetologia. 2015;58 (2):221-32.
39. Wright EM. Glucose transport families SLC5 and SLC50. Mol Aspects Med. 2013;34(2-3):183-96.
40. Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch. 2020;472(9):1273-1298. doi: 10.1007/s00424-020-02417-x
41. Huang CF, Yang CY, Chan DC, Wang CC, Huang KH, Wu CC, et al. Arsenic Exposure and Glucose Intolerance/Insulin Resistance in Estrogen-Deficient Female Mice. Environ Health Perspect. 2015;123(11):1138-44. doi: 10.1289/ehp.1408663
42. Seyer P, Vallois D, Poitry-Yamate C, Schütz F, Metref S, Tarussio D, et al. Hepatic glucose sensing is required to preserve P cell glucose competence. J Clin Invest. 2013;123(4):1662-76. doi: 10.1172/JCI65538
43. Rudland VL. Diagnosis and management of glucokinase monogenic diabetes in pregnancy: current perspectives. Diabetes Metab Syndr Obes. 2019;12:1081-1089. doi: 10.2147/DMSO.S186610
44. Westermeier F, Holyoak T, Asenjo JL, Gatica R, Nualart F, Burbulis I, et al. Gluconeogenic Enzymes in β-Cells: Pharmacological Targets for Improving Insulin Secretion. Trends Endocrinol Metab. 2019;30 (8):520-531.
45. Chen SH, Liu XN, Peng Y. MicroRNA-351 eases insulin resistance and liver gluconeogenesis via the PI3K/AKT pathway by inhibiting FLOT2 in mice of gestational diabetes mellitus. J Cell Mol Med. 2019;23(9): 5895-5906. doi: 10.1111/jcmm.14079
46. Azboy İ, Özkaya M, Demir T, Demirtaş A, Kağan Arslan A, Özkul E, et al. Biomechanical properties of osteoporotic rat femurs after different hormonal treatments: genistein, estradiol, and estradiol/progesterone. SICOT J. 2016;2:24. doi: 10.1051/sicotj/2016016
47. Getoff N, Schittl H, Hartmann J, Gerschpacher M, Ying S, Danielova I, et al. Mutual Interaction of 17β-Estradiol and Progesterone: Electron Emission. Free Radical Effect Studied by Experiments in vitro. In Vivo. 2010;24(4):535-41.