Abstract
Early weaning (EW) leads to metabolic disorders in adulthood, being one of the causes of metabolic syndrome (MS). However, the range of hormonal disorders in EW has not been studied well enough, and approaches to its correction have not been developed. The aim of this work was to study metabolic and hormonal changes, including in the hormonal status of the gonadal and thyroid axes, in adult (10-month-old) male rats that were weaned in the early postnatal period, as well as to explore the restorative effect of 4-week treatment with different doses of metformin (MF), moderate (120 mg/kg/day) and relatively high (250 mg/kg/day), on these changes. Lactation in nursing female rats was interrupted with bromocriptine (10 mg/kg/day) on days 19–21 of lactation. After forced starvation during this period, rat pups were transitioned to a standard diet. At the age of 10 months, early weaned male rats showed characteristic signs of MS, such as obesity, impaired glucose tolerance, insulin resistance, hyperleptinemia and dyslipidemia. They also had reduced levels of testosterone, luteinizing hormone (LH), and thyroid hormones, and elevated levels of the thyroid-stimulating hormone (TSH). A 4-week treatment of adult rats with MF at a moderate dose reduced body and fat weight, partially restored metabolic parameters, and completely normalized testosterone, LH, thyroxine, triiodothyronine and TSH levels. The treatment with MF at a relatively high dose restored metabolic parameters more effectively, normalized leptin and insulin levels, but had a little effect on hormonal levels of the gonadal and thyroid axes. Thus, long-term treatment of early weaned male rats with a moderate dose of MF improves metabolic parameters and completely restores the hormonal status of the gonadal and thyroid axes, which indicates the promise of using such doses for the correction of MS and endocrine dysfunctions caused by interrupted or ineffective breastfeeding.
Similar content being viewed by others
REFERENCES
Smith CJ, Ryckman KK (2015) Epigenetic and developmental influences on the risk of obesity, diabetes, and metabolic syndrome. Diabetes Metab Syndr Obes 8: 295–302. https://doi.org/10.2147/DMSO.S61296
Cwynar-Zając Ł (2021) Metformin—a new approach. Pediatr Endocrinol Diabetes Metab 27: 134–140. https://doi.org/10.5114/pedm.2021.107166
Guo Z, Priefer R (2021) Current progress in pharmacogenomics of Type 2 diabetes: A systemic overview. Diabetes Metab Syndr 15: 102239. https://doi.org/10.1016/j.dsx.2021.102239
Picó C, Reis F, Egas C, Mathias P, Matafome P (2021) Lactation as a programming window for metabolic syndrome. Eur J Clin Invest 51: e13482. https://doi.org/10.1111/eci.13482
Tulipano G (2021) Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area. Int J Mol Sci 22: 13068. https://doi.org/10.3390/ijms222313068
Kononova YA, Likhonosov NP, Babenko AY (2022) Metformin: Expanding the Scope of Application-Starting Earlier than Yesterday, Canceling Later. Int J Mol Sci 23: 2363. https://doi.org/10.3390/ijms23042363
Top WMC, Kooy A, Stehouwer CDA (2022) Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia. Pharmaceuticals (Basel) 15: 312. https://doi.org/10.3390/ph15030312
Kalra S, Aggarwal S, Khandelwal D (2019) Thyroid Dysfunction and Type 2 Diabetes Mellitus: Screening Strategies and Implications for Management. Diabetes Ther 10: 2035–2044. https://doi.org/10.1007/s13300-019-00700-4
Shpakov AO (2021) Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms. Pharmaceuticals (Basel) 14: 42. https://doi.org/10.3390/ph14010042
Kimber-Trojnar Ż, Dłuski DF, Wierzchowska-Opoka M, Ruszała M, Leszczyńska-Gorzelak B (2022) Metformin as a Potential Treatment Option for Endometriosis. Cancers (Basel) 14: 577. https://doi.org/10.3390/cancers14030577
Magzoub R, Kheirelseid EAH, Perks C, Lewis S (2022) Does metformin improve reproduction outcomes for non-obese, infertile women with polycystic ovary syndrome? Meta-analysis and systematic review. Eur J Obstet Gynecol Reprod Biol 271: 38–62. https://doi.org/10.1016/j.ejogrb.2022.01.025
Badillo-Suárez PA, Rodríguez-Cruz M, Nieves-Morales X (2017) Impact of Metabolic Hormones Secreted in Human Breast Milk on Nutritional Programming in Childhood Obesity. J Mammary Gland Biol Neoplasia 22: 171–191. https://doi.org/10.1007/s10911-017-9382-y
Lima Nda S, de Moura EG, Passos MC, Nogueira Neto FJ, Reis AM, de Oliveira E, Lisboa PC (2011) Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring. Br J Nutr 105: 1405–1413. https://doi.org/10.1017/S0007114510005064
Lima Nda S, Franco JG, Peixoto-Silva N, Maia LA, Kaezer A, Felzenszwalb I, de Oliveira E, de Moura EG, Lisboa PC (2014) Ilex paraguariensis (yerba mate) improves endocrine and metabolic disorders in obese rats primed by early weaning. Eur J Nutr 53: 73–82. https://doi.org/10.1007/s00394-013-0500-3
Francisco FA, Barella LF, Silveira SDS, Saavedra LPJ, Prates KV, Alves VS, Franco CCDS, Miranda RA, Ribeiro TA, Tófolo LP, Malta A, Vieira E, Palma-Rigo K, Pavanello A, Martins IP, Moreira VM, de Oliveira JC, Mathias PCF, Gomes RM (2018) Methylglyoxal treatment in lactating mothers leads to type 2 diabetes phenotype in male rat offspring at adulthood. Eur J Nutr 57: 477–486. https://doi.org/10.1007/s00394-016-1330-x
Souza LL, de Moura EG, Lisboa PC (2020) Does early weaning shape future endocrine and metabolic disorders? Lessons from animal models. J Dev Orig Health Dis 11: 441–451. https://doi.org/10.1017/S2040174420000410
Lisboa PC, Miranda RA, Souza LL, Moura EG (2021) Can breastfeeding affect the rest of our life? Neuropharmacology 200: 108821. https://doi.org/10.1016/j.neuropharm.2021.108821
Smith JT, Spencer SJ (2012) Preweaning over- and underfeeding alters onset of puberty in the rat without affecting kisspeptin. Biol Reprod 86: 145. https://doi.org/10.1095/biolreprod.111.097758
Ayala-Moreno R, Racotta R, Anguiano B, Aceves C, Quevedo L (2013) Perinatal undernutrition programmes thyroid function in the adult rat offspring. Br J Nutr 110: 2207–2215. https://doi.org/10.1017/S0007114513001736
Pietrobon CB, Bertasso IM, Silva BS, Peixoto-Silva N, Oliveira E, Moura EG, Lisboa PC (2020) Body Adiposity and Endocrine Profile of Female Wistar Rats of Distinct Ages that were Early Weaned. Horm Metab Res 52: 58–66. https://doi.org/10.1055/a-0966-8784
Liu L, Wang W, Sun J, Pang Z (2018) Association of famine exposure during early life with the risk of type 2 diabetes in adulthood: a meta-analysis. Eur J Nutr 57: 741–749. https://doi.org/10.1007/s00394-016-1363-1
Zhou J, Zhang L, Xuan P, Fan Y, Yang L, Hu C, Bo Q, Wang G, Sheng J, Wang S (2018) The relationship between famine exposure during early life and body mass index in adulthood: A systematic review and meta-analysis. PLoS One 13: e0192212. https://doi.org/10.1371/journal.pone.0192212
Xin X, Wang W, Xu H, Li Z, Zhang D (2019) Exposure to Chinese famine in early life and the risk of dyslipidemia in adulthood. Eur J Nutr 58: 391–398. https://doi.org/10.1007/s00394-017-1603-z
Jiang X, Ma H, Wang Y, Liu Y (2013) Early life factors and type 2 diabetes mellitus. J Diabetes Res 2013: 485082. https://doi.org/10.1155/2013/485082
Qin LL, Luo BA, Gao F, Feng XL, Liu JH (2020) Effect of Exposure to Famine during Early Life on Risk of Metabolic Syndrome in Adulthood: A Meta-Analysis. J Diabetes Res 2020: 3251275. https://doi.org/10.1155/2020/3251275
Pietrobon CB, Miranda RA, Bertasso IM, Mathias PCF, Bonfleur ML, Balbo SL, Reis MAB, Latorraca MQ, Arantes VC, de Oliveira E, Lisboa PC, de Moura EG (2020) Early weaning induces short- and long-term effects on pancreatic islets in Wistar rats of both sexes. J Physiol 598: 489–502. https://doi.org/10.1113/JP278833
Derkach KV, Bondareva VM, Kornyushin OV, Galagudza MM, Shpakov AO (2020) Restoration of β-Adrenergic Signaling and Activity of Akt-Kinase and AMP-Activated Protein Kinase with Metformin in the Myocardium of Diabetic Rats. Bull Exp Biol Med 169: 24–28. https://doi.org/10.1007/s10517-020-04816-7
Bakhtyukov AA, Derkach KV, Sorokoumov VN, Stepochkina AM, Romanova IV, Morina IY, Zakharova IO, Bayunova LV, Shpakov AO (2021) The Effects of Separate and Combined Treatment of Male Rats with Type 2 Diabetes with Metformin and Orthosteric and Allosteric Agonists of Luteinizing Hormone Receptor on Steroidogenesis and Spermatogenesis. Int J Mol Sci 23: 198. https://doi.org/10.3390/ijms23010198
Meng XM, Ma XX, Tian YL, Jiang Q, Wang LL, Shi R, Ding L, Pang SG (2017) Metformin improves the glucose and lipid metabolism via influencing the level of serum total bile acids in rats with streptozotocin-induced type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci 21: 2232–2237.
Kim HW (2021) Metabolomic Approaches to Investigate the Effect of Metformin: An Overview. Int J Mol Sci 22: 10275. https://doi.org/10.3390/ijms221910275
Lee YF, Sim XY, Teh YH, Ismail MN, Greimel P, Murugaiyah V, Ibrahim B, Gam LH (2021) The effects of high-fat diet and metformin on urinary metabolites in diabetes and prediabetes rat models. Biotechnol Appl Biochem 68: 1014–1026. https://doi.org/10.1002/bab.2021
Kanto K, Ito H, Noso S, Babaya N, Hiromine Y, Taketomo Y, Toma J, Niwano F, Yasutake S, Kawabata Y, Ikegami H (2017) Effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig 9: 587–593. https://doi.org/10.1111/jdi.12755
DeFronzo R, Fleming GA, Chen K, Bicsak TA (2016) Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism 65: 20–29. https://doi.org/10.1016/j.metabol.2015.10.014
Derkach K, Zakharova I, Zorina I, Bakhtyukov A, Romanova I, Bayunova L, Shpakov A (2019) The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect. PLoS One 14: e0213779. https://doi.org/10.1371/journal.pone.0213779
Rena G, Hardie DG, Pearson ER (2017) The mechanisms of action of metformin. Diabetologia 60: 1577–1585. https://doi.org/10.1007/s00125-017-4342-z
Dimic D, Golubovic MV, Radenkovic S, Radojkovic D, Pesic M (2016) The effect of metformin on TSH levels in euthyroid and hypothyroid newly diagnosed diabetes mellitus type 2 patients. Bratisl Lek Listy 117: 433–435. https://doi.org/10.4149/bll_2016_084
Sui M, Yu Y, Zhang H, Di H, Liu C, Fan Y (2018) Efficacy of Metformin for Benign Thyroid Nodules in Subjects With Insulin Resistance: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 9: 494. https://doi.org/10.3389/fendo.2018.00494
Haroon SM, Khan K, Maqsood M, Iqbal S, Aleem M, Khan TU (2021) Exploring the Effect of Metformin to Lower Thyroid-Stimulating Hormone in Euthyroid and Hypothyroid Type-2 Diabetic Patients. Cureus 13: e13283. https://doi.org/10.7759/cureus.13283
Alves MG, Martins AD, Vaz CV, Correia S, Moreira PI, Oliveira PF, Socorro S (2014) Metformin and male reproduction: effects on Sertoli cell metabolism. Br J Pharmacol 171: 1033–1042. https://doi.org/10.1111/bph.12522
Faure M, Bertoldo MJ, Khoueiry R, Bongrani A, Brion F, Giulivi C, Dupont J, Froment P (2018) Metformin in Reproductive Biology. Front Endocrinol (Lausanne) 9: 675. https://doi.org/10.3389/fendo.2018.00675
Hu X, Liu Y, Wang C, Hou L, Zheng X, Xu Y, Ding L, Pang S (2017) Metformin affects thyroid function in male rats. Oncotarget 8: 107589–107595. https://doi.org/10.18632/oncotarget.22536
Casulari LA, Caldas AD, Domingues Casulari Motta L, Lofrano-Porto A (2010) Effects of metformin and short-term lifestyle modification on the improvement of male hypogonadism associated with metabolic syndrome. Minerva Endocrinol 35: 145–151.
Morgante G, Tosti C, Orvieto R, Musacchio MC, Piomboni P, De Leo V (2011) Metformin improves semen characteristics of oligo-terato-asthenozoospermic men with metabolic syndrome. Fertil Steril 95: 2150–2152. https://doi.org/10.1016/j.fertnstert.2010.12.009
Yan WJ, Mu Y, Yu N, Yi TL, Zhang Y, Pang XL, Cheng D, Yang J (2015) Protective effects of metformin on reproductive function in obese male rats induced by high-fat diet. J Assist Reprod Genet 32: 1097–1104. https://doi.org/10.1007/s10815-015-0506-2
Annie L, Jeremy M, Gurusubramanian G, Derkach KV, Shpakov AO, Roy VK (2020) Effect of metformin on testicular expression and localization of leptin receptor and levels of leptin in the diabetic mice. Mol Reprod Dev 87: 620–629. https://doi.org/10.1002/mrd.23342
Derkach KV, Bakhtyukov AA, Romanova IV, Zorina II, Bayunova LV, Bondareva VM, Morina YuI, Kumar Roy V, Shpakov AO (2020) The effect of metformin treatment on the basal and gonadotropin-stimulated steroidogenesis in male rats with type 2 diabetes mellitus. Andrologia 52: e13816. https://doi.org/10.1111/and.13816
Koroglu Aydın P, Karabulut-Bulan O, Bugan I, Turkyilmaz IB, Altun S, Yanardag R (2022) The protective effect of metformin against testicular damage in diabetes and prostate cancer model. Cell Biochem Funct 40: 60–70. https://doi.org/10.1002/cbf.3674
Funding
This work was state budget funded by the Ministry of Education and Science of the Russian Federation under the state assignment to the Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences (no. 075-0152-22-00). The experiments were carried out using the equipment of the Center for Collective Use at the Sechenov Institute of Evolutionary Physiology and Biochemistry.
Author information
Authors and Affiliations
Contributions
Conceptualization and experimental design (K.V.D., A.O.S.), conducting experiments (K.V.D., V.M.B, T.S.S.), data collection and processing (K.V.D., V.M.B.), writing and editing the manuscript (K.V.D., A.O.S.).
Corresponding author
Ethics declarations
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest that might be related to the publication of this article.
Additional information
Translated by A. Polyanovsky
Russian Text © The Author(s), 2022, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2022, Vol. 108, No. 8, pp. 1028–1041https://doi.org/10.31857/S0869813922080015.
Rights and permissions
About this article
Cite this article
Derkach, K.V., Bondareva, V.M., Sharova, T.S. et al. Efficacy of Various Metformin Doses for the Restoration of Metabolic Indices and Hormonal Status in Early Weaned Male Rats. J Evol Biochem Phys 58, 1251–1261 (2022). https://doi.org/10.1134/S0022093022040275
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0022093022040275