Beneficial effects of metformin on high fructose-induced ovarian cycle abnormalities and antioxidant activity Effects of metformin on female rats


MA Demirel
https://orcid.org/0000-0002-7082-8976
E Sumlu
MO Uludağ
F Akar
Resumen

This study aimed to evaluate the effect of metformin on the regulation of the ovarian cycle through serum antioxidant activities in female rats fructose-induced metabolic syndrome model. Thirty-four, immature female Wistar rats (21 days-old) were randomly divided into five groups (n:4-8/group) control, carboxymethylcellulose (CMC), fructose, metformin, and fructose+metformin groups. The metabolic syndrome model was induced by fructose solution (20% w/v) for 15 weeks. Metformin was administrated by oral gavage in CMC solution for the last final 6 weeks. Vaginal cytology was evaluated before and at the 9th and 15th weeks of the experiment. Total antioxidant status (TAS), total oxidant status (TOS), and paraoxonase (PON)-1 levels were assessed in serum samples. The statistical analysis was performed using a one-way ANOVA test. Results are expressed as the mean ± standard error of the mean (SEM). Metformin restored the regularity of the estrous cycle, which was disturbed by a high fructose diet.  Moreover, dietary high-fructose markedly increased serum TOS and OSI values, but significantly decreased serum TAS and PON-1 levels than the other groups (p < 0.05). Metformin, through its antioxidant activity, may have had a beneficial effect on the impaired ovarian cycle associated with oxidative stress induced by high fructose diet.

Article Details
  • Sección
  • Research Articles
Descargas
Los datos de descargas todavía no están disponibles.
Citas
Acar DB, Demi̇rel MA, Akarca SÖD, Bi̇rdane MK (2019) The evaluation
of the oxidative stress index of reproductive tissues and serum thiol/
disulphide homeostasis during estrous cycle in bitches. Ank Üniversitesi
Vet Fakültesi Derg 67(1): 87-94.
Adhe-Rojekar A, Mogarekar MR, Rojekar MV (2018) Paraoxonase activity
in metabolic syndrome in children and adolescents. Casp J Intern
Med 9(2): 116-120.
Ahmed Mobasher M, Galal El-Tantawi H, Samy El-Said K (2020) Metformin
Ameliorates Oxidative Stress Induced by Diabetes Mellitus
and Hepatocellular Carcinoma in Rats. Rep Biochem Mol Biol 9(1):
-128.
Akintayo CO, Johnson AD, Badejogbin OC, Olaniyi KS, Oniyide AA,
Ajadi IO, Ojewale AO, Adeyomoye OI, Kayode AB (2021) High
fructose-enriched diet synergistically exacerbates endocrine but not
metabolic changes in letrozole-induced polycystic ovarian syndrome
in Wistar rats. Heliyon 7(1): e05890.
Algire C, Moiseeva O, Deschênes-Simard X, Amrein L, Petruccelli L,
Birman E, Viollet B, Ferbeyre G, Pollak MN (2012) Metformin Reduces
Endogenous Reactive Oxygen Species and Associated DNA
Damage. Cancer Prev Res (Phila Pa) 5(4): 536-543.
Apostolova N, Iannantuoni F, Gruevska A, Muntane J, Rocha M, Victor
VM (2020) Mechanisms of action of metformin in type 2 diabetes:
Effects on mitochondria and leukocyte-endothelium interactions. Redox
Biol 34: 101517.
Astiz S, Gonzalez-Bulnes A, Astiz I, Barbero A, Pesantez-Pacheco JL,
Garcia-Contreras C, Vazquez-Gomez M, Heras-Molina A (2020)
Metformin Alleviates Obesity and Systemic Oxidative Stress in
Obese Young Swine. Pharmaceuticals 13(7): 142.
Bai B, Chen H (2021) Metformin: A Novel Weapon Against Inflammation.
Front Pharmacol 12: 622262.
Camps J, Hernandez-Aguilera A, Garcia-Heredia A, Cabre N, Luciano-
Mateo F, Arenas M, Joven J (2016) Relationships Between Metformin,
Paraoxonase-1 and the Chemokine (C-C Motif) Ligand 2.
Curr Clin Pharmacol 11(4): 250-258.
Chen W, Pang Y (2021) Metabolic Syndrome and PCOS: Pathogenesis
and the Role of Metabolites. Metabolites 11(12): 869.
Cora MC, Kooistra L, Travlos G (2015) Vaginal Cytology of the Laboratory
Rat and Mouse: Review and Criteria for the Staging of the
Estrous Cycle Using Stained Vaginal Smears. Toxicol Pathol 43(6):
-793.
Dornas WC, Lima WG de, Santos RC dos, Souza MO de, Silva M, Diniz
MF, Silva ME (2012) Salt overload in fructose-fed insulin-resistant
rats decreases paraoxonase-1 activity. Nutr Metab 9(1): 63.
Erel O (2004) A novel automated direct measurement method for total antioxidant
capacity using a new generation, more stable ABTS radical
cation. Clin Biochem 37(4): 277-285.
Erel O (2005) A new automated colorimetric method for measuring total
oxidant status. Clin Biochem 38(12): 1103-1111.
Fahed G, Aoun L, Bou Zerdan M, Allam S, Bou Zerdan M, Bouferraa Y,
Assi HI (2022) Metabolic Syndrome: Updates on Pathophysiology
and Management in 2021. Int J Mol Sci 23(2): 786.
Faure M, Bertoldo MJ, Khoueiry R, Bongrani A, Brion F, Giulivi C, Dupont
J, Froment P (2018) Metformin in Reproductive Biology. Front
Endocrinol 9: 675.
Finan B, Yang B, Ottaway N, Stemmer K, Müller TD, Yi C-X, Habegger
K, Schriever SC, García-Cáceres C, Kabra DG, Hembree J, Holland
J, et al. (2012) Targeted estrogen delivery reverses the metabolic syndrome.
Nat Med 18(12): 1847-1856.
Gasser B, Kurz J, Buerki S, Mohaupt M (2022) Metformin-Treatment
Option for Social Impairment? An Open Clinical Trial to Elucidate
the Effects of Metformin Treatment on Steroid Hormones and Social
Behavior. Life 12(7): 998.
Gurka MJ, Vishnu A, Santen RJ, DeBoer MD (2016) Progression of Metabolic
Syndrome Severity During the Menopausal Transition. J Am
Heart Assoc 5(8): e003609.
Johnson NP (2014) Metformin use in women with polycystic ovary syndrome.
Ann Transl Med 2(6): 56.
Khan D, Sridhar A, Flatt PR, Moffett RC (2023) Disturbed ovarian morphology,
oestrous cycling and fertility of high fat fed rats are linked
to alterations of incretin receptor expression. Reproductive Biology,
(3): 100784
Ko E-A, Kim H-R, Kim Y-B, Kim H-S, Lee S-H (2017) Effect of High
Fructose Corn Syrup (HFCS) Intake on the Female Reproductive
Organs and Lipid Accumulation in Adult Rats. Dev Reprod 21(2):
-156.
Korkmaz OA, Sumlu E, Koca HB, Pektas MB, Kocabas A, Sadi G, Akar
F (2019) Effects of Lactobacillus Plantarum and Lactobacillus Helveticus
on Renal Insulin Signaling, Inflammatory Markers, and Glucose
Transporters in High-Fructose-Fed Rats. Medicina (Mex) 55(5): 207.
Liu J, Aylor KW, Chai W, Barrett EJ, Liu Z (2022) Metformin prevents endothelial
oxidative stress and microvascular insulin resistance during
obesity development in male rats. Am J Physiol-Endocrinol Metab
(3): E293-E306.
Lu J, Wang Z, Cao J, Chen Y, Dong Y (2018) A novel and compact review
on the role of oxidative stress in female reproduction. Reprod Biol
Endocrinol 16(1): 80.
Lv Z, Guo Y (2020) Metformin and Its Benefits for Various Diseases.
Front Endocrinol 11: 191.
Marca A la, Morgante G, Palumbo M, Cianci A, Petraglia F, De Leo V
(2002) Insulin-lowering treatment reduces aromatase activity in response
to follicle-stimulating hormone in women with polycystic
ovary syndrome. Fertil Steril 78(6): 1234-1239.
Meaney E, Sierra-Vargas P, Meaney A, Guzmán-Grenfell M, Ramírez-Sánchez
I, Hicks JJ, Olivares-Corichi I, Ceballos G (2012) Does metformin
increase paraoxonase activity in patients with the metabolic
syndrome? Additional data from the MEFISTO study. Clin Transl Sci
(3): 265-268.
Mohammed I, Hollenberg MD, Ding H, Triggle CR (2021) A Critical Review
of the Evidence That Metformin Is a Putative Anti-Aging Drug
That Enhances Healthspan and Extends Lifespan. Front Endocrinol
: 718942.
Pasquali R (2018) Contemporary approaches to the management of polycystic
ovary syndrome. Ther Adv Endocrinol Metab 9(4): 123-134.
Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V,
Squadrito F, Altavilla D, Bitto A (2017) Oxidative Stress: Harms and
Benefits for Human Health. Oxid Med Cell Longev 2017: 8416763.
Poojari P, Padgaonkar A, Paramanya A, Ali A (2022) Compendium of
polycystic ovarian syndrome and its relevance in glycation and diabetes.
J Exp Clin Med 39(1): 256-268.
Quaile MP, Melich DH, Jordan HL, Nold JB, Chism JP, Polli JW, Smith
GA, Rhodes MC (2010) Toxicity and toxicokinetics of metformin in rats. Toxicol Appl Pharmacol 243(3): 340-347.
Ren H, Shao Y, Wu C, Ma X, Lv C, Wang Q (2020) Metformin alleviates
oxidative stress and enhances autophagy in diabetic kidney disease
via AMPK/SIRT1-FoxO1 pathway. Mol Cell Endocrinol 500:
Rice S, Pellatt L, Ramanathan K, Whitehead SA, Mason HD (2009) Metformin
Inhibits Aromatase via an Extracellular Signal-Regulated Kinase-
Mediated Pathway. Endocrinology 150(10): 4794-4801.
Sentí M, Tomás M, Fitó M, Weinbrenner T, Covas M-I, Sala J, Masiá R,
Marrugat J (2003) Antioxidant paraoxonase 1 activity in the metabolic
syndrome. J Clin Endocrinol Metab 88(11): 5422-5426.
Singh A, Kukreti R, Saso L, Kukreti S (2022) Mechanistic Insight into
Oxidative Stress-Triggered Signaling Pathways and Type 2 Diabetes.
Molecules 27(3): 950.
Sugino N (2005) Reactive oxygen species in ovarian physiology. Reprod
Med Biol 4(1): 31-44.
Tan BL, Norhaizan ME, Liew W-P-P, Sulaiman Rahman H (2018) Antioxidant
and Oxidative Stress: A Mutual Interplay in Age-Related
Diseases. Front Pharmacol 9: 1162.
Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH (2006)
Combined lifestyle modification and metformin in obese patients
with polycystic ovary syndrome. A randomized, placebo-controlled,
double-blind multicentre study. Hum Reprod 21(1): 80-89.
Tangvarasittichai S (2015) Oxidative stress, insulin resistance, dyslipidemia
and type 2 diabetes mellitus. World J Diabetes 6(3): 456-480.
Torun AN, Vural M, Cece H, Camuzcuoglu H, Toy H, Aksoy N (2011)
Paraoxonase-1 is not affected in polycystic ovary syndrome without
metabolic syndrome and insulin resistance, but oxidative stress is altered.
Gynecol Endocrinol Off J Int Soc Gynecol Endocrinol 27(12):
-992.
Verit FF, Erel O, Celik N (2008) Serum paraoxonase-1 activity in women
with endometriosis and its relationship with the stage of the disease.
Hum Reprod Oxf Engl 23(1): 100-104.
Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F
(2012) Cellular and molecular mechanisms of metformin: an overview.
Clin Sci Lond Engl 1979 122(6): 253-270.
Vona R, Gambardella L, Cittadini C, Straface E, Pietraforte D (2019) Biomarkers
of Oxidative Stress in Metabolic Syndrome and Associated
Diseases. Oxid Med Cell Longev 2019: 8267234.
Wang HH, Lee DK, Liu M, Portincasa P, Wang DQ-H (2020-a) Novel Insights
into the Pathogenesis and Management of the Metabolic Syndrome.
Pediatr Gastroenterol Hepatol Nutr 23(3): 189-230.
Wang MX, Yin Q, Xu X (2020-b) A Rat Model of Polycystic Ovary Syndrome
with Insulin Resistance Induced by Letrozole Combined with
High Fat Diet. Med Sci Monit. 25; 26:e922136.
Wu Y, Tu M, Huang Y, Liu Y, Zhang D (2020) Association of Metformin
With Pregnancy Outcomes in Women With Polycystic Ovarian Syndrome
Undergoing In Vitro Fertilization: A Systematic Review and
Meta-analysis. JAMA Netw Open 3(8): e2011995.
Yang H, Xie Y, Yang D, Ren D (2017) Oxidative stress-induced apoptosis
in granulosa cells involves JNK, p53 and Puma. Oncotarget 8(15):
-25322.
Zhang D-M, Jiao R-Q, Kong L-D (2017) High Dietary Fructose: Direct or
Indirect Dangerous Factors Disturbing Tissue and Organ Functions.
Nutrients 9(4): 335.
Zhao Y, Gong C, Wang Z, Zhang J, Wang L, Zhang S, Cao J, Tao Z, Li
T, Wang B, Hu X (2017) A randomized phase II study of aromatase
inhibitors plus metformin in pre-treated postmenopausal patients with
hormone receptor positive metastatic breast cancer. Oncotarget 8(48):
-84236.