Objective: The study aims to investigate the effects of diabetes mellitus (DM) on ovarian injury and reserve in a rat model. Study Design: In this prospective experimental study, 16 female Sprague-Dawley albino rats (12 weeks, 220-240 g) were randomly divided into 2 groups. Group 1 included 8 normal healthy rats as controls. No drug was administered to the controls. Group 2 included the other 8 rats in which diabetes was induced by intraperitoneal injections of streptozotocin (STZ). After overt DM occurred (blood glucose >250 mg/dl), all the animals were euthanized and blood samples were collected by cardiac puncture for biochemical analysis. Bilateral oophorectomy was performed for histopathological examination. Immunoexpressions of nuclear factor-kappa B (NF-kB) and caspase-3 as well as anti-Müllerian hormone (AMH) levels were assessed. Values were analyzed by t test. Results: Immunoexpressions of NF-kB and caspase-3 were significantly higher in non-treated diabetic rats than in the control group (p = 0.011 and p = 0.010, respectively). In healthy control group, AMH levels (3.22 ± 0.58 ng/ml) were significantly higher than in the non-treated diabetic group (1.41 ± 0.25 ng/dl; p = 0.024). Conclusion: Hyperglycemia causes severe ovarian injury via NF-kB pathway and caspase-3 apoptotic pathway, leading to the decrease in ovarian reserve in STZ-induced diabetic rats.

Keywords:
Diabetes mellitus, NF-kB, Caspase-3, Ovarian failure, Rat
1.
Cai L, Lİ W, Wang G, Guo L, Jiang Y, Kang YJ: Hyperglycemia-induced apoptosis in mouse myocardium: mitachondrial cytochrome c-mediated caspase-3 activation pathway. Diabetes 2002;51:1938-1948.
2.
Brownlee M: The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54:1615-1625.
3.
Stitt AW, Moore JE, Sharkey JA, Murphy G, Simpson DA, Bucala R, et al: Advanced glycation end products in vitreous: structural and functional implications for diabetic vitreopathy. Invest Ophthalmol Vis Sci 1998;39:2517-2523.
4.
Nishino T, Horii Y, Shiiki H, Yamamoto H, Makita Z, Bucala R, et al: Immunuhistochemical detection of advanced glycosylation end products within the vascular lesions and glomeruli in diabetic nephropaty. Hum Pathol 1995;26:308-313.
5.
Horie K, Miyata T, Maeda K, Miyata S, Sugiyama S, Sakai H, et al: Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest 1997;100:2995-3004.
6.
Vincent AM, Edwards JL, Sadidi M, Feldman EL: The antioxidant response as a drug target in diabetic neuropathy. Curr Drug Targets 2008;9:94-100.
7.
Wan F, Leonardo MJ: The nuclear signaling of NF-kappaB: current knowledge, new insights, and futureperspectives. Cell Res 2010;20:24-33.
8.
Erbas O, Pala HG, Pala EE, Oltulu F, Aktug H, Yavasoglu A, Taskiran D: Ovarian failure in diabetic rat model: nuclear factor-kappaB, oxidative stress, and pentraxin-3. Taiwan J Obstet Gynecol 2014;53:498-503.
9.
Pala HG, Pala EE, Artunc Ulkumen B, Aktug H, Yavasoglu A, Korkmaz HA, Erbas O: The protective effect of granulocyte colony-stimulating factor on endometrium and ovary in a rat model of diabetes mellitus. Gynecol Obstet Invest 2014;78:94-100.
10.
Erbas O, Pala HG, Pala EE, Artunc Ulkumen B, Akman L, Akman T, Oltulu F, Aktug H, Yavasoglu A: Therapeutic effect of sunitinib on diabetes mellitus related ovarian injury: an experimental rat model study. Gynecol Endocrinol 2015;31:388-391.
11.
Buttke TM, Sandstrom PA: Oxidative stress as a mediator of apoptosis. Immunol Today 1994;15:7-10.
12.
Vaux DL, Strasser A: The molecular biology of apoptosis. Proc Natl Acad Sci U S A 1996;93:2239-2244.
13.
Ho FM, Liu SH, Liau CS, Huang PJ, Lin-Shiau SY: High glucose-induced apoptosis in human endothelial cells is mediated by sequential activations of c-Jun NH2- terminal kinase and caspase-3. Circulation 2000;101:2618-2624.
14.
Kumar S: The apoptotic cysteine protease CPP32. Int J Biochem Cell Biol 1997;29:393-396.
15.
Zarzycki W, Zieniewicz M: Reproductive disturbances in type 1 diabetic women. Neuro Endocrinol Lett 2005;26:733-738.
16.
Dorman JS, Steenkiste AR, Foley TP, Strotmeyer ES, Burke JP, Kuller LH, Kwoh CK; Familial Autoimmune and Diabetes (FAD) Study: Menopause in type 1 diabetic women: is it premature? Diabetes 2001;50:1857-1862.
17.
Giacco F, Brownlee M: Oxidative stress and diabetic complications. Circ Res 2010;107:1058-1070.
18.
Karasu C: Glycoxidative stress and cardiovascular complications in experimentally-induced diabetes: effects of antioxidant treatment. Open Cardiovasc Med J 2010;4:240-256.
19.
Cameron NE, Cotter MA: Pro-inflammatory mechanisms in diabetic neuropathy: focus on the nuclear factor kappa B pathway. Curr Drug Targets 2008;9:60-67.
20.
Kiriakidis S, Andreakos E, Monaco C, Foxwell B, Feldmann M, Paleolog E: VEGF expression in human macrophages is NF-kappaB-dependent: studies using adenoviruses expressing the endogenous NF-kappaB inhibitor IkappaBalpha and a kinase-defective form of the IkappaB kinase 2. J Cell Sci 2003;116:665-674.
21.
Pala HG, Erbas O, Oltulu F, Pala EE, Aktug H, Yavasoglu A: Glucose injury in diabetic rats' ovaries and effect of NF-kappa B way. Ege J Med 2013;52:32-36.
22.
Artunc-Ulkumen B, Pala HG, Pala EE, Yavasoglu A, Yigitturk G, Erbas O: Exenatide improves ovarian and endometrial injury and preserves ovarian reserve in streptozocin induced diabetic rats. Gynecol Endocrinol 2014;4:1-6.
23.
Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS, et al: Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 1995;267:2000-2003.
24.
Tatone C, Amicarelli F, Carbone MC, et al: Cellular and molecular aspects of ovarian follicle ageing. Hum Reprod Update 2008;14:131-142.
25.
Allen DA, Yaqoob MM, Harwood SM: Mechanisms of high glucose-induced apoptosis and its relationship to diabetic complications. J Nutr Biochem 2005;16:705-713.
26.
Cahng AS, Dale AN, Moley KH: Maternal diabetes adversely affects preovulatory oocyte maturation, development, and granulosa cell apoptosis. Endocrinology 2005;146:2445-2453.
27.
Salvesen GS, Dixit VM: Caspases: intracellular signaling by proteolysis. Cell 1997;91:443-446.
28.
Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF, Gardner TW, Levison SW: Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 2005;54:1559-1565.
29.
Arrais RF, Dib SA: The hypothalamus-pituitary-ovary axis and type 1 diabetes mellitus: a mini review. Hum Reprod 2006;21:327-337.
30.
Yeshaya A, Orvieto R, Dicker D, Karp M, Ben-Rafael Z: Menstrual characteristics of women suffering from insulin-dependent diabetes mellitus. Int J Fertil Menopausal Stud 1995;40:269-273.
31.
Tesone M, Ladenheim RG, Oliveira-Filho RM, Chiauzzi VA, Foglia VG, Charreau EH: Ovarian dysfunction in streptozotocin-induced diabetic rats. Proc Soc Exp Biol Med 1983;174:123-130.
32.
Katayama S, Brownscheidle CM, Wootten V, Lee JB, Shimaoka K: Absent or delayed preovulatory luteinizing hormone surge in experimental diabetes mellitus. Diabetes 1984;33:324-327.
33.
Feyereisen E, Méndez Lozano DH, Taieb J, Hesters L, Frydman R, Fanchin R: Anti-müllerian hormone: clinical insights into a promising biomarker of ovarian follicular status. Reprod Biomed Online 2006;12:695-703.
34.
Cook CL, Siow Y, Taylor S, Fallat ME: Serum müllerian-inhibiting substance levels during normal menstrual cycles. Fertil Steril 2000;73:859-861.
35.
Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB: A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006;12:685-718.
36.
Soto N, Iñiguez G, López P, Larenas G, Mujica V, Rey RA, Codner E: Anti-mullerian hormone and inhibin B levels as markers of premature ovarian aging and transition to menopause in type 1 diabetes mellitus. Hum Reprod 2009;24:2838-2844.
37.
Chang AS, Dale AN, Moley KH: Maternal diabetes adversely affects preovulatory oocyte maturation, development, and granulosa cell apoptosis. Endocrinology 2005;146:2445-2453.
© 2015 S. Karger AG, Basel
2015
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