ÖZ
Amaç
Gestasyonel diabetes mellitus (GDM), anne ve fetüs sağlığını tehdit eden önemli bir gebelik komplikasyonudur. GDM’nin plasenta üzerindeki histopatolojik etkilerini ve olası moleküler belirteçleri anlamak, hastalığın tanısı ve tedavisi için çok önemlidir. Hücre proliferasyonu, farklılaşması ve glikoz metabolizmasında rol oynayan nörogulin-1 (NRG-1), bu bağlamda en umut verici aday moleküllerden biridir. Bu çalışmada, GDM tanısı alan ve sağlıklı gebe kadınların plasentalarında histopatolojik bulgular ve NRG-1 ekspresyonunun immünohistokimyasal yöntemlerle karşılaştırılması ve GDM’ye özgü olası mikromorfolojik ve moleküler değişikliklerin belirlenmesi amaçlanmıştır.
Gereç ve Yöntem
Çalışma grupları; Grup 1 (kontrol, n=22) sağlıklı gebeler ve Grup 2 (GDM, n=22) GDM tanılı gebelerden oluşmuştur. Tüm plasental dokulara hematoksilen ve eozin (H&E) ve NRG-1 immünohistokimyasal boyama uygulanmıştır. H&E kesitlerinde villöz ödem, fibrinoid birikim, fetal kapiller ve sinsityal düğümler değerlendirilmiştir. İmmünohistokimyasal kesitlerde boyanma yoğunluğu; negatif (-), düşük (+), orta (++), ve yüksek (+++) olarak sınıflandırılmıştır. Demografik veriler ve vital bulgular SPSS programı ile analiz edilmiştir.
Bulgular
GDM grubunda kontrol grubuna göre; incelenen plasenta kesitlerinde villus sayısında artış, villöz ödem, fetal kapiller yapılarında dilatasyon ve kapiller sayısında artış, sinsityal düğüm oluşumunda artış ile belirgin fibrinoid birikimi ve villus çevresindeki trofoblast hücrelerinde, villus mezenkimal bağ doku hücrelerinde ve damar endotel hücrelerinde NRG-1 ekspresyonunda artış tespit edilmiştir.
Sonuç
GDM, plasentada ışık mikroskobik düzeyde patolojik değişikliklere neden olmakla birlikte NRG-1 ekspresyonunu artırmıştır. Bu çalışma, GDM tanılı olgulara ait plasental dokularda NRG-1 rolünü inceleyen literatürdeki ilk çalışmadır. NRG-1, GDM patofizyolojisinde potansiyel bir belirteç görevi görebilmekte ve bu alanda daha fazla araştırma gerekmektedir.
Anahtar Kelimeler:
Gestasyonel diabetes mellitus, nörogulin-1, plasenta, immünohistokimya
Kaynaklar
1
Sweeting A, Wong J, Murphy HR, Ross GP. A clinical update on gestational diabetes Mellitus. Endocr Rev. 2022;43:763-93.
2
International Diabetes Federation. IDF Diabetes Atlas. 8th ed. Brussels, Belgium: International Diabetes Federation; 2017. p. 40-65.
3
Zhang C, Tobias DK, Chavarro JE, Bao W, Wang D, Ley SH, et al. Adherence to healthy lifestyle and risk of gestational diabetes mellitus: prospective cohort study. BMJ. 2014;349:g5450.
4
Jenum AK, Mørkrid K, Sletner L, Vangen S, Torper JL, Nakstad B, et al. Impact of ethnicity on gestational diabetes identified with the WHO and the modified International Association of Diabetes and Pregnancy Study Groups criteria: a population-based cohort study. Eur J Endocrinol. 2012;166:317-24.
5
Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes. Diabet Med. 2004;21:103-13.
6
Plows JF, Stanley JL, Baker PN, Reynolds CM, Vickers MH. The pathophysiology of gestational diabetes mellitus. Int J Mol Sci. 2018;19:3342.
7
Tan PC, Ling LP, Omar SZ. The 50-g glucose challenge test and pregnancy outcome in a multiethnic Asian population at high risk for gestational diabetes. Int J Gynaecol Obstet. 2009;105:50-5.
8
Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358:1991-2002.
9
Lowe WL Jr, Lowe LP, Kuang A, Catalano PM, Nodzenski M, Talbot O, et al. Maternal glucose levels during pregnancy and childhood adiposity in the hyperglycemia and adverse pregnancy outcome follow-up study. Diabetologia. 2019;62:598-610.
10
Vohr BR, Boney CM. Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome?. J Matern Fetal Neonatal Med. 2008;21:149-57.
11
Tam WH, Ma RCW, Ozaki R, Li AM, Chan MHM, Yuen LY, et al. In Utero exposure to maternal hyperglycemia ıncreases childhood cardiometabolic risk in offspring. Diabetes Care. 2017;40:679-86.
12
Peters RK, Kjos SL, Xiang A, Buchanan TA. Long-term diabetogenic effect of single pregnancy in women with previous gestational diabetes mellitus. Lancet. 1996;347:227-30.
13
Homko C, Sivan E, Chen X, Reece EA, Boden G. Insulin secretion during and after pregnancy in patients with gestational diabetes mellitus. J Clin Endocrinol Metab. 2001;86:568-73.
14
Shostrom DCV, Sun Y, Oleson JJ, Snetselaar LG, Bao W. History of gestational diabetes mellitus in relation to cardiovascular disease and cardiovascular risk factors in US women. Front Endocrinol (Lausanne). 2017;8:144.
15
Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. Circulation. 2011;123:1243-62.
16
Schaefer-Graf UM, Pawliczak J, Passow D, Hartmann R, Rossi R, Bührer C, et al. Birth weight and parental BMI predict overweight in children from mothers with gestational diabetes. Diabetes Care. 2005;28:1745-50.
17
Desoye G, Hauguel-de Mouzon S. The human placenta in gestational diabetes mellitus. The insulin and cytokine network. Diabetes Care. 2007;30:120-6.
18
Calderon IM, Damasceno DC, Amorin RL, Costa RA, Brasil MA, Rudge MV. Morphometric study of placental villi and vessels in women with mild hyperglycemia or gestational or overt diabetes. Diabetes Res Clin Pract. 2007;78:65-71.
19
Carrasco-Wong I, Moller A, Giachini FR, Lima VV, Toledo F, Stojanova J, et al. Placental structure in gestational diabetes mellitus. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165535.
20
Ladfors L, Shaat N, Wiberg N, Katasarou A, Berntorp K, Kristensen K. Fetal overgrowth in women with type 1 and type 2 diabetes mellitus. PLoS One. 2017;12:e0187917.
21
Nelson SM, Coan PM, Burton GJ, Lindsay RS. Placental structure in type 1 diabetes: relation to fetal insulin, leptin, and IGF-I. Diabetes. 2009;58:2634-41.
22
Stirm L, Kovárová M, Perschbacher S, Michlmaier R, Fritsche L, Siegel-Axel D, et al. BMI-independent effects of gestational diabetes on human placenta. J Clin Endocrinol Metab. 2018;103:3299-309.
23
Abu Samra N, Jelinek HF, Alsafar H, Asghar F, Seoud M, Hussein SM, et al. Genomics and epigenomics of gestational diabetes mellitus: understanding the molecular pathways of the disease pathogenesis. Int J Mol Sci. 2022;23:3514.
24
Munro SK, Balakrishnan B, Lissaman AC, Gujral P, Ponnampalam AP. Cytokines and pregnancy: potential regulation by histone deacetylases. Mol Reprod Dev. 2021;88:321-37.
25
Martin RJ, Fanaroff AA, Walsh MC: Fanaroff and Martin’s Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant (11th ed). Philadelphia (PA): Elsevier, 2019.
26
Wang Y, Wei J, Zhang P, Zhang X, Wang Y, Chen W, et al. Neuregulin-1, a potential therapeutic target for cardiac repair. Front Pharmacol. 2022;13:945206.
27
Talmage DA. Mechanisms of neuregulin action. Novartis Found Symp. 2008;289:74-93.
28
Grieco SF, Holmes TC, Xu X. Neuregulin directed molecular mechanisms of visual cortical plasticity. J Comp Neurol. 2019;527:668-78.
29
Zhang L, Lu B, Wang W, Miao S, Zhou S, Cheng X, et al. Alteration of serum neuregulin 4 and neuregulin 1 in gestational diabetes mellitus. Ther Adv Endocrinol Metab. 2021;12:20420188211049614.
30
International association of diabetes and pregnancy study groups Consensus Panel, Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676-82.
31
Kilis S, Tosun M, Günaydın B, Çetinavcı D, Kasap B, Elbe H. Immunohistochemical examination of placental NRG-1 expression in pregnant women diagnosed with preeclampsia. Namık Kemal Tıp Dergisi. 2023;11:322-7.
32
Aldahmash WM, Alwasel SH, Aljerian K. Gestational diabetes mellitus induces placental vasculopathies. Environ Sci Pollut Res Int. 2022;29:19860-8.
33
ElSawy NA, Iqbal MS, Alkushi AG. Histomorphological study of placenta in gestational diabetes mellitus. Int J Morphol. 2018;36:687-92.
34
Lai YM, Tan GC, Shah SA, Abd Rahman R, Mohd Saleh MF, Mansor S, et al. Non-hypertensive gestational diabetes mellitus: placental histomorphology and its association with perinatal outcomes. Placenta. 2024;147:21-7.
35
Verma R, Mishra S, Kaul JM. Cellular changes in the placenta in pregnancies complicated with diabetes. Int J Morphol. 2010;28:259-64.
36
Meng Q, Shao L, Luo X, Mu Y, Xu W, Gao C, et al. Ultrastructure of placenta of gravidas with gestational diabetes mellitus. Obstet Gynecol Int. 2015;2015:283124.
37
Gheorman L, Pleşea IE, Gheorman V. Histopathological considerations of placenta in pregnancy with diabetes. Rom J Morphol Embryol. 2012;53:329-36.
38
Lee KW, Ching SM, Devaraj NK, Hoo FK. Genetic polymorphisms in neuroendocrine disorder-related candidate genes associated with pre-pregnancy obesity in gestational diabetes mellitus patients by using a stratification approach. Ann Transl Med. 2020;8:1060.
39
Lee KW, Ching SM, Ramachandran V, Tusimin M, Mohd Nordin N, Chong SC, et al. Association analysis of 14 candidate gene polymorphism with depression and stress among gestational diabetes mellitus. genes (Basel). 2019;10:988.
40
Ennequin G, Caillaud K, Chavanelle V, Teixeira A, Etienne M, Li X, et al. Neuregulin 1 treatment improves glucose tolerance in diabetic db/db mice, but not in healthy mice. Arch Physiol Biochem. 2020;126:320-5.
41
Caillaud K, Boisseau N, Ennequin G, Chavanelle V, Etienne M, Li X, et al. Neuregulin 1 improves glucose tolerance in adult and old rats. Diabetes Metab. 2016;42:96-104.
42
Vandekerckhove L, Vermeulen Z, Liu ZZ, Boimvaser S, Patzak A, Segers VF, et al. Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk. Am J Physiol Endocrinol Metab. 2016;310:E495-504.
43
Arutjunyan AV, Milyutina YP, Shcherbitskaia AD, Kerkeshko GO, Zalozniaia IV, Mikhel AV. Neurotrophins of the fetal brain and placenta in prenatal hyperhomocysteinemia. Biochemistry (Mosc). 2020;85:213-23.
