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Differential Expressions of Ki-67, Bcl-2, and Apoptosis Index in Endometrial Cells of Women With and Without Type II Diabetes Mellitus and Their Correlation with Clinicopathological Variables

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Abstract

The objective of this study was to investigate proliferation, apoptosis, and antiapoptotic molecule expression in endometrial cells of reproductive-aged women with and without type II diabetes mellitus (T2D). In this case-control study, a total of 80 endometrial tissue specimens from reproductive-aged women (35 in the proliferative phase and 45 in the secretory phase) were examined. The age and body mass index (BMI) were matched between the groups. Formalin-fixed and paraffin-embedded endometrial tissue samples were used for immunohistochemistry analysis. The presence of proliferation was evaluated with Ki-67 expression, antiapoptotic function of cells was evaluated with Bcl-2 expression, and apoptosis was evaluated with terminal deoxynucleotidyl transferase (TUNEL) immunoreactivity in both the glandular epithelium and stroma of endometrial tissue samples from women with and without T2D. Ki-67 expression in the glandular epithelium and Bcl-2 expression in both the glandular epithelium and stroma were significantly higher in endometrial tissue samples of women in the T2D group than the control group (p = 0.0008, p = 0.0022, and p = 0.0261, respectively). TUNEL immunoreactivity was significantly lower in the glandular epithelium of women in the T2D group than the control group (p = 0.0001). Glandular Ki-67 expression correlated positively with BMI, use of insulin, and hemoglobin A1c level (p = 0.0034, p = 0.0154, and p = 0.0011, respectively). Glandular Bcl-2 expression correlated positively with BMI and duration of T2D (p = 0.0090 and p = 0.0109, respectively). Stromal Bcl-2 expression correlated positively with duration of T2D (p = 0.0069). TUNEL immunoreactivity in the glandular epithelium correlated negatively with duration of T2D (p = 0.0340) and positively with the use of oral antidiabetic agents (p = 0.0226). Compared to age and BMI-matched controls, women with T2D experienced increased cell proliferation and decreased apoptosis in the glandular epithelium and increased antiapoptotic function in both the glandular epithelium and stromal cells. High BMI values in women with diabetes seemed to contribute to increased cell proliferation and increased antiapoptotic function in the glandular epithelium but not the stromal cells.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

ASCVD:

atherosclerotic cardiovascular diseases

Ki-67:

MKI67

Bcl-2:

B cell leukemia/lymphoma 2

T2D:

type II diabetes mellitus

BMI:

body mass index

TUNEL:

terminal dUTP nick-end labeling

ADA:

American Diabetes Association

HbA1c:

hemoglobin A1c

EC:

endometrial cancer

DM:

diabetes mellitus

SD:

standard deviation

FFA:

plasma free fatty acid

EP:

early proliferative

LP:

late proliferative

ES:

early secretory

MS:

mid secretory

LS:

late secretory

IGFBP1:

insulin-like growth factor binding protein 1

ROS:

reactive oxygen species

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Acknowledgments

The author would like to thank the subjects that participated in this study.

Funding

The study was supported by the Scientific Investigations Foundation of Balikesir University (project number: BAP.2020/010).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, School of Medicine, Balikesir University, Cagis Yerleskesi Bigadic yolu 17 km pc, 10145, Balikesir, Turkey

    Ceyda Sancakli Usta, Cagla Bahar Bulbul, Kubra Kılıc, Akin Usta & Ertan Adalı

  2. Department of Pathology, School of Medicine, Balikesir University, Balikesir, Turkey

    Gulay Turan

  3. Department of Obstetrics and Gynecology, Goztepe Research and Training Hospital, Istanbul Medeniyet University, Istanbul, Turkey

    Meryem Hocaoglu

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  1. Ceyda Sancakli Usta
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Contributions

CSU: Protocol/project development, data collection, data management, manuscript writing/editing. GT: interpretation, data management, manuscript writing/editing. CBB: data collection, data management, manuscript writing. KK: data collection, data management. MH: data management, manuscript writing/editing. AU: protocol/project development, manuscript writing/editing. EA: protocol/project development, manuscript writing/editing.

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Correspondence to Ceyda Sancakli Usta.

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The authors declare that they have no competing interests.

Ethics Approval and Consent to Participate

The authors have no connection to any companies or products mentioned in this article. The Ethics Committee at Balikesir University School of Medicine approved this study (date: 10.04.2019/ registration number: 2019/65) and all participating patients provided written informed consent before starting the study. All participants were aware during the informed consent process that the results of this study may be published.

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Sancakli Usta, C., Turan, G., Hocaoglu, M. et al. Differential Expressions of Ki-67, Bcl-2, and Apoptosis Index in Endometrial Cells of Women With and Without Type II Diabetes Mellitus and Their Correlation with Clinicopathological Variables. Reprod. Sci. 28, 1447–1456 (2021). https://doi.org/10.1007/s43032-020-00423-z

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