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Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway

Approximately 90% of male diabetes mellitus patients have varying degrees of testicular dysfunction. The molecular mechanism underlying diabetes-induced testicular damage has not been thoroughly elucidated. In this research, we sought to determine the influence of metformin (Met) on diabetes-induced...

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Autores principales: Liu, Yuning, Yang, Zhen, Kong, Dongbo, Zhang, Youzhi, Yu, Wei, Zha, Wenliang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906848/
https://www.ncbi.nlm.nih.gov/pubmed/31871550
http://dx.doi.org/10.1155/2019/5681701
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author Liu, Yuning
Yang, Zhen
Kong, Dongbo
Zhang, Youzhi
Yu, Wei
Zha, Wenliang
author_facet Liu, Yuning
Yang, Zhen
Kong, Dongbo
Zhang, Youzhi
Yu, Wei
Zha, Wenliang
author_sort Liu, Yuning
collection PubMed
description Approximately 90% of male diabetes mellitus patients have varying degrees of testicular dysfunction. The molecular mechanism underlying diabetes-induced testicular damage has not been thoroughly elucidated. In this research, we sought to determine the influence of metformin (Met) on diabetes-induced testicular injury and the mechanism involved with a focus on testicular dysfunction, apoptosis, autophagy, and prokineticin 2 (PK2) signalling. In our study, C57BL/6J mice were randomly divided into the normal control group, the diabetes group, and the Met-treated group. Streptozotocin (50 mg·kg(−1)·d(−1)) was injected intraperitoneally into the mice for 5 days in a row to induce type 1 diabetes, which was diagnosed by a blood glucose level ≥ 16.7 mmol/L after 7 days. The experimental animals were orally administered Met (250 mg·kg(−1)·d(−1)) for 16 weeks. Properties of testicular function, including sperm motility and the total concentration of epididymal sperm, were assessed. Changes in testicular structure, such as the blood-testis barrier, histological pathology, and organelles, were observed. The levels of apoptosis and expression of related proteins, such as Bax and Bcl-2, were measured. Moreover, autophagy-related proteins, including Beclin-1, p62, and LC3B, as well as the PK2/PKR pathway, which consists of PK2, PKR1, PKR2, AKT, and GSK3β, were analysed. Upon the induction of diabetes, reproductive capacity was significantly impaired and a disordered arrangement of testicular seminiferous tubules and destroyed organelles in spermatogenic cells was observed. Met administration preserved testicular function and structure. In addition, in mice with diabetes, the levels of PK2, PKR2, p-Akt, and p-GSK3β were significantly decreased at different times, while that of PKR1 was markedly increased, and these changes were normalized by Met. Furthermore, diabetic mice showed increased apoptosis and decreased autophagy in the testes, the effects of which were nullified by Met. These results suggest that Met rescues diabetes-induced testicular damage by attenuating apoptosis and inducing autophagy. This effect is likely mediated by the PK2/PKR/AKT/GSK3β signalling pathway.
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spelling pubmed-69068482019-12-23 Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway Liu, Yuning Yang, Zhen Kong, Dongbo Zhang, Youzhi Yu, Wei Zha, Wenliang Oxid Med Cell Longev Research Article Approximately 90% of male diabetes mellitus patients have varying degrees of testicular dysfunction. The molecular mechanism underlying diabetes-induced testicular damage has not been thoroughly elucidated. In this research, we sought to determine the influence of metformin (Met) on diabetes-induced testicular injury and the mechanism involved with a focus on testicular dysfunction, apoptosis, autophagy, and prokineticin 2 (PK2) signalling. In our study, C57BL/6J mice were randomly divided into the normal control group, the diabetes group, and the Met-treated group. Streptozotocin (50 mg·kg(−1)·d(−1)) was injected intraperitoneally into the mice for 5 days in a row to induce type 1 diabetes, which was diagnosed by a blood glucose level ≥ 16.7 mmol/L after 7 days. The experimental animals were orally administered Met (250 mg·kg(−1)·d(−1)) for 16 weeks. Properties of testicular function, including sperm motility and the total concentration of epididymal sperm, were assessed. Changes in testicular structure, such as the blood-testis barrier, histological pathology, and organelles, were observed. The levels of apoptosis and expression of related proteins, such as Bax and Bcl-2, were measured. Moreover, autophagy-related proteins, including Beclin-1, p62, and LC3B, as well as the PK2/PKR pathway, which consists of PK2, PKR1, PKR2, AKT, and GSK3β, were analysed. Upon the induction of diabetes, reproductive capacity was significantly impaired and a disordered arrangement of testicular seminiferous tubules and destroyed organelles in spermatogenic cells was observed. Met administration preserved testicular function and structure. In addition, in mice with diabetes, the levels of PK2, PKR2, p-Akt, and p-GSK3β were significantly decreased at different times, while that of PKR1 was markedly increased, and these changes were normalized by Met. Furthermore, diabetic mice showed increased apoptosis and decreased autophagy in the testes, the effects of which were nullified by Met. These results suggest that Met rescues diabetes-induced testicular damage by attenuating apoptosis and inducing autophagy. This effect is likely mediated by the PK2/PKR/AKT/GSK3β signalling pathway. Hindawi 2019-11-28 /pmc/articles/PMC6906848/ /pubmed/31871550 http://dx.doi.org/10.1155/2019/5681701 Text en Copyright © 2019 Yuning Liu et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Liu, Yuning
Yang, Zhen
Kong, Dongbo
Zhang, Youzhi
Yu, Wei
Zha, Wenliang
Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway
title Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway
title_full Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway
title_fullStr Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway
title_full_unstemmed Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway
title_short Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway
title_sort metformin ameliorates testicular damage in male mice with streptozotocin-induced type 1 diabetes through the pk2/pkr pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906848/
https://www.ncbi.nlm.nih.gov/pubmed/31871550
http://dx.doi.org/10.1155/2019/5681701
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