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Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals

Obesity is strongly associated with insulin sensitivity in type 2 diabetes (T2D), mainly because free fatty acids (FFAs) are released from excess fat tissue. Long-term exposure to high levels of FFAs and glucose leads to glucolipotoxicity, causing damage to pancreatic β-cells, thus accelerating the...

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Autores principales: Lin, Sheng-Chieh, Tsou, Sing-Hua, Kuo, Chien-Yin, Chen, Wei-Liang, Wu, Kuan-Wen, Lin, Chih-Li, Huang, Chien-Ning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10299032/
https://www.ncbi.nlm.nih.gov/pubmed/37373436
http://dx.doi.org/10.3390/ijms241210289
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author Lin, Sheng-Chieh
Tsou, Sing-Hua
Kuo, Chien-Yin
Chen, Wei-Liang
Wu, Kuan-Wen
Lin, Chih-Li
Huang, Chien-Ning
author_facet Lin, Sheng-Chieh
Tsou, Sing-Hua
Kuo, Chien-Yin
Chen, Wei-Liang
Wu, Kuan-Wen
Lin, Chih-Li
Huang, Chien-Ning
author_sort Lin, Sheng-Chieh
collection PubMed
description Obesity is strongly associated with insulin sensitivity in type 2 diabetes (T2D), mainly because free fatty acids (FFAs) are released from excess fat tissue. Long-term exposure to high levels of FFAs and glucose leads to glucolipotoxicity, causing damage to pancreatic β-cells, thus accelerating the progression of T2D. Therefore, the prevention of β-cell dysfunction and apoptosis is essential to prevent the development of T2D. Unfortunately, there are currently no specific clinical strategies for protecting β-cells, highlighting the need for effective therapies or preventive approaches to improve the survival of β-cells in T2D. Interestingly, recent studies have shown that the monoclonal antibody denosumab (DMB), used in osteoporosis, displays a positive effect on blood glucose regulation in patients with T2D. DMB acts as an osteoprotegerin (OPG) by inhibiting the receptor activator of the NF-κB ligand (RANKL), preventing the maturation and function of osteoclasts. However, the exact mechanism by which the RANK/RANKL signal affects glucose homeostasis has not been fully explained. The present study used human 1.4 × 10(7) β-cells to simulate the T2D metabolic condition of high glucose and free fatty acids (FFAs), and it investigated the ability of DMB to protect β-cells from glucolipotoxicity. Our results show that DMB effectively attenuated the cell dysfunction and apoptosis caused by high glucose and FFAs in β-cells. This may be caused by blocking the RANK/RANKL pathway that reduced mammalian sterile 20-like kinase 1 (MST1) activation and indirectly increased pancreatic and duodenal homeobox 1 (PDX-1) expression. Furthermore, the increase in inflammatory cytokines and ROS caused by the RANK/RANKL signal also played an important role in glucolipotoxicity-induced cytotoxicity, and DMB can also protect β-cells by reducing the mechanisms mentioned above. These findings provide detailed molecular mechanisms for the future development of DMB as a potential protective agent of β-cells.
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spelling pubmed-102990322023-06-28 Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals Lin, Sheng-Chieh Tsou, Sing-Hua Kuo, Chien-Yin Chen, Wei-Liang Wu, Kuan-Wen Lin, Chih-Li Huang, Chien-Ning Int J Mol Sci Article Obesity is strongly associated with insulin sensitivity in type 2 diabetes (T2D), mainly because free fatty acids (FFAs) are released from excess fat tissue. Long-term exposure to high levels of FFAs and glucose leads to glucolipotoxicity, causing damage to pancreatic β-cells, thus accelerating the progression of T2D. Therefore, the prevention of β-cell dysfunction and apoptosis is essential to prevent the development of T2D. Unfortunately, there are currently no specific clinical strategies for protecting β-cells, highlighting the need for effective therapies or preventive approaches to improve the survival of β-cells in T2D. Interestingly, recent studies have shown that the monoclonal antibody denosumab (DMB), used in osteoporosis, displays a positive effect on blood glucose regulation in patients with T2D. DMB acts as an osteoprotegerin (OPG) by inhibiting the receptor activator of the NF-κB ligand (RANKL), preventing the maturation and function of osteoclasts. However, the exact mechanism by which the RANK/RANKL signal affects glucose homeostasis has not been fully explained. The present study used human 1.4 × 10(7) β-cells to simulate the T2D metabolic condition of high glucose and free fatty acids (FFAs), and it investigated the ability of DMB to protect β-cells from glucolipotoxicity. Our results show that DMB effectively attenuated the cell dysfunction and apoptosis caused by high glucose and FFAs in β-cells. This may be caused by blocking the RANK/RANKL pathway that reduced mammalian sterile 20-like kinase 1 (MST1) activation and indirectly increased pancreatic and duodenal homeobox 1 (PDX-1) expression. Furthermore, the increase in inflammatory cytokines and ROS caused by the RANK/RANKL signal also played an important role in glucolipotoxicity-induced cytotoxicity, and DMB can also protect β-cells by reducing the mechanisms mentioned above. These findings provide detailed molecular mechanisms for the future development of DMB as a potential protective agent of β-cells. MDPI 2023-06-17 /pmc/articles/PMC10299032/ /pubmed/37373436 http://dx.doi.org/10.3390/ijms241210289 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lin, Sheng-Chieh
Tsou, Sing-Hua
Kuo, Chien-Yin
Chen, Wei-Liang
Wu, Kuan-Wen
Lin, Chih-Li
Huang, Chien-Ning
Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals
title Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals
title_full Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals
title_fullStr Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals
title_full_unstemmed Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals
title_short Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals
title_sort denosumab attenuates glucolipotoxicity-induced β-cell dysfunction and apoptosis by attenuating rank/rankl signals
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10299032/
https://www.ncbi.nlm.nih.gov/pubmed/37373436
http://dx.doi.org/10.3390/ijms241210289
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