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Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery

Insulin is critical for glucose homeostasis, and insulin deficiency or resistance leads to the development of diabetes. Recent evidence suggests that diabetes can be remitted independent of insulin. However, the underlying mechanism remains largely elusive. In this study, we utilized metabolic surge...

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Autores principales: Lu, Zongshi, Wei, Xiao, Sun, Fang, Zhang, Hexuan, Gao, Peng, Pu, Yunfei, Wang, Anlong, Chen, Jing, Tong, Weidong, Li, Qiang, Zhou, Xunmei, Yan, Zhencheng, Zheng, Hongting, Yang, Gangyi, Huang, Yu, Liu, Daoyan, Zhu, Zhiming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155125/
https://www.ncbi.nlm.nih.gov/pubmed/30275974
http://dx.doi.org/10.1038/s41421-018-0062-x
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author Lu, Zongshi
Wei, Xiao
Sun, Fang
Zhang, Hexuan
Gao, Peng
Pu, Yunfei
Wang, Anlong
Chen, Jing
Tong, Weidong
Li, Qiang
Zhou, Xunmei
Yan, Zhencheng
Zheng, Hongting
Yang, Gangyi
Huang, Yu
Liu, Daoyan
Zhu, Zhiming
author_facet Lu, Zongshi
Wei, Xiao
Sun, Fang
Zhang, Hexuan
Gao, Peng
Pu, Yunfei
Wang, Anlong
Chen, Jing
Tong, Weidong
Li, Qiang
Zhou, Xunmei
Yan, Zhencheng
Zheng, Hongting
Yang, Gangyi
Huang, Yu
Liu, Daoyan
Zhu, Zhiming
author_sort Lu, Zongshi
collection PubMed
description Insulin is critical for glucose homeostasis, and insulin deficiency or resistance leads to the development of diabetes. Recent evidence suggests that diabetes can be remitted independent of insulin. However, the underlying mechanism remains largely elusive. In this study, we utilized metabolic surgery as a tool to identify the non-insulin determinant mechanism. Here, we report that the most common metabolic surgery, Roux-en-Y gastric bypass (RYGB), reduced insulin production but persistently maintained euglycemia in healthy Sprague-Dawley (SD) rats and C57 mice. This reduction in insulin production was associated with RYGB-mediated inhibition of pancreatic preproinsulin and polypyrimidine tract-binding protein 1. In addition, RYGB also weakened insulin sensitivity that was evaluated by hyperinsulinemic-euglycemic clamp test and downregulated signaling pathways in insulin-sensitive tissues. The mechanistic evidence suggests that RYGB predominately shifted the metabolic profile from glucose utilization to fatty acid oxidation, enhanced the energy expenditure and activated multiple metabolic pathways through reducing gut energy uptake. Importantly, the unique effect of RYGB was extended to rats with islet disruption and patients with type 2 diabetes. These results demonstrate that compulsory rearrangement of the gastrointestinal tract can initiate non-insulin determinant pathways to maintain glucose homeostasis. Based on the principle of RYGB action, the development of a noninvasive intervention of the gastrointestinal tract is a promising therapeutic route to combat disorders characterized by energy metabolism dysregulation.
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spelling pubmed-61551252018-10-01 Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery Lu, Zongshi Wei, Xiao Sun, Fang Zhang, Hexuan Gao, Peng Pu, Yunfei Wang, Anlong Chen, Jing Tong, Weidong Li, Qiang Zhou, Xunmei Yan, Zhencheng Zheng, Hongting Yang, Gangyi Huang, Yu Liu, Daoyan Zhu, Zhiming Cell Discov Article Insulin is critical for glucose homeostasis, and insulin deficiency or resistance leads to the development of diabetes. Recent evidence suggests that diabetes can be remitted independent of insulin. However, the underlying mechanism remains largely elusive. In this study, we utilized metabolic surgery as a tool to identify the non-insulin determinant mechanism. Here, we report that the most common metabolic surgery, Roux-en-Y gastric bypass (RYGB), reduced insulin production but persistently maintained euglycemia in healthy Sprague-Dawley (SD) rats and C57 mice. This reduction in insulin production was associated with RYGB-mediated inhibition of pancreatic preproinsulin and polypyrimidine tract-binding protein 1. In addition, RYGB also weakened insulin sensitivity that was evaluated by hyperinsulinemic-euglycemic clamp test and downregulated signaling pathways in insulin-sensitive tissues. The mechanistic evidence suggests that RYGB predominately shifted the metabolic profile from glucose utilization to fatty acid oxidation, enhanced the energy expenditure and activated multiple metabolic pathways through reducing gut energy uptake. Importantly, the unique effect of RYGB was extended to rats with islet disruption and patients with type 2 diabetes. These results demonstrate that compulsory rearrangement of the gastrointestinal tract can initiate non-insulin determinant pathways to maintain glucose homeostasis. Based on the principle of RYGB action, the development of a noninvasive intervention of the gastrointestinal tract is a promising therapeutic route to combat disorders characterized by energy metabolism dysregulation. Nature Publishing Group UK 2018-09-25 /pmc/articles/PMC6155125/ /pubmed/30275974 http://dx.doi.org/10.1038/s41421-018-0062-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lu, Zongshi
Wei, Xiao
Sun, Fang
Zhang, Hexuan
Gao, Peng
Pu, Yunfei
Wang, Anlong
Chen, Jing
Tong, Weidong
Li, Qiang
Zhou, Xunmei
Yan, Zhencheng
Zheng, Hongting
Yang, Gangyi
Huang, Yu
Liu, Daoyan
Zhu, Zhiming
Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery
title Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery
title_full Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery
title_fullStr Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery
title_full_unstemmed Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery
title_short Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery
title_sort non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155125/
https://www.ncbi.nlm.nih.gov/pubmed/30275974
http://dx.doi.org/10.1038/s41421-018-0062-x
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