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ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH

Extracellular ADP, a derivative of ATP, interacts with the purinergic receptors in the cell membrane to regulate cellular activities. This signaling pathway remains unknown in the regulation of blood glucose in vivo. We investigated the acute activity of ADP in mice through a peritoneal injection. I...

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Autores principales: Cao, Xinyu, Ye, Xiaotong, Zhang, Shuang, Wang, Li, Xu, Yanhong, Peng, Shiqiao, Zhou, Yang, Peng, Yue, Li, Junhua, Zhang, Xiaoying, Han, Xiao, Huang, Wen-ying, Jia, Weiping, Ye, Jianping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111448/
https://www.ncbi.nlm.nih.gov/pubmed/33986729
http://dx.doi.org/10.3389/fendo.2021.663530
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author Cao, Xinyu
Ye, Xiaotong
Zhang, Shuang
Wang, Li
Xu, Yanhong
Peng, Shiqiao
Zhou, Yang
Peng, Yue
Li, Junhua
Zhang, Xiaoying
Han, Xiao
Huang, Wen-ying
Jia, Weiping
Ye, Jianping
author_facet Cao, Xinyu
Ye, Xiaotong
Zhang, Shuang
Wang, Li
Xu, Yanhong
Peng, Shiqiao
Zhou, Yang
Peng, Yue
Li, Junhua
Zhang, Xiaoying
Han, Xiao
Huang, Wen-ying
Jia, Weiping
Ye, Jianping
author_sort Cao, Xinyu
collection PubMed
description Extracellular ADP, a derivative of ATP, interacts with the purinergic receptors in the cell membrane to regulate cellular activities. This signaling pathway remains unknown in the regulation of blood glucose in vivo. We investigated the acute activity of ADP in mice through a peritoneal injection. In the lean mice, in response to the ADP treatment, the blood glucose was elevated, and pyruvate tolerance was impaired. Hepatic gluconeogenesis was enhanced with elevated expression of glucogenic genes (G6pase and Pck1) in the liver. An elevation was observed in NADH, cAMP, AMP, GMP and citrate in the liver tissue in the targeted metabolomics assay. In the primary hepatocytes, ADP activated the cAMP/PKA/CREB signaling pathway, which was blocked by the antagonist (2211) of the ADP receptor P2Y13. In the circulation, gluconeogenic hormones including glucagon and corticosterone were elevated by ADP. Insulin and thyroid hormones (T3 and T4) were not altered in the blood. In the diet-induced obese (DIO) mice, NADH was elevated in the liver tissue to match the hepatic insulin resistance. Insulin resistance was intensified by ADP for further impairment in insulin tolerance. These data suggest that ADP induced the blood glucose through direct and indirect actions in liver. One of the potential pathways involves activation of the P2Y13/cAMP/PKA/CREB signaling pathway in hepatocytes and the indirect pathway may involve induction of the gluconeogenic hormones. NADH is a signal for gluconeogenesis in the liver of both DIO mice and lean mice.
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spelling pubmed-81114482021-05-12 ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH Cao, Xinyu Ye, Xiaotong Zhang, Shuang Wang, Li Xu, Yanhong Peng, Shiqiao Zhou, Yang Peng, Yue Li, Junhua Zhang, Xiaoying Han, Xiao Huang, Wen-ying Jia, Weiping Ye, Jianping Front Endocrinol (Lausanne) Endocrinology Extracellular ADP, a derivative of ATP, interacts with the purinergic receptors in the cell membrane to regulate cellular activities. This signaling pathway remains unknown in the regulation of blood glucose in vivo. We investigated the acute activity of ADP in mice through a peritoneal injection. In the lean mice, in response to the ADP treatment, the blood glucose was elevated, and pyruvate tolerance was impaired. Hepatic gluconeogenesis was enhanced with elevated expression of glucogenic genes (G6pase and Pck1) in the liver. An elevation was observed in NADH, cAMP, AMP, GMP and citrate in the liver tissue in the targeted metabolomics assay. In the primary hepatocytes, ADP activated the cAMP/PKA/CREB signaling pathway, which was blocked by the antagonist (2211) of the ADP receptor P2Y13. In the circulation, gluconeogenic hormones including glucagon and corticosterone were elevated by ADP. Insulin and thyroid hormones (T3 and T4) were not altered in the blood. In the diet-induced obese (DIO) mice, NADH was elevated in the liver tissue to match the hepatic insulin resistance. Insulin resistance was intensified by ADP for further impairment in insulin tolerance. These data suggest that ADP induced the blood glucose through direct and indirect actions in liver. One of the potential pathways involves activation of the P2Y13/cAMP/PKA/CREB signaling pathway in hepatocytes and the indirect pathway may involve induction of the gluconeogenic hormones. NADH is a signal for gluconeogenesis in the liver of both DIO mice and lean mice. Frontiers Media S.A. 2021-04-27 /pmc/articles/PMC8111448/ /pubmed/33986729 http://dx.doi.org/10.3389/fendo.2021.663530 Text en Copyright © 2021 Cao, Ye, Zhang, Wang, Xu, Peng, Zhou, Peng, Li, Zhang, Han, Huang, Jia and Ye https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Cao, Xinyu
Ye, Xiaotong
Zhang, Shuang
Wang, Li
Xu, Yanhong
Peng, Shiqiao
Zhou, Yang
Peng, Yue
Li, Junhua
Zhang, Xiaoying
Han, Xiao
Huang, Wen-ying
Jia, Weiping
Ye, Jianping
ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH
title ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH
title_full ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH
title_fullStr ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH
title_full_unstemmed ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH
title_short ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH
title_sort adp induces blood glucose through direct and indirect mechanisms in promotion of hepatic gluconeogenesis by elevation of nadh
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111448/
https://www.ncbi.nlm.nih.gov/pubmed/33986729
http://dx.doi.org/10.3389/fendo.2021.663530
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