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2 "Glucose transporter type 2"
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Original Article
Metabolic Risk/Epidemiology
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Kidney Gastrin/CCKBR Attenuates Type 2 Diabetes Mellitus by Inhibiting SGLT2-Mediated Glucose Reabsorption through Erk/NF-κB Signaling Pathway
Xue Zhang, Yuhan Zhang, Yang Shi, Dou Shi, Min Niu, Xue Liu, Xing Liu, Zhiwei Yang, Xianxian Wu
Received November 6, 2023  Accepted September 7, 2024  Published online December 24, 2024  
DOI: https://doi.org/10.4093/dmj.2023.0397    [Epub ahead of print]
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption.
Methods
Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells.
Results
CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erk/nuclear factor-kappa B (NF-κB) pathway.
Conclusion
Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.
Review
Others
A Journey to Understand Glucose Homeostasis: Starting from Rat Glucose Transporter Type 2 Promoter Cloning to Hyperglycemia
Yong Ho Ahn
Diabetes Metab J. 2018;42(6):465-471.   Published online November 2, 2018
DOI: https://doi.org/10.4093/dmj.2018.0116
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  • 7 Web of Science
  • 6 Crossref
AbstractAbstract PDFPubReader   

My professional journey to understand the glucose homeostasis began in the 1990s, starting from cloning of the promoter region of glucose transporter type 2 (GLUT2) gene that led us to establish research foundation of my group. When I was a graduate student, I simply thought that hyperglycemia, a typical clinical manifestation of type 2 diabetes mellitus (T2DM), could be caused by a defect in the glucose transport system in the body. Thus, if a molecular mechanism controlling glucose transport system could be understood, treatment of T2DM could be possible. In the early 70s, hyperglycemia was thought to develop primarily due to a defect in the muscle and adipose tissue; thus, muscle/adipose tissue type glucose transporter (GLUT4) became a major research interest in the diabetology. However, glucose utilization occurs not only in muscle/adipose tissue but also in liver and brain. Thus, I was interested in the hepatic glucose transport system, where glucose storage and release are the most actively occurring.

Citations

Citations to this article as recorded by  
  • Physiological functions of glucose transporter-2: From cell physiology to links with diabetes mellitus
    Zhean Shen, Yingze Hou, Guo Zhao, Libi Tan, Jili Chen, Ziqi Dong, Chunxiao Ni, Longying Pei
    Heliyon.2024; 10(3): e25459.     CrossRef
  • Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes
    Juan Zhang, Rong Zhang, Chanwei Liu, Xiaoxu Ge, Ying Wang, Fusong Jiang, Langen Zhuang, Tiantian Li, Qihan Zhu, Yanyan Jiang, Yating Chen, Ming Lu, Yanzhong Wang, Meisheng Jiang, Yanjun Liu, Limei Liu
    Diabetologia.2024; 67(8): 1698.     CrossRef
  • Estimation and implications of the genetic architecture of fasting and non-fasting blood glucose
    Zhen Qiao, Julia Sidorenko, Joana A. Revez, Angli Xue, Xueling Lu, Katri Pärna, Harold Snieder, Peter M. Visscher, Naomi R. Wray, Loic Yengo
    Nature Communications.2023;[Epub]     CrossRef
  • Umbilical Cord-Mesenchymal Stem Cell-Conditioned Medium Improves Insulin Resistance in C2C12 Cell
    Kyung-Soo Kim, Yeon Kyung Choi, Mi Jin Kim, Jung Wook Hwang, Kyunghoon Min, Sang Youn Jung, Soo-Kyung Kim, Yong-Soo Choi, Yong-Wook Cho
    Diabetes & Metabolism Journal.2021; 45(2): 260.     CrossRef
  • Aging-related modifications to G protein-coupled receptor signaling diversity
    Jaana van Gastel, Hanne Leysen, Jan Boddaert, Laura vangenechten, Louis M. Luttrell, Bronwen Martin, Stuart Maudsley
    Pharmacology & Therapeutics.2021; 223: 107793.     CrossRef
  • Glucose transporters in the small intestine in health and disease
    Hermann Koepsell
    Pflügers Archiv - European Journal of Physiology.2020; 472(9): 1207.     CrossRef

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