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Pathophysiology
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Deficiency of ASGR1 Alleviates Diet-Induced Systemic Insulin Resistance via Improved Hepatic Insulin Sensitivity
Xiaorui Yu, Jiawang Tao, Yuhang Wu, Yan Chen, Penghui Li, Fan Yang, Miaoxiu Tang, Abdul Sammad, Yu Tao, Yingying Xu, Yin-Xiong Li
Diabetes Metab J. 2024;48(4):802-815.   Published online February 1, 2024
DOI: https://doi.org/10.4093/dmj.2023.0124
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Insulin resistance (IR) is the key pathological basis of many metabolic disorders. Lack of asialoglycoprotein receptor 1 (ASGR1) decreased the serum lipid levels and reduced the risk of coronary artery disease. However, whether ASGR1 also participates in the regulatory network of insulin sensitivity and glucose metabolism remains unknown.
Methods
The constructed ASGR1 knockout mice and ASGR1-/- HepG2 cell lines were used to establish the animal model of metabolic syndrome and the IR cell model by high-fat diet (HFD) or drug induction, respectively. Then we evaluated the glucose metabolism and insulin signaling in vivo and in vitro.
Results
ASGR1 deficiency ameliorated systemic IR in mice fed with HFD, evidenced by improved insulin intolerance, serum insulin, and homeostasis model assessment of IR index, mainly contributed from increased insulin signaling in the liver, but not in muscle or adipose tissues. Meanwhile, the insulin signal transduction was significantly enhanced in ASGR1-/- HepG2 cells. By transcriptome analyses and comparison, those differentially expressed genes between ASGR1 null and wild type were enriched in the insulin signal pathway, particularly in phosphoinositide 3-kinase-AKT signaling. Notably, ASGR1 deficiency significantly reduced hepatic gluconeogenesis and glycogenolysis.
Conclusion
The ASGR1 deficiency was consequentially linked with improved hepatic insulin sensitivity under metabolic stress, hepatic IR was the core factor of systemic IR, and overcoming hepatic IR significantly relieved the systemic IR. It suggests that ASGR1 is a potential intervention target for improving systemic IR in metabolic disorders.
Basic Research
DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice
Youjin Kim, Si Woo Lee, Hyejin Wang, Ryeong-Hyeon Kim, Hyun Ki Park, Hangkyu Lee, Eun Seok Kang
Diabetes Metab J. 2022;46(2):337-348.   Published online January 21, 2022
DOI: https://doi.org/10.4093/dmj.2021.0056
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  • 10 Web of Science
  • 12 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
We investigated the antidiabetic effects of DA-1241, a novel G protein-coupled receptor (GPR) 119 agonist, in vitro and in vivo.
Methods
DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks after hyperglycaemia developed. Oral/intraperitoneal glucose tolerance test and insulin tolerance test were performed. Serum insulin and glucagon-like peptide-1 (GLP-1) levels were measured during oral glucose tolerance test. Insulinoma cell line (INS-1E) cells and mouse islets were used to find whether DA-1241 directly stimulate insulin secretion in beta cell. HepG2 cells were used to evaluate the gluconeogenesis and autophagic process. Autophagic flux was evaluated by transfecting microtubule-associated protein 1 light chain 3-fused to green fluorescent protein and monomeric red fluorescent (mRFP-GFP-LC3) expression vector to HepG2 cells.
Results
Although DA-1241 treatment did not affect body weight gain and amount of food intake, fasting blood glucose level decreased along with increase in GLP-1 level. DA-1241 improved only oral glucose tolerance test and showed no effect in intraperitoneal glucose tolerance test. No significant effect was observed in insulin tolerance test. DA-1241 did not increase insulin secretion in INS-1E cell and mouse islets. DA-1241 reduced triglyceride content in the liver thereby improved fatty liver. Additionally, DA-1241 reduced gluconeogenic enzyme expression in HepG2 cells and mouse liver. DA-1241 reduced autophagic flow in HepG2 cells.
Conclusion
These findings suggested that DA-1241 augmented glucose-dependent insulin release via stimulation of GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.

Citations

Citations to this article as recorded by  
  • G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype?
    Mohan Patil, Ilaria Casari, Leon N. Warne, Marco Falasca
    Biomedicine & Pharmacotherapy.2024; 172: 116245.     CrossRef
  • GPR119 agonists for type 2 diabetes: past failures and future hopes for preclinical and early phase candidates
    Deanne H Hryciw, Rhiannon K Patten, Raymond J Rodgers, Joseph Proietto, Dana S Hutchinson, Andrew J McAinch
    Expert Opinion on Investigational Drugs.2024; 33(3): 183.     CrossRef
  • Immunomodulation through Nutrition Should Be a Key Trend in Type 2 Diabetes Treatment
    Katarzyna Napiórkowska-Baran, Paweł Treichel, Marta Czarnowska, Magdalena Drozd, Kinga Koperska, Agata Węglarz, Oskar Schmidt, Samira Darwish, Bartłomiej Szymczak, Zbigniew Bartuzi
    International Journal of Molecular Sciences.2024; 25(7): 3769.     CrossRef
  • Advances in small-molecule insulin secretagogues for diabetes treatment
    Jingqian Su, Jingran Xu, Shan Hu, Hui Ye, Lian Xie, Songying Ouyang
    Biomedicine & Pharmacotherapy.2024; 178: 117179.     CrossRef
  • Investigational new drug approval of DA-1241: what we know about GPR119 targeting for MASH therapy?
    Khaled Al Smadi, Ammar Qureshi, Besher Ashouri, Zeid Kayali
    Expert Opinion on Investigational Drugs.2024; 33(9): 877.     CrossRef
  • Discovery of orally active sulfonylphenyl thieno[3,2-d]pyrimidine derivatives as GPR119 agonists
    Heecheol Kim, Minjung Kim, Kyujin Oh, Sohee Lee, Sunyoung Lim, Sangdon Lee, Young Hoon Kim, Kwee Hyun Suh, Kyung Hoon Min
    European Journal of Medicinal Chemistry.2023; 258: 115584.     CrossRef
  • Increased expression of sodium-glucose cotransporter 2 and O-GlcNAcylation in hepatocytes drives non-alcoholic steatohepatitis
    Hye Jin Chun, Eun Ran Kim, Minyoung Lee, Da Hyun Choi, Soo Hyun Kim, Eugene Shin, Jin-Hong Kim, Jin Won Cho, Dai Hoon Han, Bong-Soo Cha, Yong-ho Lee
    Metabolism.2023; 145: 155612.     CrossRef
  • Human skin stem cell-derived hepatic cells as in vitro drug discovery model for insulin-driven de novo lipogenesis
    Karolien Buyl, Martine Vrints, Ruani Fernando, Terry Desmae, Thomas Van Eeckhoutte, Mia Jans, Jan Van Der Schueren, Joost Boeckmans, Robim M. Rodrigues, Veerle De Boe, Vera Rogiers, Joery De Kock, Filip Beirinckx, Tamara Vanhaecke
    European Journal of Pharmacology.2023; 957: 175989.     CrossRef
  • GPR119 activation by DA-1241 alleviates hepatic and systemic inflammation in MASH mice through inhibition of NFκB signaling
    Seung-Ho Lee, Hansu Park, Eun-Kyoung Yang, Bo Ram Lee, Il-Hoon Jung, Tae-Hyoung Kim, Moon Jung Goo, Yuna Chae, Mi-Kyung Kim
    Biomedicine & Pharmacotherapy.2023; 166: 115345.     CrossRef
  • Characteristics of the Latest Therapeutic Agent for Diabetes
    Nuri Yun
    The Journal of Korean Diabetes.2023; 24(3): 148.     CrossRef
  • DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice
    Youjin Kim, Si Woo Lee, Hyejin Wang, Ryeong-Hyeon Kim, Hyun Ki Park, Hangkyu Lee, Eun Seok Kang
    Diabetes & Metabolism Journal.2022; 46(2): 337.     CrossRef
  • Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target
    Chun-Liang Chen, Yu-Cheng Lin
    International Journal of Molecular Sciences.2022; 23(17): 10055.     CrossRef
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
  • 4,535 View
  • 65 Download
  • 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
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    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
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    Hermann Koepsell
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Original Article
AMPK Activator AICAR Inhibits Hepatic Gluconeogenesis and Fatty Acid Oxidation.
Jin Yob Kim, Eun Hee Koh, Woo Je Lee, Seong Min Han, Ji Young Youn, Hye Sun Park, Hyun Sik Kim, Min Seon Kim, Joong Yeol Park, Ki Up Lee
Korean Diabetes J. 2005;29(1):6-14.   Published online January 1, 2005
  • 1,387 View
  • 36 Download
AbstractAbstract PDF
BACKGROUND
Recent studies have demonstrated that adiponectin and metformin activate AMPK in the liver, and adiponectin and metformin stimulate fatty acid oxidation while inhibiting glucose production in liver. These results are in contrast to previous studies that have demonstrated that increased fatty acid oxidation in the liver is associated with increased gluconeogenesis. The present study was undertaken to reinvestigate the effects of AMPK activation by AICAR on hepatic fatty acid oxidation and gluconeogenesis. METHODS: HePG2 cells were treated with various concentrations of AICAR, and then the fatty acid oxidation and gluconeogenesis of the cells were determined. To investigate the in vivo effect of AICAR, Sprague-Dawely rats were infused with AICAR (bolus, 40 mg/g; constant, 7.5 mg/g/min-1) for 90min. RESULTS: Incubation of the HePG2 cells with higher concentrations (=1 mM) of AICAR increased fatty acid oxidation and gluconeogenesis. On the other hand, incubation of HePG2 cells with lower concentrations (0.05 and 0.1 mM) of AICAR decreased fatty acid oxidation and gluconeogenesis. Consistent with this in vitro data, the intravenous administration of AICAR to rats lowered their plasma glucose concentration and inhibited hepatic gluconeogenesis. Fatty acid oxidation in the liver tissue was significantly decreased by the administration of AICAR. CONCLUSION: The present study has demonstrated that AICAR decreased gluconeo-genesis in the liver. In contrast to previous studies, AICAR profoundly decreased hepatic fatty acid oxidation in rats and also in cultured hepatocytes

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