Diabetes & Metabolism Journal

Original Article

Basic Research
Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway: Ji-Yeon Lee, Minyoung Lee, Ji Young Lee, Jaehyun Bae, Eugene Shin, Yong-ho Lee, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha; Diabetes Metab J. 2021;45(6):921-932. Published online February 22, 2021; DOI: https://doi.org/10.4093/dmj.2020.0187

8,491 View
410 Download
20 Web of Science
21 Crossref

Graphical Abstract Abstract PDF Supplementary Material PubReader ePub

Background
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism.
Methods
Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks.
Results
The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue.
Conclusion
SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.

Citations

Citations to this article as recorded by

SGLT2 inhibitors and AMPK: The road to cellular housekeeping?
Nasser Safaie, Shahab Masoumi, Shaban Alizadeh, Pourya Mirzajanzadeh, Hamid Reza Nejabati, Mobasher Hajiabbasi, Vahid Alivirdiloo, Neda Chobdari Basmenji, Aysan Derakhshi Radvar, Ziba Majidi, Yousef Faridvand
Cell Biochemistry and Function.2024;[Epub] CrossRef
Mechanisms of SGLT2 Inhibitors in Heart Failure and Their Clinical Value
Yafei Xie, Yujie Wei, Dan Li, Jie Pu, Hong Ding, Xiaowei Zhang
Journal of Cardiovascular Pharmacology.2023; 81(1): 4. CrossRef
Current Treatment Options, Including Diet, Exercise, and Medications
Mazen Noureddin, Manal F. Abdelmalek
Clinics in Liver Disease.2023; 27(2): 397. CrossRef
SGLT2 Inhibitors and Kidney Diseases: A Clinical Perspective
Panagiotis Theofilis, Rigas G. Kalaitzidis
Current Medicinal Chemistry.2023; 30(23): 2595. CrossRef
Treatment of obesity-related diabetes: significance of thermogenic adipose tissue and targetable receptors
Ruping Pan, Jiadai Liu, Yong Chen
Frontiers in Pharmacology.2023;[Epub] CrossRef
Immunomodulatory Effects of SGLT2 Inhibitors—Targeting Inflammation and Oxidative Stress in Aging
Ema Schönberger, Vjera Mihaljević, Kristina Steiner, Sandra Šarić, Tomislav Kurevija, Ljiljana Trtica Majnarić, Ines Bilić Ćurčić, Silvija Canecki-Varžić
International Journal of Environmental Research and Public Health.2023; 20(17): 6671. CrossRef
SGLT‐2 inhibitors enhance the effect of metformin to ameliorate hormonal changes and inflammatory markers in a rat PCOS model
Manal Moustafa Mahmoud, Laila Ahmed Rashed, Somia Abdulatif Soliman, Safaa Mostafa Sayed, Omneya Kamel, Samaa Samir Kamar, Rania El Sayed Hussien
Physiological Reports.2023;[Epub] CrossRef
Resting energy expenditure based on equation estimation can predict renal outcomes in patients with type 2 diabetes mellitus and biopsy-proven diabetic kidney disease
Xiang Xiao, Shuming Ji, Junlin Zhang, Deying Kang, Fang Liu
Renal Failure.2023;[Epub] CrossRef
Sodium-glucose Cotransporter 2 Inhibitors and Pathological Myocardial Hypertrophy
Zhicheng Gao, Jiaqi Bao, Yilan Hu, Junjie Tu, Lifang Ye, Lihong Wang
Current Drug Targets.2023; 24(13): 1009. CrossRef
SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1
Weijie Wang, Yilan Li, Yanxiu Zhang, Tao Ye, Kui Wang, Shuijie Li, Yao Zhang
Cardiovascular Diabetology.2023;[Epub] CrossRef
Direct cardio-protection of Dapagliflozin against obesity-related cardiomyopathy via NHE1/MAPK signaling
Ke Lin, Na Yang, Wu Luo, Jin-fu Qian, Wei-wei Zhu, Shi-ju Ye, Chen-xin Yuan, Di-yun Xu, Guang Liang, Wei-jian Huang, Pei-ren Shan
Acta Pharmacologica Sinica.2022; 43(10): 2624. CrossRef
Pleiotropic effects of SGLT2 inhibitors and heart failure outcomes
Panagiotis Theofilis, Marios Sagris, Evangelos Oikonomou, Alexios S. Antonopoulos, Gerasimos Siasos, Kostas Tsioufis, Dimitris Tousoulis
Diabetes Research and Clinical Practice.2022; 188: 109927. CrossRef
Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models
Sandra Feijóo-Bandín, Alana Aragón-Herrera, Manuel Otero-Santiago, Laura Anido-Varela, Sandra Moraña-Fernández, Estefanía Tarazón, Esther Roselló-Lletí, Manuel Portolés, Oreste Gualillo, José Ramón González-Juanatey, Francisca Lago
International Journal of Molecular Sciences.2022; 23(10): 5634. CrossRef
Potential molecular mechanism of action of sodium-glucose co-transporter 2 inhibitors in the prevention and management of diabetic retinopathy
Lia Meuthia Zaini, Arief S Kartasasmita, Tjahjono D Gondhowiardjo, Maimun Syukri, Ronny Lesmana
Expert Review of Ophthalmology.2022; 17(3): 199. CrossRef
New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure
Juexing Li, Lei Zhou, Hui Gong
Frontiers in Cardiovascular Medicine.2022;[Epub] CrossRef
Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis
Milton Packer
Circulation.2022; 146(18): 1383. CrossRef
Nutraceutical activation of Sirt1: a review
James J DiNicolantonio, Mark F McCarty, James H O'Keefe
Open Heart.2022; 9(2): e002171. CrossRef
Dapagliflozin Restores Impaired Autophagy and Suppresses Inflammation in High Glucose-Treated HK-2 Cells
Jing Xu, Munehiro Kitada, Yoshio Ogura, Haijie Liu, Daisuke Koya
Cells.2021; 10(6): 1457. CrossRef
Could Sodium/Glucose Co-Transporter-2 Inhibitors Have Antiarrhythmic Potential in Atrial Fibrillation? Literature Review and Future Considerations
Dimitrios A. Vrachatis, Konstantinos A. Papathanasiou, Konstantinos E. Iliodromitis, Sotiria G. Giotaki, Charalampos Kossyvakis, Konstantinos Raisakis, Andreas Kaoukis, Vaia Lambadiari, Dimitrios Avramides, Bernhard Reimers, Giulio G. Stefanini, Michael C
Drugs.2021; 81(12): 1381. CrossRef
Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes
Milton Packer
JACC: Heart Failure.2021; 9(8): 535. CrossRef
Ketone bodies: from enemy to friend and guardian angel
Hubert Kolb, Kerstin Kempf, Martin Röhling, Martina Lenzen-Schulte, Nanette C. Schloot, Stephan Martin
BMC Medicine.2021;[Epub] CrossRef

First
Prev
Page of 1
Next
Last

Search