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

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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

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Cell Biochemistry and Function.2024;[Epub] CrossRef
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Journal of Cardiovascular Pharmacology.2023; 81(1): 4. CrossRef
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Current Medicinal Chemistry.2023; 30(23): 2595. CrossRef
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Current Drug Targets.2023; 24(13): 1009. CrossRef
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Acta Pharmacologica Sinica.2022; 43(10): 2624. CrossRef
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International Journal of Molecular Sciences.2022; 23(10): 5634. CrossRef
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Expert Review of Ophthalmology.2022; 17(3): 199. CrossRef
New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure
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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
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Drugs.2021; 81(12): 1381. CrossRef
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Response

Response: Predictors of the Therapeutic Efficacy and Consideration of the Best Combination Therapy of Sodium-Glucose Co-transporter 2 Inhibitors (Diabetes Metab J 2019;43:158–73): Ji-Yeon Lee, Eun Seok Kang; Diabetes Metab J. 2019;43(3):379-380. Published online June 13, 2019; DOI: https://doi.org/10.4093/dmj.2018.0106

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Original Article

Clinical Diabetes & Therapeutics
Predictors of the Therapeutic Efficacy and Consideration of the Best Combination Therapy of Sodium-Glucose Co-transporter 2 Inhibitors: Ji-Yeon Lee, Yongin Cho, Minyoung Lee, You Jin Kim, Yong-ho Lee, Byung-Wan Lee, Bong-Soo Cha, Eun Seok Kang; Diabetes Metab J. 2019;43(2):158-173. Published online January 25, 2019; DOI: https://doi.org/10.4093/dmj.2018.0057

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160 Download
15 Web of Science
15 Crossref

Abstract PDF Supplementary Material PubReader

Background

We investigated the predictive markers for the therapeutic efficacy and the best combination of sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin, dapagliflozin, and ipragliflozin) therapy in patients with type 2 diabetes mellitus (T2DM).

Methods

A total of 804 patients with T2DM who had taken SGLT2 inhibitor as monotherapy or an add-on therapy were analyzed. Multivariate regression analyses were performed to identify the predictors of SGLT2 inhibitor response including the classes of baseline anti-diabetic medications.

Results

After adjusting for age, sex, baseline body mass index (BMI), diabetes duration, duration of SGLT2 inhibitor use, initial glycosylated hemoglobin (HbA1c) level, estimated glomerular filtration rate (eGFR), and other anti-diabetic agent usage, multivariate analysis revealed that shorter diabetes duration, higher initial HbA1c and eGFR were associated with better glycemic response. However, baseline BMI was inversely correlated with glycemic status; lean subjects with well-controlled diabetes and obese subjects with inadequately controlled diabetes received more benefit from SGLT2 inhibitor treatment. In addition, dipeptidyl peptidase 4 (DPP4) inhibitor use was related to a greater reduction in HbA1c in patients with higher baseline HbA1c ≥7%. Sulfonylurea users experienced a larger change from baseline HbA1c but the significance was lost after adjustment for covariates and metformin and thiazolidinedione use did not affect the glycemic outcome.

Conclusion

A better response to SGLT2 inhibitors is expected in Korean T2DM patients who have higher baseline HbA1c and eGFR with a shorter diabetes duration. Moreover, the add-on of an SGLT2 inhibitor to a DPP4 inhibitor is likely to show the greatest glycemic response.

Citations

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Journal of Endocrinological Investigation.2023; 46(7): 1429. CrossRef
Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review
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Diabetes & Metabolism Journal.2023; 47(6): 808. CrossRef
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Seung-Hwan Lee, Kyung-Wan Min, Byung-Wan Lee, In-Kyung Jeong, Soon-Jib Yoo, Hyuk-Sang Kwon, Yoon-Hee Choi, Kun-Ho Yoon
Diabetes & Metabolism Journal.2021; 45(3): 339. CrossRef
Angiotensin II up-regulates sodium-glucose co-transporter 2 expression and SGLT2 inhibitor attenuates Ang II-induced hypertensive renal injury in mice
Kana N. Miyata, Chao-Sheng Lo, Shuiling Zhao, Min-Chun Liao, Yuchao Pang, Shiao-Ying Chang, Junzheng Peng, Matthias Kretzler, Janos G. Filep, Julie R. Ingelfinger, Shao-Ling Zhang, John S.D. Chan
Clinical Science.2021; 135(7): 943. CrossRef
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Diabetes & Metabolism Journal.2020; 44(4): 489. CrossRef
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Biological and Pharmaceutical Bulletin.2020; 43(5): 782. CrossRef
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Kidney Research and Clinical Practice.2020; 39(3): 269. CrossRef
Efficacy of Once-Weekly Semaglutide vs Empagliflozin Added to Metformin in Type 2 Diabetes: Patient-Level Meta-analysis
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The Journal of Clinical Endocrinology & Metabolism.2020; 105(12): e4593. CrossRef
Letter: Predictors of the Therapeutic Efficacy and Consideration of the Best Combination Therapy of Sodium-Glucose Co-transporter 2 Inhibitors (Diabetes Metab J 2019;43:158–73)
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Diabetes & Metabolism Journal.2019; 43(3): 377. CrossRef
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Diabetes & Metabolism Journal.2019; 43(5): 578. CrossRef

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