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Review Article
Diabetes, obesity and metabolism
SGLT2 Inhibitors as Systemic Metabolic Modulators: Linking Glucose Excretion to Liver Function Restoration
Seung Wan Noh, Han Sol Ryu, Yong-Ho Kim, Byung-Chul Oh
Endocrinol Metab. 2025;40(6):851-865.   Published online December 24, 2025
DOI: https://doi.org/10.3803/EnM.2025.2786
  • 1,365 View
  • 61 Download
  • 1 Web of Science
  • 1 Crossref
AbstractAbstract PDFPubReader   ePub   
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as paradigm-shifting therapeutics that extend beyond glycemic regulation, to conferring profound hepatometabolic benefits. This review delineates the multifaceted mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD), with an emphasis on systemic metabolic remodeling, mitochondrial protection, and intracellular calcium restoration. By promoting glucosuria-induced energy depletion, SGLT2 inhibition alleviates insulin resistance, suppresses hepatic lipogenesis, and activates adenosine monophosphate-activated protein kinase (AMPK)–sirtuin 1 (SIRT1)–peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α pathways that reprogram hepatocellular metabolism toward achieving lipid oxidation and autophagy. Mechanistically, SGLT2 inhibitors restore intracellular Ca2+ homeostasis via sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activation, mitigating endoplasmic reticulum (ER) stress and normalizing Ca2+–phosphoinositide (PIP)–protein kinase B (AKT) signaling, collectively reinforcing insulin responsiveness and ER-mitochondrial crosstalk. Clinically, these effects translate into consistently reducing hepatic fat, aminotransferases, and fibrosis markers in both diabetic and nondiabetic patients with MASLD. Furthermore, SGLT2 inhibitors uniquely integrate renal energy regulation with hepatic resilience through the Ca2+–PIP–SERCA axis, positioning them as prototype systemic modulators of metabolic homeostasis. Future translational efforts should refine patient stratification using metabolomic and Ca2+-imaging biomarkers to delineate therapeutic responders and advance next-generation SGLT2 analogs targeting Ca2+-dependent metabolic signaling. Collectively, SGLT2 inhibitors represent a new metabolic therapeutic class that unify glucose, lipid, and Ca2+ regulation to restore hepatocellular functions in metabolic liver diseases.

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Citations to this article as recorded by  
  • Immune Determinants of MASLD Progression: From Immunometabolic Reprogramming to Fibrotic Transformation
    Senping Xu, Zhaoshan Zhang, Zhongquan Zhou, Jiawei Guo
    Biology.2026; 15(2): 148.     CrossRef
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Original Articles
Effects of Progranulin Deficiency on Inflammation and Fibrosis in the Kidneys and Liver of Diabetic Mice Fed a High-Fat Diet
Hiroko Sakuma, Maki Murakoshi, Shinji Hagiwara, Terumi Shibata, Yusuke Suzuki, Tomohito Gohda
Received February 6, 2025  Accepted July 23, 2025  Published online September 30, 2025  
DOI: https://doi.org/10.3803/EnM.2025.2339    [Epub ahead of print]
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Progranulin (PGRN) is an important regulator of inflammation, insulin resistance, and autophagy. However, the effects of PGRN deficiency on these processes in the kidneys and liver in diabetes remain unclear. In addition, the differential effects of PGRN deficiency and sodium-glucose co-transporter-2 (SGLT2) inhibitors on these organs are unknown.
Methods
Three diabetic mouse models were used: high-fat diet and nicotinamide/streptozotocin-induced diabetic wild-type (WT) and PGRN-knockout (KO) mice (WT-diabetes mellitus [DM] and KO-DM, respectively) and WT-DM mice treated with an SGLT2 inhibitor (tofogliflozin; WT-DM/Tofo).
Results
Despite similar glycemic control in WT-DM/Tofo and KO-DM mice, expression of inflammation- and fibrosis-related genes in the kidneys was highest in WT-DM mice, lower in KO-DM mice, and lowest in WT-DM/Tofo mice. WT-DM/Tofo mice also showed increased anti-microtubule-associated protein 1A/1B-light chain 3B and decreased p62 protein levels compared with KO-DM mice. In contrast, hepatic mRNA levels related to inflammation and fibrosis were improved in both WT-DM/Tofo and KO-DM mice. Moreover, hepatic protein levels of peroxisome proliferator-activated receptor γ (PPARγ) were elevated in both groups compared with WT-DM mice, while those of PPARα were increased in WT-DM/Tofo mice compared with both WT-DM and KO-DM mice.
Conclusion
Kidney inflammation and fibrosis were ameliorated in WT-DM/Tofo mice, but these improvements were limited by autophagy insufficiency in KO-DM mice. Additionally, both WT-DM/Tofo and KO-DM mice demonstrated improved liver inflammation and fibrosis; in the former, this was associated with enhanced fatty acid oxidation via PPARα activation, while in the latter, it appeared to result from improved insulin sensitivity and anti-inflammatory effects through PPARγ activation.

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  • Effect of Tofogliflozin on Skeletal Muscle Mitochondrial Function in Male Diabetic Mice With Muscle Atrophy
    Chiaki Kishida, Maki Murakoshi, Hiroko Sakuma, Terumi Shibata, Yusuke Suzuki, Tomohito Gohda
    Journal of the Endocrine Society.2026;[Epub]     CrossRef
  • SGLT2 Inhibitors as Systemic Metabolic Modulators: Linking Glucose Excretion to Liver Function Restoration
    Seung Wan Noh, Han Sol Ryu, Yong-Ho Kim, Byung-Chul Oh
    Endocrinology and Metabolism.2025; 40(6): 851.     CrossRef
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Diabetes, obesity and metabolism
Discrepancies in Dapagliflozin Response in Terms of Glycemic Control and Body Weight Reduction
Ji Eun Jun, Kyoung-Ah Kim, Nan-Hee Kim, Kwan-Woo Lee, In-Kyung Jeong, on Behalf of the BEYOND Investigators
Endocrinol Metab. 2025;40(2):278-288.   Published online March 19, 2025
DOI: https://doi.org/10.3803/EnM.2024.2142
  • 4,399 View
  • 143 Download
  • 2 Web of Science
  • 3 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduces hyperglycemia and obesity by inhibiting renal glucose reabsorption. This post hoc study evaluated clinical factors influencing patient response to dapagliflozin.
Methods
The analysis focused on patients treated with dapagliflozin (10 mg/day for 52 weeks) within the randomized, double-blind, parallel-group BEYOND trial. Adequate glycemic control (GC) was defined as a reduction in glycated hemoglobin (HbA1c) of ≥ 1.0% or the achievement of an HbA1c level <7.0% at week 52. Significant weight loss (WL) referred to a reduction in body weight of ≥3.0% at week 52. Participants were classified into four groups based on their GC and WL responses: GC+/WL+, GC+/WL−, GC−/WL+, and GC−/WL−.
Results
Among dapagliflozin recipients (n=56), at 52 weeks, HbA1c had decreased by 1.0%±0.8% from baseline, while body weight had declined by 2.4±3.1 kg. Overall, 69.6% of participants achieved GC+, and 57.1% achieved WL+. Male sex and shorter diabetes duration were significantly associated with achieving GC+. Conversely, higher estimated glomerular filtration rate was significantly linked to WL+. The only factor significantly associated with both GC+ and WL+ was shorter diabetes duration (odds ratio, 0.81; 95% confidence interval, 0.68 to 0.97; P=0.023). The GC+ and WL+ groups exhibited favorable responses beginning soon after dapagliflozin therapy was initiated. Furthermore, HbA1c decline was more strongly associated with reduction in visceral fat than with WL.
Conclusion
A short duration of diabetes and early response to treatment appear to represent key factors in maximizing the benefits of dapagliflozin for blood glucose and weight management.

Citations

Citations to this article as recorded by  
  • A Pre‐Post Assessment of Blood Glucose Control Following Pharmacist‐Led Professional Continuous Glucose Monitoring in Rhode Island Primary Care Practices
    Kelley Doherty Sanzen, Natalya S. Salganik, Susanne M. Campbell, Carolyn A. Karner, Pano M. Yeracaris, Stephen J. Kogut
    JACCP: JOURNAL OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY.2026;[Epub]     CrossRef
  • Identification of IL18/IL18R1 signaling as a predictive biomarker of SGLT2 inhibitor efficacy in type 2 diabetes
    I-Jou Teng, Chien-Hsing Lee, Ying-Chen Chen, Sheng-Chiang Su, Chieh-Hua Lu, Peng-Fei Li, Chia-Luen Huang, Li-Ju Ho, Ming-Hsun Lin, Hsin-Ya Liu, Feng-Chih Kuo
    iScience.2025; 28(10): 113594.     CrossRef
  • Sodium‐glucose cotransporter 2 inhibitor ameliorates thiazolidinedione‐induced fluid retention through vascular leakage reduction in white adipose tissue
    Ji Yoon Kim, Hye‐Min Jang, Hye‐Jin Lee, Ah Hyeon Lee, Dong‐Hoon Kim, Sin Gon Kim, Nam Hoon Kim
    Diabetes, Obesity and Metabolism.2025;[Epub]     CrossRef
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Brief Report
Diabetes, obesity and metabolism
Ketonuria as an Indicator of Improvement of Renal Function in Patients with Type 2 Diabetes Receiving SGLT2 Inhibitor Treatment
Hyun Ah Kim, Han Na Jang, Sung Hye Kong, Young Lee, Sung Hee Choi, Young Min Cho, Hak Chul Jang, Tae Jung Oh
Endocrinol Metab. 2024;39(4):653-658.   Published online May 16, 2024
DOI: https://doi.org/10.3803/EnM.2024.1919
  • 5,573 View
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  • 3 Web of Science
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
We investigated the potential association between ketonuria during treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors and its renoprotective effect in patients with type 2 diabetes. We included 192 patients who had received SGLT2 inhibitors for more than 6 months. After propensity score matching, 52 patients each were allocated into groups with or without ketonuria, respectively. The estimated glomerular filtration rate exhibited a significant improvement only in subjects with ketonuria (without ketonuria: mean difference, –0.02 mL/min/1.73 m2 [95% confidence interval (CI), –3.87 to 3.83 mL/min/1.73 m2] vs. with ketonuria: mean difference, 6.81 mL/min/1.73 m2 [95% CI, 3.16 to 10.46 mL/min/1.73 m2]; P<0.001). Improvement in estimated glomerular filtration rate at 6 months was associated with female sex and lower baseline body weight, blood pressure, and triglyceride levels in patients with ketonuria. In conclusion, the presence of ketonuria was associated with the renoprotective effect of SGLT2 inhibitors, and female sex and the absence of metabolic syndrome components may serve as additional indicators of these medications’ substantial renoprotective effects in individuals with ketonuria.

Citations

Citations to this article as recorded by  
  • Effects of a continuous remote care intervention including nutritional ketosis on kidney function and inflammation in adults with type 2 diabetes: a post-hoc latent class trajectory analysis
    Shaminie J. Athinarayanan, Caroline G. P. Roberts, Stephen D. Phinney, Thomas Weimbs, Allon N. Friedman, Jeff S. Volek
    Frontiers in Nutrition.2025;[Epub]     CrossRef
  • SGLT2 Inhibitors as Systemic Metabolic Modulators: Linking Glucose Excretion to Liver Function Restoration
    Seung Wan Noh, Han Sol Ryu, Yong-Ho Kim, Byung-Chul Oh
    Endocrinology and Metabolism.2025; 40(6): 851.     CrossRef
  • Trigger Warning: How Modern Diet, Lifestyle, and Environment Pull the Trigger on Autosomal Dominant Polycystic Kidney Disease Progression
    Melina Messing, Jacob A. Torres, Nickolas Holznecht, Thomas Weimbs
    Nutrients.2024; 16(19): 3281.     CrossRef
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Original Article
Diabetes, obesity and metabolism
Inhibition of Sodium-Glucose Cotransporter-2 during Serum Deprivation Increases Hepatic Gluconeogenesis via the AMPK/AKT/FOXO Signaling Pathway
Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Yu-Mi Lim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee
Endocrinol Metab. 2024;39(1):98-108.   Published online January 3, 2024
DOI: https://doi.org/10.3803/EnM.2023.1786
  • 6,280 View
  • 201 Download
  • 4 Web of Science
  • 4 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Sodium-dependent glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in the renal proximal tubules, and SGLT2 inhibitors are used as therapeutic agents for treating type 2 diabetes mellitus. This study aimed to elucidate the effects and mechanisms of SGLT2 inhibition on hepatic glucose metabolism in both serum deprivation and serum supplementation states.
Methods
Huh7 cells were treated with the SGLT2 inhibitors empagliflozin and dapagliflozin to examine the effect of SGLT2 on hepatic glucose uptake. To examine the modulation of glucose metabolism by SGLT2 inhibition under serum deprivation and serum supplementation conditions, HepG2 cells were transfected with SGLT2 small interfering RNA (siRNA), cultured in serum-free Dulbecco’s modified Eagle’s medium for 16 hours, and then cultured in media supplemented with or without 10% fetal bovine serum for 8 hours.
Results
SGLT2 inhibitors dose-dependently decreased hepatic glucose uptake. Serum deprivation increased the expression levels of the gluconeogenesis genes peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), glucose 6-phosphatase (G6pase), and phosphoenolpyruvate carboxykinase (PEPCK), and their expression levels during serum deprivation were further increased in cells transfected with SGLT2 siRNA. SGLT2 inhibition by siRNA during serum deprivation induces nuclear localization of the transcription factor forkhead box class O 1 (FOXO1), decreases nuclear phosphorylated-AKT (p-AKT), and p-FOXO1 protein expression, and increases phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK) protein expression. However, treatment with the AMPK inhibitor, compound C, reversed the reduction in the protein expression levels of nuclear p- AKT and p-FOXO1 and decreased the protein expression levels of p-AMPK and PEPCK in cells transfected with SGLT2 siRNA during serum deprivation.
Conclusion
These data show that SGLT2 mediates glucose uptake in hepatocytes and that SGLT2 inhibition during serum deprivation increases gluconeogenesis via the AMPK/AKT/FOXO1 signaling pathway.

Citations

Citations to this article as recorded by  
  • Development of Cellular Energy Metabolism During Differentiation of Human iPSCs into Cortical Neurons
    Šárka Danačíková, Petr Pecina, Alena Pecinová, Jan Svoboda, David Vondrášek, Davide Alessandro Basello, Tomáš Čajka, Daniel Hadraba, Tomáš Mráček, Vladimír Kořínek, Jakub Otáhal
    Molecular Neurobiology.2026;[Epub]     CrossRef
  • Differential expression and correlation analysis of whole transcriptome for type 2 diabetes mellitus
    Fang Liu, Aihong Peng, Xiaoli Zhu, Guangming Wang
    Frontiers in Endocrinology.2025;[Epub]     CrossRef
  • Effects of Sodium–Glucose Cotransporter 2 Inhibitors on Transcription Regulation of AgRP and POMC Genes
    Dong Hee Kim, Min Jin Lee, Dasol Kang, Ah Reum Khang, Ji Hyun Bae, Joo Yeon Kim, Su Hyun Kim, Yang Ho Kang, Dongwon Yi
    Current Issues in Molecular Biology.2024; 46(7): 7505.     CrossRef
  • Sodium-glucose cotransporter 2 inhibitors ameliorate ER stress-induced pro-inflammatory cytokine expression by inhibiting CD36 in NAFLD progression in vitro
    Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Yu-Mi Lim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee
    Biochemical and Biophysical Research Communications.2024; 735: 150620.     CrossRef
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Review Article
Diabetes, obesity and metabolism
Intrarenal Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors on Tubuloglomerular Feedback and Natriuresis
Eun Sil Koh, Gheun-Ho Kim, Sungjin Chung
Endocrinol Metab. 2023;38(4):359-372.   Published online July 24, 2023
DOI: https://doi.org/10.3803/EnM.2023.1764
  • 14,899 View
  • 761 Download
  • 17 Web of Science
  • 25 Crossref
AbstractAbstract PDFPubReader   ePub   
When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule of the kidney and then recovers tubuloglomerular feedback, whereby SGLT2 inhibitors reduce glomerular hyperfiltration. This simple demonstration of their beneficial effects has perplexed experts in seeking more plausible and as yet undisclosed explanations for the whole effects of SGLT2 inhibitors, including metabolism reprogramming and the modulation of hypoxia, inflammation, and oxidative stress. Given that the renal benefits of SGLT2 inhibitors in patients with kidney disease but without diabetes were comparable to those seen in patients with diabetes, it may be reasonable to keep the emphasis on their hemodynamic actions. In this context, the aim of the present review is to provide a comprehensive overview of renal hemodynamics in individuals with diabetes who are treated with SGLT2 inhibitors, with a focus on natriuresis associated with the regulation of tubuloglomerular feedback and potential aquaresis. Throughout the discussion of alterations in renal sodium and water transports, particular attention will be given to the potential enhancement of adenosine and its receptors following SGLT2 inhibition.

Citations

Citations to this article as recorded by  
  • Sodium‐glucose cotransporter 2 inhibitor ameliorates thiazolidinedione‐induced fluid retention through vascular leakage reduction in white adipose tissue
    Ji Yoon Kim, Hye‐Min Jang, Hye‐Jin Lee, Ah Hyeon Lee, Dong‐Hoon Kim, Sin Gon Kim, Nam Hoon Kim
    Diabetes, Obesity and Metabolism.2026; 28(3): 1764.     CrossRef
  • Molecular mechanisms of PCSK9 in cardiology: therapeutic implications and clinical impacts on the cardiorenal axis
    Sandeep Kaur, Drishti Panjwani, Shareen Singh, Souvik Banerjee, Sukriti Wadehra, Amritpal Kaur, Thakur Gurjeet Singh
    Molecular and Cellular Biochemistry.2026;[Epub]     CrossRef
  • Hepatorenal vulnerability flagged by glomerular hyperfiltration in metabolic liver disease: a large health-screening cohort evidence
    Dae-Jeong Koo, Yun Tae Kim, Sun-Joon Moon, Hyemi Kwon, Se Eun Park, Sang Min Lee, Cheol-Young Park, Won-Young Lee, Sung Rae Cho, Eun-Jung Rhee
    Diabetology & Metabolic Syndrome.2026;[Epub]     CrossRef
  • Effects of SGLT2 inhibitors on NSAID-associated acute kidney injury in type 2 diabetes: a claims-based cohort study
    Yuki Kunitsu, Hiroyoshi Koide, Keiko Ikuta, Daiki Hira, Shunsaku Nakagawa, Masahiro Tsuda, Shin-Ya Morita, Tomohiro Terada
    BMC Nephrology.2026;[Epub]     CrossRef
  • Redefining SGLT2 inhibitors through cytoprotective mechanisms
    Sanja Stankovic, Zoran Miloradovic, Vladimir Petrovic, Milan Stoiljkovic
    European Journal of Pharmacology.2026; 1016: 178647.     CrossRef
  • Analysis of the Endocrine Responses to Anti-Diabetes Drugs: An Issue of Elevated Plasma Renin Concentration in Sodium-Glucose Co-Transporter 2 Inhibitor
    Cheng-Wei Lin, Shih-Yuan Hung, I-Wen Chen
    International Journal of General Medicine.2025; Volume 18: 135.     CrossRef
  • Advances in understanding and managing diabetic kidney disease: An updated review
    Elmukhtar Habas, Amnna Rayani, Aml Habas, Kalifa Farfar, Eshrak Habas, Khaled Alarbi, Ala Habas, Elmehdi Errayes, Gamal Alfitori
    Ukrainian Journal of Nephrology and Dialysis.2025; (1(85)): 66.     CrossRef
  • Dietary Polyunsaturated Fatty Acid Deficiency Impairs Renal Lipid Metabolism and Adaptive Response to Proteinuria in Murine Renal Tubules
    Yaping Wang, Pan Diao, Daiki Aomura, Takayuki Nimura, Makoto Harada, Fangping Jia, Takero Nakajima, Naoki Tanaka, Yuji Kamijo
    Nutrients.2025; 17(6): 961.     CrossRef
  • Diuretics: a review of the pharmacology and effects on glucose homeostasis
    Mauricio Di Fulvio, Yakshkumar Dilipbhai Rathod, Shorooq Khader
    Frontiers in Pharmacology.2025;[Epub]     CrossRef
  • SGLT2 Inhibitors in Cancer Patients: A Comprehensive Review of Clinical, Biochemical, and Therapeutic Implications in Cardio-Oncology
    Alessandra Greco, Maria Laura Canale, Vincenzo Quagliariello, Stefano Oliva, Andrea Tedeschi, Alessandro Inno, Marzia De Biasio, Irma Bisceglia, Luigi Tarantini, Nicola Maurea, Alessandro Navazio, Marco Corda, Attilio Iacovoni, Furio Colivicchi, Massimo G
    International Journal of Molecular Sciences.2025; 26(10): 4780.     CrossRef
  • Dual-faced guardians: SGLT2 inhibitors’ kidney protection and health challenges: a position statement by Kasralainy nephrology group (KANG)
    Amin Roshdy Soliman, Mohamed Elkhatib, Sahier El-Khashab, Rasha Ahmed Darwish, Ahmed Fayed, Tarek S. Abdelaziz, Hany Hammad, Rabab Mahmoud Ahmed, Hoda Abdelhamid Maamoun
    Diabetology & Metabolic Syndrome.2025;[Epub]     CrossRef
  • Cardiovascular and Renal Outcomes Following Repeated Naringenin Exposure in Normotensive and Hypertensive Rats
    Anelize Dada, Rita de Cássia Vilhena da Silva, Mariana Zanovello, Anelise Felício Macarini, Thaise Boeing, Valdir Cechinel Filho, Priscila de Souza
    Pharmaceuticals.2025; 18(6): 873.     CrossRef
  • Investigating the effect of SGLT2 inhibitors on cardiovascular related health status in HFmrEF and HFpEF: systematic review and meta analysis
    Tabitha Kusi-Yeboah, Isaac Gianfrancesco, Muzammil Arif Din Abdul Jabbar, Phoebe Collins, Dalton James Bally, Juliet Thornton, Kieran Williams, Ayoola Ishola, Lucy Hong, Ping Jing Toong, Milindu Wickramarachchi
    Frontiers in Cardiovascular Medicine.2025;[Epub]     CrossRef
  • Sodium-glucose co-transporter 2 inhibitor-induced increase in adenosine promotes lipolysis and weight reduction by activating reno-adipose autonomic neurocircuitry
    Aika Hagiwara, Shintaro Yamaguchi, Kazutoshi Miyashita, Kenichiro Kinouchi, Kaori Hayashi, Hiroshi Itoh
    Hypertension Research.2025; 48(10): 2664.     CrossRef
  • Chronic kidney disease in the primary care setting: A narrative review
    Faryal Safdar, Ahsan Aslam
    Journal of General and Family Medicine.2025; 26(5): 385.     CrossRef
  • Determining the role of SGLT2 inhibitors (dapagliflozin) on progression of proteinuria among non-diabetic adult patients with chronic kidney disease: a randomized controlled trial
    Shivam Srivastava, Saurabh Agarwal, Yuvraj Gulati, Alok Kumar Singh, Prakhar Aggarwal
    International Journal of Advances in Medicine.2025; 12(6): 553.     CrossRef
  • 2025 Taiwan consensus recommendations for primary care of chronic kidney disease
    Yi-Chun Tsai, Pei-Yu Wu, Tai-Shuan Lai, Chih-Chien Sung, Yi-Wen Chiu, Shang-Jyh Hwang, Yung-Ho Hsu, Mai-Szu Wu, Chung-Liang Shih
    Journal of the Formosan Medical Association.2025;[Epub]     CrossRef
  • Bridging Cardiorenal and Hepatic Disease: The Emerging Role of SGLT2 Inhibitors in Cirrhosis
    Omar Alkasabrah, Sameeha Ibrahim, Abdullah Hafeez, Muhammad Qasim Chaudhry, Faiza Jajja, Maharshi Raval, Hritvik Jain, Darshil Maheta, Siddharth Pravin Agrawal, William H. Frishman, Wilbert S. Aronow
    Cardiology in Review.2025;[Epub]     CrossRef
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    Bassant M. Mahboub, Ayman F. Refaie, Sahar M. El-Haggar, Yasser M. Hafez, Tarek M. Mostafa
    Diabetology & Metabolic Syndrome.2025;[Epub]     CrossRef
  • Results from a cross-specialty consensus on optimal management of patients with chronic kidney disease (CKD): from screening to complications
    Mustafa Arici, Samir Helmy Assaad-Khalil, Marcello Casaccia Bertoluci, Jason Choo, Yau-Jiunn Lee, Magdalena Madero, Guillermo Javier Rosa Diez, Vicente Sánchez Polo, Sungjin Chung, Teerawat Thanachayanont, Carol Pollock
    BMJ Open.2024; 14(3): e080891.     CrossRef
  • Chronic Kidney Disease and SGLT2 Inhibitors
    Eun Sil Koh, Sungjin Chung
    The Journal of Korean Diabetes.2024; 25(1): 16.     CrossRef
  • Genitourinary Tract Infections in Patients Taking SGLT2 Inhibitors
    Veraprapas Kittipibul, Zachary L. Cox, Supavit Chesdachai, Mona Fiuzat, JoAnn Lindenfeld, Robert J. Mentz
    Journal of the American College of Cardiology.2024; 83(16): 1568.     CrossRef
  • Effects of Sodium–Glucose Co-Transporter 2 Inhibitors on Serum Chloride Concentrations in Patients with Heart Failure
    Ivana Jurin, Vanja Ivanović Mihajlović, Zrinka Šakić, Marin Pavlov, Tomislav Šipić, Petra Vitlov, Hrvoje Falak, Danijela Grizelj, Šime Manola, Mario Udovičić
    Journal of Cardiovascular Development and Disease.2024; 11(11): 364.     CrossRef
  • Hemodynamic Effects of SGLT2 Inhibitors in Patients with and Without Diabetes Mellitus—A Narrative Review
    Roxana Brata, Andrei Vasile Pascalau, Ovidiu Fratila, Ioana Paul, Mihaela Mirela Muresan, Andreea Camarasan, Tiberia Ilias
    Healthcare.2024; 12(23): 2464.     CrossRef
  • Synopsis of the Korean Society of Nephrology 2023 Practical Recommendations for the Management of Diabetic Kidney Disease
    Sungjin Chung
    The Korean Journal of Medicine.2023; 98(6): 270.     CrossRef
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Original Articles
Diabetes, obesity and metabolism
Efficacy of Gemigliptin Add-on to Dapagliflozin and Metformin in Type 2 Diabetes Patients: A Randomized, Double-Blind, Placebo-Controlled Study (SOLUTION)
Byung Wan Lee, KyungWan Min, Eun-Gyoung Hong, Bon Jeong Ku, Jun Goo Kang, Suk Chon, Won-Young Lee, Mi Kyoung Park, Jae Hyeon Kim, Sang Yong Kim, Keeho Song, Soon Jib Yoo
Endocrinol Metab. 2023;38(3):328-337.   Published online June 28, 2023
DOI: https://doi.org/10.3803/EnM.2023.1688
  • 8,109 View
  • 437 Download
  • 4 Web of Science
  • 5 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
This study evaluated the efficacy and safety of add-on gemigliptin in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with metformin and dapagliflozin.
Methods
In this randomized, placebo-controlled, parallel-group, double-blind, phase III study, 315 patients were randomized to receive either gemigliptin 50 mg (n=159) or placebo (n=156) with metformin and dapagliflozin for 24 weeks. After the 24-week treatment, patients who received the placebo were switched to gemigliptin, and all patients were treated with gemigliptin for an additional 28 weeks.
Results
The baseline characteristics were similar between the two groups, except for body mass index. At week 24, the least squares mean difference (standard error) in hemoglobin A1c (HbA1c) changes was –0.66% (0.07) with a 95% confidence interval of –0.80% to –0.52%, demonstrating superior HbA1c reduction in the gemigliptin group. After week 24, the HbA1c level significantly decreased in the placebo group as gemigliptin was administered, whereas the efficacy of HbA1c reduction was maintained up to week 52 in the gemigliptin group. The safety profiles were similar: the incidence rates of treatment-emergent adverse events up to week 24 were 27.67% and 29.22% in the gemigliptin and placebo groups, respectively. The safety profiles after week 24 were similar to those up to week 24 in both groups, and no new safety findings, including hypoglycemia, were noted.
Conclusion
Add-on gemigliptin was well tolerated, providing comparable safety profiles and superior efficacy in glycemic control over placebo for long-term use in patients with T2DM who had poor glycemic control with metformin and dapagliflozin.

Citations

Citations to this article as recorded by  
  • Efficacy and safety of combination therapy using SGLT2 and DPP4 inhibitors to treat type 2 diabetes: An updated systematic review and meta‐analysis with focus on an Asian subpopulation
    Myung Jin Kim, Yun Kyung Cho, Sehee Kim, Jung Yoon Moon, Chang Hee Jung, Woo Je Lee
    Diabetes, Obesity and Metabolism.2025; 27(9): 5019.     CrossRef
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    Miao Yu, Tong Wang, Chun Xu, Yan Bi, Ling Gao, Guang Wang, Guangda Xiang, Yaoming Xue, Tao Yang, Deying Kang, Zhiguang Zhou, Lixin Guo, Xinhua Xiao
    Diabetes, Obesity and Metabolism.2025; 27(S9): 3.     CrossRef
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    Patrizia Natale, Suetonia C Green, David J Tunnicliffe, Giovanni Pellegrino, Tadashi Toyama, Giovanni FM Strippoli
    Cochrane Database of Systematic Reviews.2025;[Epub]     CrossRef
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    Jaehyuk Kim, Eunjung Song, Siyoen Kil
    Communications for Statistical Applications and Methods.2025; 32(6): 783.     CrossRef
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    Kyung Ah Han, You‐Cheol Hwang, Shin Je Moon, Ho Chan Cho, Hye Jin Yoo, Sung Hee Choi, Suk Chon, Kyoung‐Ah Kim, Tae Nyun Kim, Jun Goo Kang, Cheol‐Young Park, Jong Chul Won, Eunjoo Cho, Jeongyun Kim, Kyong Soo Park
    Diabetes, Obesity and Metabolism.2024; 26(9): 3743.     CrossRef
Close layer
Thyroid
Seaweed and Iodine Intakes and SLC5A5 rs77277498 in Relation to Thyroid Cancer
Tung Hoang, Eun Kyung Lee, Jeonghee Lee, Yul Hwangbo, Jeongseon Kim
Endocrinol Metab. 2022;37(3):513-523.   Published online May 24, 2022
DOI: https://doi.org/10.3803/EnM.2021.1306
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
This study aims to elucidate the associations among dietary seaweed (gim and miyeok/dashima) and iodine intakes, the rs77277498 polymorphism of the SLC5A5 gene codifying the sodium/iodine symporter, and thyroid cancer risk in a Korean population.
Methods
We conducted a case-control study of 117 thyroid cancer cases and 173 controls who participated in the Cancer Screenee Cohort between 2002 and 2014 at the National Cancer Center, Korea. The amount of seaweed and iodine consumption (g/day) was estimated using the residual energy adjustment method. We calculated odds ratios (ORs) and their 95% confidence intervals (CIs) using a multivariable logistic regression model for the separate and combined effect of dietary iodine-based intake and SLC5A5 polymorphism (rs77277498, C>G) on thyroid cancer.
Results
Dietary gim and iodine intakes were inversely associated with thyroid cancer, with ORs of 0.50 (95% CI, 0.30 to 0.83) and 0.57 (95% CI, 0.35 to 0.95), respectively, whereas the associations for dietary miyeok/dashima and total seaweed intakes were not significant. However, compared with individuals carrying the C/C genotype of the rs77277498 polymorphism with a low intake of all dietary factors, those carrying the G allele with a high intake had a lower risk of thyroid cancer, with ORs of 0.25 (95% CI, 0.10 to 0.56), 0.31 (95% CI, 0.12 to 0.77), 0.26 (95% CI, 0.10 to 0.62), and 0.30 (95% CI, 0.12 to 0.73) for the consumption of gim, miyeok/dashima, total seaweed, and iodine, respectively.
Conclusion
In summary, our results supported the evidence of the protective effects of dietary gim and iodine intake against thyroid cancer risk, and this association can be strengthened by SLC5A5 rs77277498 genotypes.

Citations

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Close layer
Mineral, Bone & Muscle
Comparison of the Effects of Various Antidiabetic Medication on Bone Mineral Density in Patients with Type 2 Diabetes Mellitus
Jeonghoon Ha, Yejee Lim, Mee Kyoung Kim, Hyuk-Sang Kwon, Ki-Ho Song, Seung Hyun Ko, Moo Il Kang, Sung Dae Moon, Ki-Hyun Baek
Endocrinol Metab. 2021;36(4):895-903.   Published online August 9, 2021
DOI: https://doi.org/10.3803/EnM.2021.1026
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AbstractAbstract PDFPubReader   ePub   
Background
Prospective comparative studies on the effects of various antidiabetic agents on bone metabolism are limited. This study aimed to assess changes in bone mass and biochemical bone markers in postmenopausal patients with type 2 diabetes mellitus (T2DM).
Methods
This prospective, multicenter, open-label, comparative trial included 264 patients with T2DM. Patients who had received a metformin, or sulfonylurea/metformin combination (Group 1); a thiazolidinedione combination (Group 2); a dipeptidyl peptidase-4 inhibitor (gemigliptin) combination (Group 3); or an sodium-glucose cotransporter 2 inhibitor (empagliflozin) combination (Group 4) were prospectively treated for 12 months; bone mineral density (BMD) and bone turnover marker (BTM) changes were evaluated.
Results
The femoral neck BMD percentage changes were −0.79%±2.86% (Group 1), −2.50%±3.08% (Group 2), −1.05%±2.74% (Group 3), and −1.24%±2.91% (Group 4) (P<0.05). The total hip BMD percentage changes were −0.57%±1.79% (Group 1), −1.74%±1.48% (Group 2), −0.75%±1.87% (Group 3), and −1.27%±1.72% (Group 4) (P<0.05). Mean serum BTM (C-terminal type 1 collagen telopeptide and procollagen type 1 amino-terminal propeptide) levels measured during the study period did not change over time or differ between groups.
Conclusion
Significant bone loss in the femoral neck and total hip was associated with thiazolidinedione combination regimens. However, bone loss was not significantly associated with combination regimens including gemigliptin or empagliflozin. Caution should be exercised during treatment with antidiabetic medications that adversely affect the bone in patients with diabetes at a high risk of bone loss.

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Close layer
Review Article
Diabetes
Cardiorenal Protection in Diabetic Kidney Disease
Jason F. Lee, Ecaterina Berzan, Vikas S. Sridhar, Ayodele Odutayo, David Z.I. Cherney
Endocrinol Metab. 2021;36(2):256-269.   Published online April 19, 2021
DOI: https://doi.org/10.3803/EnM.2021.987
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AbstractAbstract PDFPubReader   ePub   
Over the last 5 years there have been many new developments in the management of diabetic kidney disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 (SGLT2) inhibitors were initially used for glycemic control, but more recent studies have now shown that their benefits extend to cardiovascular and kidney outcomes. The recent addition of data on the novel mineralocorticoid receptor antagonist (MRA) gives us another approach to further decrease the residual risk of diabetic kidney disease progression. In this review we describe the mechanism of action, key studies, and possible adverse effects related to these three classes of medications. The management of type 2 diabetes now includes an increasing number of medications for the management of comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors, GLP-1 RA and MRAs in patients with type 2 diabetes for heart and kidney protection.

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Close layer
Original Article
Clinical Study
Comparative Renal Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-Glucose Cotransporter 2 Inhibitors on Individual Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis
Jae Hyun Bae, Eun-Gee Park, Sunhee Kim, Sin Gon Kim, Seokyung Hahn, Nam Hoon Kim
Endocrinol Metab. 2021;36(2):388-400.   Published online March 31, 2021
DOI: https://doi.org/10.3803/EnM.2020.912
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  • 17 Web of Science
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
To compare the renal effects of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors on individual outcomes in patients with type 2 diabetes.
Methods
We searched electronic databases (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) from inception to June 2019 to identity eligible randomized controlled trials of DPP-4 inhibitors or SGLT2 inhibitors that reported at least one kidney outcome in patients with type 2 diabetes. Outcomes of interest were microalbuminuria, macroalbuminuria, worsening nephropathy, and end-stage kidney disease (ESKD). We performed an arm-based network meta-analysis using Bayesian methods and calculated absolute risks and rank probabilities of each treatment for the outcomes.
Results
Seventeen studies with 87,263 patients were included. SGLT2 inhibitors significantly lowered the risks of individual kidney outcomes, including microalbuminuria (odds ratio [OR], 0.64; 95% credible interval [CrI], 0.41 to 0.93), macroalbuminuria (OR, 0.48; 95% CrI, 0.24 to 0.72), worsening nephropathy (OR, 0.65; 95% CrI, 0.44 to 0.91), and ESKD (OR, 0.65; 95% CrI, 0.46 to 0.98) as compared with placebo. However, DPP-4 inhibitors did not lower the risks. SGLT2 inhibitors were considerably associated with higher absolute risk reductions in all kidney outcomes than DPP-4 inhibitors, although the benefits were statistically insignificant. The rank probabilities showed that SGLT2 inhibitors were better treatments for lowering the risk of albuminuria and ESKD than placebo or DPP-4 inhibitors.
Conclusion
SGLT2 inhibitors were superior to DPP-4 inhibitors in reducing the risk of albuminuria and ESKD in patients with type 2 diabetes.

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Close layer
Review Article
Diabetes
Best Achievements in Clinical Medicine in Diabetes and Dyslipidemia in 2020
Eun-Jung Rhee, Mee-Kyung Kim, Won-Young Lee
Endocrinol Metab. 2021;36(1):41-50.   Published online February 24, 2021
DOI: https://doi.org/10.3803/EnM.2021.106
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  • 190 Download
  • 3 Web of Science
  • 4 Crossref
AbstractAbstract PDFPubReader   ePub   
Over the last two decades, our understanding of diabetes and treatment strategies have evolved tremendously, from scientific, mechanistic, and human perspectives. The categories of anti-diabetic medications expanded from a few to numerous, enabling clinicians to personalize diabetes care and treatment. Thanks to rapid growth in the field of science and medical engineering, newer treatment options are coming to the market with various advantages and disadvantages to be aware of. Therefore, clinicians should rapidly adopt new trends based on guidelines and data from many clinical trials in the field of diabetes. In the treatment of dyslipidemia, trends and guidelines are changing every year, and novel therapies are being developed. In this review, we would like to summarize the major achievements in clinical medicine in 2020 in the field of diabetes mellitus and dyslipidemia.

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Original Article
Clinical Study
Glycemic Efficacy and Metabolic Consequences of an Empagliflozin Add-on versus Conventional Dose-Increasing Strategy in Patients with Type 2 Diabetes Inadequately Controlled by Metformin and Sulfonylurea
Yujin Shin, Ji Hye Moon, Ho Jun Chin, Ele Ferrannini, Soo Lim
Endocrinol Metab. 2020;35(2):329-338.   Published online June 24, 2020
DOI: https://doi.org/10.3803/EnM.2020.35.2.329
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
We assessed the glucose-lowering efficacy of adding empagliflozin versus dose escalating existing medications in patients with uncontrolled type 2 diabetes (T2D).
Methods
This was a 6-month retrospective case-control study in subjects with uncontrolled T2D (glycated hemoglobin [HbA1c] >7%) on conventional treatment. The study group started add-on therapy with empagliflozin (10 mg once a day) while the control group was up-titrated with existing medication, using either monotherapy or a combination of metformin, sulfonylurea, and a dipeptidyl peptidase-4 inhibitor. The primary endpoints included changes in HbA1c, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PP2) levels. Secondary outcomes included changes in body composition, body mass index (BMI), and serum ketone bodies, and urinary excretion of sodium, potassium, chlorine, calcium, phosphorus, and glucose.
Results
After treatment, the reduction in HbA1c was significantly greater in the empagliflozin group than in controls (from 8.6%±1.6% to 7.6%±1.5% vs. 8.5%±1.1% to 8.1%±1.1%; P<0.01). Similar patterns were found in FPG and PP2 levels. Empagliflozin decreased systolic and diastolic blood pressure, triglycerides, and alanine and aspartate aminotransferase levels. Body weight, BMI, waist circumference, fat mass, and abdominal visceral fat area decreased significantly while lean body mass was maintained. Total ketones, β-hydroxybutyrate, and acetoacetate levels increased significantly after empagliflozin.
Conclusion
In addition to glucose lowering, an empagliflozin add-on regimen decreased blood pressure and body fat, and improved metabolic profiles significantly. Empagliflozin add-on is superior to dose escalation in patients with T2D who have inadequate glycemic control on standard medications.

Citations

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Review Articles
Diabetes
A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans
Jack Alistair Sargeant, Joseph Henson, James Adam King, Thomas Yates, Kamlesh Khunti, Melanie Jane Davies
Endocrinol Metab. 2019;34(3):247-262.   Published online September 26, 2019
DOI: https://doi.org/10.3803/EnM.2019.34.3.247
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  • 150 Web of Science
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AbstractAbstract PDFPubReader   ePub   

Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance.

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Close layer
Thyroid
Radioactive Iodine-Refractory Differentiated Thyroid Cancer and Redifferentiation Therapy
Jierui Liu, Yanqing Liu, Yansong Lin, Jun Liang
Endocrinol Metab. 2019;34(3):215-225.   Published online September 26, 2019
DOI: https://doi.org/10.3803/EnM.2019.34.3.215
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AbstractAbstract PDFPubReader   ePub   

The retained functionality of the sodium iodide symporter (NIS) expressed in differentiated thyroid cancer (DTC) cells allows the further utilization of post-surgical radioactive iodine (RAI) therapy, which is an effective treatment for reducing the risk of recurrence, and even the mortality, of DTC. Whereas, the dedifferentiation of DTC could influence the expression of functional NIS, thereby reducing the efficacy of RAI therapy in advanced DTC. Genetic alternations (such as BRAF and the rearranged during transfection [RET]/papillary thyroid cancer [PTC] rearrangement) have been widely reported to be prominently responsible for the onset, progression, and dedifferentiation of PTC, mainly through activating the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling cascades. These genetic alternations have been suggested to associate with the reduced expression of iodide-handling genes in thyroid cancer, especially the NIS gene, disabling iodine uptake and causing resistance to RAI therapy. Recently, novel and promising approaches aiming at various targets have been attempted to restore the expression of these iodine-metabolizing genes and enhance iodine uptake through in vitro studies and studies of RAI-refractory (RAIR)-DTC patients. In this review, we discuss the regulation of NIS, known mechanisms of dedifferentiation including the MAPK and PI3K pathways, and the current status of redifferentiation therapy for RAIR-DTC patients.

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Close layer
Original Articles
Thyroid
99mTc-Pertechnetate Scintigraphy Predicts Successful Postoperative Ablation in Differentiated Thyroid Carcinoma Patients Treated with Low Radioiodine Activities
Luca Giovanella, Gaetano Paone, Teresa Ruberto, Luca Ceriani, Pierpaolo Trimboli
Endocrinol Metab. 2019;34(1):63-69.   Published online February 15, 2019
DOI: https://doi.org/10.3803/EnM.2019.34.1.63
  • 7,327 View
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AbstractAbstract PDFPubReader   ePub   
Background

Postoperative routine radioiodine (RAI) treatment is currently debated for patients with low-risk differentiated thyroid carcinoma (DTC) patients. If performed, a low 131I activity (i.e., 1 to 2 GBq) is recommended with the aim to ablate thyroid remnant and facilitate subsequent follow-up by thyroglobulin measurement. The purpose of this study was to evaluate the relationship between postsurgical technetium-99m (99mTc)-pertechnetate scintigraphy and the rate of successful remnant ablation after low activity radioiodine ablation in patients with DTC.

Methods

Enrolled were 193 patients with low risk DTC who underwent total thyroidectomy and RAI ablation with a fixed 1.1 GBq activity of 131I. 99mTc-pertechnetate scans were done and thyrotropin stimulated thyroglobulin (sTg) levels measured just before ablation. Ablation effectiveness was assessed 6 to 12 months later by sTg measurement, neck ultrasound and diagnostic whole body scan.

Results

A negative 99mTc-perthecnetate scans was the best predictor of successful ablation (P<0.001) followed by preablative sTg levels <0.8 ng/mL (P=0.008) and 99mTc-pertechnetate uptake rate values <0.9% (P=0.065). Neither sex nor age of the patient at the time of ablation or tumor histology and size showed a significant association with the rate of successful ablation.

Conclusion

The 99mTc-pertechnetate scintigraphy is a simple and feasible tool to predict effectiveness of low activity 131I thyroid to ablate thyroid remnants in patients with DTC.

Citations

Citations to this article as recorded by  
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Close layer
Clinical Study
Effect of Dapagliflozin on Alanine Aminotransferase Improvement in Type 2 Diabetes Mellitus with Non-alcoholic Fatty Liver Disease
Dug-Hyun Choi, Chan-Hee Jung, Ji-Oh Mok, Chul-Hee Kim, Sung-Koo Kang, Bo-Yeon Kim
Endocrinol Metab. 2018;33(3):387-394.   Published online September 18, 2018
DOI: https://doi.org/10.3803/EnM.2018.33.3.387
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  • 135 Download
  • 40 Web of Science
  • 43 Crossref
AbstractAbstract PDFPubReader   ePub   
Background

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are expected to improve the liver function of patients with non-alcoholic fatty liver disease (NAFLD) combined type 2 diabetes mellitus (T2DM) by its characteristic mechanism. This study was designed to investigate the effect of dapagliflozin, one of the SGLT2i, on the liver function of T2DM with NAFLD when combined with metformin.

Methods

Among patients who received dual oral hypoglycemic agents within the 3 months of diagnosing NAFLD, patients who had abnormal alanine aminotransferase (ALT) level (>40 IU/L) were included. Patients were divided into two groups: metformin+dapagliflozin group and metformin+dipeptidyl peptidase-4 inhibitors (DPP4i) group. Demographic data, biochemical data and the clinical and treatment histories of all patients were reviewed.

Results

A total of 102 patients were included (dapagliflozin group, n=50; DPP4i group, n=52). Dapagliflozin group showed more weight loss and more ALT decline than DPP4i group (−2.9 kg vs. −0.4 kg, P=0.005; −21.1 U/L vs. −9.5 U/L, P=0.008, respectively) and the proportion of patients with ALT normalization after treatment was also significantly higher in the dapagliflozin group (80.0% vs. 61.5%, P=0.041). The effect of dapagliflozin with metformin on ALT normalization remained significant after adjustment for confounding variables including body weight loss (odds ratio, 3.489; P=0.046).

Conclusion

ALT improvement was statistically significant in the dapagliflozin than the DPP4i when combined with metformin and the result was consistent after adjustment for confounding variables including body weight loss.

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Close layer
The Effects of Altered Membrane Cholesterol Levels on Sodium Pump Activity in Subclinical Hypothyroidism
Suparna Roy, Anindya Dasgupta
Endocrinol Metab. 2017;32(1):129-139.   Published online February 28, 2017
DOI: https://doi.org/10.3803/EnM.2017.32.1.129
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AbstractAbstract PDFPubReader   
Background

Metabolic dysfunctions characteristic of overt hypothyroidism (OH) start at the early stage of subclinical hypothyroidism (SCH). Na+/K+-ATPase (the sodium pump) is a transmembrane enzyme that plays a vital role in cellular activities in combination with membrane lipids. We evaluated the effects of early changes in thyroid hormone and membrane cholesterol on sodium pump activity in SCH and OH patients.

Methods

In 32 SCH patients, 35 OH patients, and 34 euthyroid patients, sodium pump activity and cholesterol levels in red blood cell membranes were measured. Serum thyroxine (T4) and thyroid stimulating hormone (TSH) levels were measured using enzyme-linked immunosorbent assays. Differences in their mean values were analysed using post hoc analysis of variance. We assessed the dependence of the sodium pump on other metabolites by multiple regression analysis.

Results

Sodium pump activity and membrane cholesterol were lower in both hypothyroid groups than in control group, OH group exhibiting lower values than SCH group. In SCH group, sodium pump activity showed a significant direct dependence on membrane cholesterol with an inverse relationship with serum TSH levels. In OH group, sodium pump activity depended directly on membrane cholesterol and serum T4 levels. No dependence on serum cholesterol was observed in either case.

Conclusion

Despite the presence of elevated serum cholesterol in hypothyroidism, membrane cholesterol contributed significantly to maintain sodium pump activity in the cells. A critical reduction in membrane cholesterol levels heralds compromised enzyme activity, even in the early stage of hypothyroidism, and this can be predicted by elevated TSH levels alone, without any evident clinical manifestations.

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Review Article
Thyroid
Radioiodine Therapy in Differentiated Thyroid Cancer: The First Targeted Therapy in Oncology
June-Key Chung, Gi Jeong Cheon
Endocrinol Metab. 2014;29(3):233-239.   Published online September 25, 2014
DOI: https://doi.org/10.3803/EnM.2014.29.3.233
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  • 34 Web of Science
  • 34 Crossref
AbstractAbstract PDFPubReader   

Iodide uptake across the membranes of thyroid follicular cells and cancer cells occurs through an active transport process mediated by the sodium-iodide symporter (NIS). The rat and human NIS-coding genes were cloned and identified in 1996. Evaluation of NIS gene and protein expression is critical for the management of thyroid cancer, and several approaches to increase NIS levels have been tried. Identification of the NIS gene has provided a means of expanding its role in radionuclide therapy and molecular target-specific theragnosis (therapy and diagnosis using the same molecular target). In this article, we describe the relationship between NIS expression and the thyroid carcinoma treatment using I-131 and alternative therapeutic approaches.

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Case Report
Mediastinal Uptake Misinterpreted as Metastasis in Papillary Thyroid Cancer.
Eun Kyung Lee, Kyung Won Kim, So Yeon Park, Young Joo Park, Young Tae Kim, June Key Chung, Hwa Young Cho, Yun Hyi Ku, Hee Suk Min, Seong Hoe Park, Do Joon Park, Bo Youn Cho
J Korean Endocr Soc. 2007;22(6):460-464.   Published online December 1, 2007
DOI: https://doi.org/10.3803/jkes.2007.22.6.460
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AbstractAbstract PDF
Radioactive iodine (RAI) therapy is used for the removal of remnant thyroid tissue or metastatic thyroid cancer cells in differentiated thyroid cancer. The main mechanism of the therapy is destruction of cells by radioactive iodine that penetrates the cells though the action of the sodium-iodide symporter (NIS). We experienced a case of a 26-year-old woman with mediastinal uptake as detected on a radioiodine scan, who was previously diagnosed with papillary thyroid cancer. For diagnostic tests including chest computed tomography (CT) and a radioiodine scan, the stimulated thyroglobulin level did not show a definite cause of the mediastinal uptake. During regular follow-up, the thymus became triangular with clear margins. The patient had neither specific symptoms nor physical findings related to the presence of a thymic mass. A subsequent CT scan showed an irregular margin of the thymus, suggestive of thymic metastasis. The patient underwent a mediastinectomy. The removed specimen was composed of normal thymic tissue. Moreover, we demonstrated the presence of human NIS by immunohistochemical analysis. After thymectomy, the mediastinal uptake was markedly decreased as compared to the previous scan. This case suggests that a clinician should be suspicious for the functional uptake of thymus when metastasis is unlikely in a clinical situation.

Citations

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  • Clinical Significance of Diffuse Intrathoracic Uptake on Post-Therapy I-131 Scans in Thyroid Cancer Patients
    Hyun Su Choi, Sung Hoon Kim, Sonya Youngju Park, Hye Lim Park, Ye Young Seo, Woo Hee Choi
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Original Articles
Relationship between The Expressions of Sodium/Iodide Symporter and The Findings of Thallium-201 Scan in Thyroid Nodules.
Joon Hyop An, Min Ah Na, Sang Soo Kim, Ok Nyu Kong, Ju Won Seok, Chang Hun Lee, Chang Won Lee, In Joo Kim, Yong Ki Kim
J Korean Endocr Soc. 2004;19(2):165-174.   Published online April 1, 2004
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AbstractAbstract PDF
BACKGROUND
The sodium/iodide symporter (NIS) has an important role in the diagnosis and treatment of well differentiated thyroid carcinoma. The relationship between the uptake of thallium- 201 scan (201Tl scan) and the expression of sodium/iodide symporter (hNIS) was studied in thyroid nodules. METHODS: Patients that had undergone operations for thyroid nodules, and who received a 201Tl scan before their operations, were investigated. Anti-NIS antibodies were used to analyze the presence and distribution of the hNIS protein by immunohistochemical staining of their thyroid tissues. RESULTS: Forty-four patients (papillary carcinoma; 18, follicular adenoma; 11, adenomatous goiter; 14, nonspecific thyroiditis; 1) 30 with no immunoreactivity and 14 with a positive reaction to the anti-NIS antibody, were included. The NIS negative patients (12/30) had no 201Tl uptake, but all others were positive on 201Tl scan, and the NIS-positive patients (13/14) had positive 201Tl uptake, with 1 negative on 201Tl scan, with significant difference (p=0.035). Of the 18 patients with a papillary thyroid carcinoma, the NIS negative patients (2/10) had no 201Tl uptake and the others were positive on 201Tl scan, but without significant difference. NIS positive patients (1/8) with a papillary thyroid carcinoma had no 201Tl uptake, and the others were positive on 201Tl scan, but without significant difference. Whether the results of NIS staining and 201Tl scan were positive or not did not affect the responses of radioactive iodine therapy in our study. CONCLUSION: These results suggest that thallium-201 uptake may be correlated with hNIS expression in thyroid nodules
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The Aging-related Change of Responses to TSH in Thyroid Cells.
Young Joo Park, Tae Yong Kim, Ji Eun Kim, Young Cheol Kim, In Kyeong Chung, Chan Soo Shin, Do Joon Park, Kyoung Soo Park, Seong Yeon Kim, Sang Chul Park, Hong Kyu Lee, Bo Youn Cho
J Korean Endocr Soc. 2004;19(2):141-151.   Published online April 1, 2004
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AbstractAbstract PDF
BACKGROUND
To understand the mechanism of aging-related changes of the thyroid, the differentiated functions and growth of thyroid cells in response to TSH were investigated using aged or young thyrocytes. METHODS: FRTL-5 cells, with less than 10 or more than 45 passages, were used. After treatment with 1 U/L TSH or 1-100 mM NaI, the cAMP generation, iodide uptake, cellular proliferation or the expression of NIS mRNA or protein were measured. Sprague-Dawley rats were sacrificed at 5 and 16 weeks and 23 months, and their thyroids used for Northern blot analysis or immunohistochemistry of NIS. RESULTS: There were no differences in cAMP generation, iodide uptake, the proportions of G1/M or S phase, or intracellular DNA contents between the young and aged cells at basel levels. After TSH stimulation, these were increased in dose-dependent manners, with larger increments in the young cells. The changes in the NIS mRNA expression were similar in both the young and aged cells, but to a greater extent in the young cells. A similar phenomenon was observed in rat. However, the amount or intracellular distribution of NIS protein was not different. There was also no difference in the function or expression of NIS after treatment with a high dose of iodide. CONCLUSION: The aging-related decrease in the generation of cAMP might be thought of as one of the mechanisms of the decrement of iodide uptake or cellular proliferation with aging. The decreased expression of NIS mRNA seems to be the most important mechanism for the decreased iodide uptake capacity
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Effect of LiCl on Iodine Kinetics in Thyroid Cancer Cell Lines Transduced by Recombinant Adenovirus Containing Sodium Iodide Symporter(NIS) Gene.
Won Bae Kim, Ja Young Song, Sung Min Han, Jeong Seok Yeo, Heui ran Lee, Young Kee Shong, Dae Hyuk Moon
J Korean Endocr Soc. 2003;18(2):166-176.   Published online April 1, 2003
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AbstractAbstract PDF
BACKGROUND
Lithium is known to increase the retention of iodide in the thyroid gland, or in well differentiated thyroid cancer tissue. The effects of lithium on the function of the sodium iodide symporter (NIS) protein, especially when the lithium is increased in the retention of iodide in NIS-producing cells, the effect of lithium, on the kinetics of undifferentiated thyroid cancer cells transduced by a recombinant adenovirus containing the NIS gene, were checked. METHOD: Human NIS cDNA was inserted into pAxCAwt, a recombinant adenoviral cosmid vector, where the E1 & E2 genes have been deleted, making Rad-hNIS, which was propagated in 293 cells. The iodide uptake was evaluated by the 125I uptake assay in the undifferentiated thyroid cancer cells, ARO, FRO and NPA, following the infection with Rad-hNIS (1 or 10 MOI) in the presence, or absence, of LiCl at optimized concentrations. The iodide efflux was evaluated by the 125I efflux assay, for 1 hour, in the same cells expressing the NIS in the presence, or absence, of LiCl. Similar experiments were performed in the normal thyroid cell line, FRTL-5, cultured in 6H5 media. RESULTS: LiCl, at concentrations over 1.0mM, caused a significant decrease in the cell viability, as evaluated by trypan blue dye exclusion, in a dose dependent manner. When infected with Rad-hNIS, the iodide uptake was not affected by the LiCl in the ARO or NPA cells. However, LiCl(0.1and 1.0mM) increased the iodide uptake by 50 to 100%(vs. control) in the Rad-hNIS transduced FRO cells. In the Rad-hNIS transduced FRO cells, the iodide was released rapidly from the cells, with only 20.7+/-4.8% of the iodide uptake remaining at 1 hour, which was no different in the presence of LiCl (24.5+/-7.9%). The iodide efflux was not affected by the LiCl in the FRTL-5 cells cultured in the presence of TSH. CONCLUSION: These results suggest that the lithium-induced iodide retention in the thyroid gland, or in well differentiated thyroid cancer tissue, is not caused by the effect of the lithium on the NIS function, or the function of proteins or channels, involved in iodide transport via cell membranes. Although the iodide uptake can be markedly increased by the expression of NIS, with the transduction of Rad-hNIS, in undifferentiated thyroid cancer cells, the iodide taken up is rapidly released from the cells. A method for inducing the iodide retention in the cell should be elucidated in order to render the NIS gene therapy effective.
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Expression of Human Sodium Iodide Symporter mRNA in Papillary Thyroid Carcinoma.
Hong Kyu Kim, Il Min Ahn, Young Il Kim, Eun Sook Kim, Hyun Soo Park, Ki Young Park, Seok Jun Hong
J Korean Endocr Soc. 1998;13(2):181-188.   Published online January 1, 2001
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AbstractAbstract PDF
BACKGROUND
The sodium iodide symporter(NIS) is a plasma membrane protein which is respoasibIe for iodide transport into thyroid cell. The cDNA sequence of NIS has recently been cloned from rat and human. Intrinsic ability and its differences in iodide accumulation have been exploited as a useful tool for diagnosis and therapy of thyroid diseases. It is also known that some differentiated thyroid cancers do not take up radioactive iodine at therapeutic dose. METHODS: To understand the expression and regulation of NIS in thyroid tumars, we measured the expressons of human NIS(hNIS), TSH-receptor(R), and thyroglohulin(Tg) mRNAs from papillary thyroid carcinoma(PTC) tissues by reverse transcriptase-polymerase chain reaction (RT-PCR) and RNase protection assay(RPA). RESULT: By RT-PCR analysis, 87% of PTC expressed hNIS mRNA, but the degree of expression were variable. Interestingly, 32% of PTC showed significant level of hNIS expression even though pre-operative technetium thyroid scan of all thyroid tumors were cold but the level was lower than normal control tissues. All of PTC showed the expressions of Tg and TSH-R mRNAs and there was a correlation between hNIS mRNA and TSH-R mRNA(Rsq 0.35, p=0.01). By RPA, the expression of hNIS and TSH-R in normal control tissue were detected with 20microgram and 40microgram of total RNA respectively, but the higher concentrations(> or =60microgram for hNIS and > or =40microgram for TSH-R) were required to detect in PTC, showing that tbe expression of hNIS in FTC was lower than TSH-R expression. CONCLUSION: PTC tends to lose hNIS mRNA expression earlier than TSH-R mRNA and the measurement of hNIS mRNA in PTC may be useful as an indicator of the therapeutic response to radioactive iodine.
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Clinical Significance of Human Sodium Iodide Symporter mRNA Expressions in Primary and Metastatic Papillary Thyroid Carcinoma.
Seong Jin Lee, Hyun Joo Park, Eun Ju Lee, Ha Young Kim, Jin Kyu Koh, Ki Young Park, Sung Bae Kim, Gyung Yup Gong, Suk Joon Hong, Il Min Ahn, Sang Hee Kim
J Korean Endocr Soc. 1999;14(3):514-519.   Published online January 1, 2001
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AbstractAbstract PDF
BACKGROUND
The iodide transport into thyroid cells is an essential step in the biosynthesis of thyroid hormones. The sodium iodide symporter (NIS) which is responsible for iodide transport was cloned recently and identified as a plasma membrane glycoprotein. Recent report suggested the absence of human NIS (hNIS) mRNA expression of papillary carcinoma in thyroid indicates absence of response on radioiodine therapy for distant metastasis. To understand the change of hNIS expression at the stage of metastasis in papillary thyroid carcinomas, we evaluated the expression levels of hNIS mRNA in primary and lymph node metastatic papillary carcinoma tissues. METHODS: Seven pairs of primary and lymph node metastatic tissues were included in this study. The level of hNIS mRNA in lymph node metastatic tissues and primary tissues were evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). The level of GAPDH mRNA was used as internal control. RESULTS: Two among 6 lymph node metastatic tissues did not show hNIS mRNA even with significant hNIS expressions in papillary carcinoma tissues in thyroid. The levels of hNIS expression of remaining 4 lymph node metastatic tissues were lower than those of corresponding primary tissues. Interestingly, one case showed no hNIS expression in primary tissue, but significant hNIS expression in lymph node metastatic tissue. There was no correlation in hNIS mRNA expression between primary and lymph node metastatic tissues. CONCLUSION: No correlation was found in hNIS mRNA expression between primary and lymph node metastatic tissues, suggesting the measurements of hNIS mRNA level in primary tissues may not predict therapeutic response to radioactive iodine.
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Endocrinol Metab : Endocrinology and Metabolism
© Korean Endocrine Society.
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