Diabetes & Metabolism Journal

Review

Metabolic Risk/Epidemiology
Hepatic Fibrosis and Cancer: The Silent Threats of Metabolic Syndrome: Scott L. Friedman; Diabetes Metab J. 2024;48(2):161-169. Published online January 26, 2024; DOI: https://doi.org/10.4093/dmj.2023.0240

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Metabolic dysfunction-associated steatotic (fatty) liver disease (MASLD), previously termed non-alcoholic fatty liver disease, is a worldwide epidemic that can lead to hepatic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The disease is typically a component of the metabolic syndrome that accompanies obesity, and is often overlooked because the liver manifestations are clinically silent until late-stage disease is present (i.e., cirrhosis). Moreover, Asian populations, including Koreans, have a higher fraction of patients who are lean, yet their illness has the same prognosis or worse than those who are obese. Nonetheless, ongoing injury can lead to hepatic inflammation and ballooning of hepatocytes as classic features. Over time, fibrosis develops following activation of hepatic stellate cells, the liver’s main fibrogenic cell type. The disease is usually more advanced in patients with type 2 diabetes mellitus, indicating that all diabetic patients should be screened for liver disease. Although there has been substantial progress in clarifying pathways of injury and fibrosis, there no approved therapies yet, but current research seeks to uncover the pathways driving hepatic inflammation and fibrosis, in hopes of identifying new therapeutic targets. Emerging molecular methods, especially single cell sequencing technologies, are revolutionizing our ability to clarify mechanisms underlying MASLD-associated fibrosis and HCC.

Citations

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Prognostic Impact of Metabolic Syndrome and Steatotic Liver Disease in Hepatocellular Carcinoma Using Machine Learning Techniques
Sergio Gil-Rojas, Miguel Suárez, Pablo Martínez-Blanco, Ana M. Torres, Natalia Martínez-García, Pilar Blasco, Miguel Torralba, Jorge Mateo
Metabolites.2024; 14(6): 305. CrossRef
Interplay between YAP/TAZ and metabolic dysfunction-associated steatotic liver disease progression
Na Young Lee, Myeung Gi Choi, Eui Jin Lee, Ja Hyun Koo
Archives of Pharmacal Research.2024; 47(6): 558. CrossRef
New Biomarkers in Liver Fibrosis: A Pass through the Quicksand?
Marzia Tagliaferro, Mariapaola Marino, Valerio Basile, Krizia Pocino, Gian Ludovico Rapaccini, Gabriele Ciasca, Umberto Basile, Valeria Carnazzo
Journal of Personalized Medicine.2024; 14(8): 798. CrossRef
AI Digital Pathology Using qFibrosis Shows Heterogeneity of Fibrosis Regression in Patients with Chronic Hepatitis B and C with Viral Response
Feng Liu, Yameng Sun, Dean Tai, Yayun Ren, Elaine L. K. Chng, Aileen Wee, Pierre Bedossa, Rui Huang, Jian Wang, Lai Wei, Hong You, Huiying Rao
Diagnostics.2024; 14(16): 1837. CrossRef
Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation
Harrison T. Muturi, Hilda E. Ghadieh, Suman Asalla, Sumona G. Lester, Getachew D. Belew, Sobia Zaidi, Raziyeh Abdolahipour, Abhishek P. Shrestha, Agnes O. Portuphy, Hannah L. Stankus, Raghd Abu Helal, Stefaan Verhulst, Sergio Duarte, Ali Zarrinpar, Leo A.
Molecular Metabolism.2024; 88: 102010. CrossRef

Original Articles

Basic Research
DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis: Dong-Keon Lee, Su Ho Jo, Eun Soo Lee, Kyung Bong Ha, Na Won Park, Deok-Hoon Kong, Sang-In Park, Joon Seok Park, Choon Hee Chung; Diabetes Metab J. 2024;48(1):97-111. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0367

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Abstract PDF Supplementary Material PubReader ePub: Background
Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression.
Methods
Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture.
Results
DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor β (TGFβ)-induced pro-fibrotic gene expression by suppressing TGFβ receptor 1 (TGFβR1)/Smad2/3 and TGFβR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis.
Conclusion
Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.

Basic Research
Alantolactone Attenuates Renal Fibrosis via Inhibition of Transforming Growth Factor β/Smad3 Signaling Pathway: Kyeong-Min Lee, Yeo Jin Hwang, Gwon-Soo Jung; Diabetes Metab J. 2024;48(1):72-82. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0231

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Background
Renal fibrosis is characterized by the accumulation of extracellular matrix proteins and interstitial fibrosis. Alantolactone is known to exert anticancer, anti-inflammatory, antimicrobial and antifungal effects; however, its effects on renal fibrosis remains unknown. Here, we investigated whether alantolactone attenuates renal fibrosis in mice unilateral ureteral obstruction (UUO) and evaluated the effect of alantolactone on transforming growth factor (TGF) signaling pathway in renal cells.
Methods
To evaluate the therapeutic effect of alantolactone, cell counting kit-8 (CCK-8) assay, histological staining, Western blot analysis, and real-time quantitative polymerase chain reaction were performed in UUO kidneys in vivo and in TGF-β-treated renal cells in vitro.
Results
Alantolactone (0.25 to 4 µM) did not affect the viability of renal cells. Mice orally administered 5 mg/kg of alantolactone daily for 15 days did not show mortality or liver toxicity. Alantolactone decreased UUO-induced blood urea nitrogen and serum creatinine levels. In addition, it significantly alleviated renal tubulointerstitial damage and fibrosis and decreased collagen type I, fibronectin, and α-smooth muscle actin (α-SMA) expression in UUO kidneys. In NRK-49F cells, alantolactone inhibited TGF-βstimulated expression of fibronectin, collagen type I, plasminogen activator inhibitor-1 (PAI-1), and α-SMA. In HK-2 cells, alantolactone inhibited TGF-β-stimulated expression of collagen type I and PAI-1. Alantolactone inhibited UUO-induced phosphorylation of Smad3 in UUO kidneys. In addition, it not only decreased TGF-β secretion but also Smad3 phosphorylation and translocation to nucleus in both kidney cell lines.
Conclusion
Alantolactone improves renal fibrosis by inhibiting the TGF-β/Smad3 signaling pathway in obstructive nephropathy. Thus, alantolactone is a potential therapeutic agent for chronic kidney disease.

Citations

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TGF-β-Based Therapies for Treating Ocular Surface Disorders
Fernando T. Ogata, Sudhir Verma, Vivien J. Coulson-Thomas, Tarsis F. Gesteira
Cells.2024; 13(13): 1105. CrossRef
Alantolactone alleviates epithelial-mesenchymal transition by regulating the TGF-β/STAT3 signaling pathway in renal fibrosis
Yeo Jin Hwang, Gwon-Soo Jung, Kyeong-Min Lee
Heliyon.2024; 10(16): e36253. CrossRef

Basic Research
Beneficial Effects of a Curcumin Derivative and Transforming Growth Factor-β Receptor I Inhibitor Combination on Nonalcoholic Steatohepatitis: Kyung Bong Ha, Eun Soo Lee, Na Won Park, Su Ho Jo, Soyeon Shim, Dae-Kee Kim, Chan Mug Ahn, Choon Hee Chung; Diabetes Metab J. 2023;47(4):500-513. Published online April 25, 2023; DOI: https://doi.org/10.4093/dmj.2022.0110

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Background
Curcumin 2005-8 (Cur5-8), a derivative of curcumin, improves fatty liver disease via AMP-activated protein kinase activation and autophagy regulation. EW-7197 (vactosertib) is a small molecule inhibitor of transforming growth factor β (TGF-β) receptor I and may scavenge reactive oxygen species and ameliorate fibrosis through the SMAD2/3 canonical pathway. This study aimed to determine whether co-administering these two drugs having different mechanisms is beneficial.
Methods
Hepatocellular fibrosis was induced in mouse hepatocytes (alpha mouse liver 12 [AML12]) and human hepatic stellate cells (LX-2) using TGF-β (2 ng/mL). The cells were then treated with Cur5-8 (1 μM), EW-7197 (0.5 μM), or both. In animal experiments were also conducted during which, methionine-choline deficient diet, Cur5-8 (100 mg/kg), and EW-7197 (20 mg/kg) were administered orally to 8-week-old C57BL/6J mice for 6 weeks.
Results
TGF-β-induced cell morphological changes were improved by EW-7197, and lipid accumulation was restored on the administration of EW-7197 in combination with Cur5-8. In a nonalcoholic steatohepatitis (NASH)-induced mouse model, 6 weeks of EW-7197 and Cur5-8 co-administration alleviated liver fibrosis and improved the nonalcoholic fatty liver disease (NAFLD) activity score.
Conclusion
Co-administering Cur5-8 and EW-7197 to NASH-induced mice and fibrotic hepatocytes reduced liver fibrosis and steatohepatitis while maintaining the advantages of both drugs. This is the first study to show the effect of the drug combination against NASH and NAFLD. Similar effects in other animal models will confirm its potential as a new therapeutic agent.

Citations

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Molecular Pathways Governing the Termination of Liver Regeneration
Lianne R. de Haan, Rowan F. van Golen, Michal Heger, Martin Michel
Pharmacological Reviews.2024; 76(3): 500. CrossRef
Nicotinate-curcumin improves NASH by inhibiting the AKR1B10/ACCα-mediated triglyceride synthesis
Xiu-lian Lin, Ya-ling Zeng, Jie Ning, Zhe Cao, Lan-lan Bu, Wen-Jing Liao, Zhi-min Zhang, Tan-jun Zhao, Rong-geng Fu, Xue-Feng Yang, Yong-zhen Gong, Li-Mei Lin, De-liang Cao, Cai-ping Zhang, Duan-fang Liao, Ya-Mei Li, Jian-Guo Zeng
Lipids in Health and Disease.2024;[Epub] CrossRef
The pivotal role of dysregulated autophagy in the progression of non-alcoholic fatty liver disease
Qiaohui Shen, Ming Yang, Song Wang, Xingyu Chen, Sulan Chen, Rui Zhang, Zhuang Xiong, Yan Leng
Frontiers in Endocrinology.2024;[Epub] CrossRef

Complications
Advanced Liver Fibrosis Is Associated with Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease: Da Hea Seo, Young Ju Suh, Yongin Cho, Seong Hee Ahn, Seongha Seo, Seongbin Hong, Yong-ho Lee, Young Ju Choi, Eunjig Lee, So Hun Kim; Diabetes Metab J. 2022;46(4):630-639. Published online January 26, 2022; DOI: https://doi.org/10.4093/dmj.2021.0130

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Background
Nonalcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). However, the causal relationship between NAFLD and CKD is uncertain, particularly in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the association between the presence and severity of NAFLD and incident CKD in patients with T2DM.
Methods
In this longitudinal cohort study of patients with T2DM, 3,188 patients with preserved renal function were followed up for the occurrence of incident CKD. NAFLD was defined as the presence of hepatic steatosis on ultrasonography, without any other causes of chronic liver disease. Advanced liver fibrosis of NAFLD was defined as a fibrosis-4 index ≥2.67. CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m².
Results
At baseline, 1,729 (54.2%) patients had NAFLD, of whom 94 (5.4%) had advanced liver fibrosis. During the follow-up of 8.3±3.6 years, 472 (14.8%) patients developed incident CKD: 220 (15.1%) in the non-NAFLD group, 231 (14.1%) in the NAFLD without advanced fibrosis group and 28 (31.1%) in the NAFLD with advanced fibrosis group. There was no increased risk of incident CKD in the NAFLD group compared to the non-NAFLD group (P=0.435). However, among patients with NAFLD, advanced liver fibrosis was associated with an increased risk of CKD (adjusted hazard ratio, 1.75; 95% confidence interval, 1.15 to 2.66; P=0.009).
Conclusion
Advanced liver fibrosis in patients with NAFLD is independently associated with an increased risk of incident CKD in patients with T2DM.

Citations

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Esteatosis hepática metabólica y nefropatía diabética: una llamada a la acción
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Nefrología.2024; 44(2): 129. CrossRef
Longitudinal Outcomes Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-analysis of 129 Studies
Kai En Chan, Elden Yen Hng Ong, Charlotte Hui Chung, Christen En Ya Ong, Benjamin Koh, Darren Jun Hao Tan, Wen Hui Lim, Jie Ning Yong, Jieling Xiao, Zhen Yu Wong, Nicholas Syn, Apichat Kaewdech, Margaret Teng, Jiong-Wei Wang, Nicholas Chew, Dan Yock Young
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Association of NAFLD/NASH, and MAFLD/MASLD with chronic kidney disease: an updated narrative review
Amedeo Lonardo
Metabolism and Target Organ Damage.2024;[Epub] CrossRef
Targeting metabolic-associated fatty liver disease in diabetic kidney disease: A call to action
Salvador Benlloch, Francesc Moncho, Jose Luis Górriz
Nefrología (English Edition).2024; 44(2): 129. CrossRef
Epidemiology, screening, and co-management of type 2 diabetes mellitus and metabolic dysfunction–associated steatotic liver disease
Xiaolong Qi, Jie Li, Cyrielle Caussy, Gao-Jun Teng, Rohit Loomba
Hepatology.2024;[Epub] CrossRef
Impact of dietary fiber intake on non-alcoholic fatty liver disease risk in Korean patients with obesity and type 2 diabetes mellitus
Ji-Sook Park, Hina Akbar, Young-Seol Kim, Jung-Eun Yim
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A.M. Osadchuk, I.D. Loranskaya, M.A. Osadchuk
Russian Journal of Preventive Medicine.2024; 27(7): 108. CrossRef
MAFLD and NAFLD in the prediction of incident chronic kidney disease
So Yoon Kwon, Jiyun Park, So Hee Park, You-Bin Lee, Gyuri Kim, Kyu Yeon Hur, Janghyun Koh, Jae Hwan Jee, Jae Hyeon Kim, Mira Kang, Sang-Man Jin
Scientific Reports.2023;[Epub] CrossRef
Associations of non-invasive indices of liver steatosis and fibrosis with progressive kidney impairment in adults with type 2 diabetes
Mei Chung Moh, Sharon Li Ting Pek, Kenny Ching Pan Sze, Serena Low, Tavintharan Subramaniam, Keven Ang, Wern Ee Tang, Simon Biing Ming Lee, Chee Fang Sum, Su Chi Lim
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Rudi Supriyadi, Theo Audi Yanto, Timotius Ivan Hariyanto, Ketut Suastika
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Biomedicines.2022; 10(3): 699. CrossRef
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Advanced Liver Fibrosis Is Associated with Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease (Diabetes Metab J 2022;46:630-9)
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Review

Metabolic Risk/Epidemiology
Nonalcoholic Fatty Liver Disease: A Drug Revolution Is Coming: Soung Won Jeong; Diabetes Metab J. 2020;44(5):640-657. Published online October 21, 2020; DOI: https://doi.org/10.4093/dmj.2020.0115

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The worldwide prevalence of non-alcoholic fatty liver disease is around 25%, and that of nonalcoholic steatohepatitis (NASH) ranges from 1.5% to 6.45%. Patients with NASH, especially those with fibrosis, are at higher risk for adverse outcomes such as cirrhosis and liver-related mortality. Although vitamin E, pioglitazone, and liraglutide improved liver histology in randomized trials, there are currently no Food and Drug Administration-approved drugs for NASH. Five pharmacologic agents—obeticholic acid, elafibranor, cenicriviroc, resmetirom, and aramchol—are being evaluated in large, histology-based phase 3 trials. Within 2 to 4 years, new and effective drugs for the treatment of NASH are expected. Additionally, many phase 2 trials are ongoing for various agents. Based on the results of phase 2 and 3 trials, combination treatments are also being investigated. Future treatment strategies will comprise drug combinations and precision medicine based on the different phenotypes of NASH and treatment response of the individual patient.

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Recent Progresses on Pathophysiology, Diagnosis, Therapeutic Modalities, and Management of Non-alcoholic Fatty Liver Disorder
Mahdi Barazesh, Sajad Jalili, Morteza Akhzari, Fouzieyeh Faraji, Ebrahim Khorramdin
Current Drug Therapy.2024; 19(1): 20. CrossRef
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Shibing Tao, Shanlan Guo, Nanwei Tong
Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy.2024; 44(8): 642. CrossRef
Metabolic Dysfunction-Associated Fatty Liver Disease and Mortality: A Population-Based Cohort Study
Kyung-Soo Kim, Sangmo Hong, Hong-Yup Ahn, Cheol-Young Park
Diabetes & Metabolism Journal.2023; 47(2): 220. 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
Effect of bariatric surgery on NAFLD/NASH: a single-centre observational prospective cohort study
Willy B Theel, Bianca M Boxma-de Klerk, Femme Dirksmeier-Harinck, Elisabeth FC van Rossum, Danny A Kanhai, Jan A Apers, Bas M van Dalen, Robert J De Knegt, Bojou Neecke, Ellen M van der Zwan, Diederick E Grobbee, Thomas Hankemeier, Janneke Wiebolt, Manuel
BMJ Open.2023; 13(7): e070431. CrossRef
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Endocrinology and Metabolism.2022; 37(6): 918. CrossRef
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International Journal of Molecular Sciences.2022; 24(1): 158. CrossRef
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International Journal of Molecular Sciences.2021; 22(9): 4495. CrossRef
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Scientific Reports.2021;[Epub] CrossRef
Effects of intragastric balloon placement in metabolic dysfunction-associated fatty liver disease: A systematic review and meta-analysis
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World Journal of Hepatology.2021; 13(7): 815. CrossRef
The New Therapeutic Approaches in the Treatment of Non-Alcoholic Fatty Liver Disease
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International Journal of Molecular Sciences.2021; 22(24): 13219. CrossRef

Original Articles

Complications
Therapeutic Effects of Fibroblast Growth Factor-21 on Diabetic Nephropathy and the Possible Mechanism in Type 1 Diabetes Mellitus Mice: Wenya Weng, Tingwen Ge, Yi Wang, Lulu He, Tinghao Liu, Wanning Wang, Zongyu Zheng, Lechu Yu, Chi Zhang, Xuemian Lu; Diabetes Metab J. 2020;44(4):566-580. Published online May 15, 2020; DOI: https://doi.org/10.4093/dmj.2019.0089

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Background

Fibroblast growth factor 21 (FGF21) has been only reported to prevent type 1 diabetic nephropathy (DN) in the streptozotocin-induced type 1 diabetes mellitus (T1DM) mouse model. However, the FVB (Cg)-Tg (Cryaa-Tag, Ins2-CALM1) 26OVE/PneJ (OVE26) transgenic mouse is a widely recommended mouse model to recapture the most important features of T1DM nephropathy that often occurs in diabetic patients. In addition, most previous studies focused on exploring the preventive effect of FGF21 on the development of DN. However, in clinic, development of therapeutic strategy has much more realistic value compared with preventive strategy since the onset time of DN is difficult to be accurately predicted. Therefore, in the present study OVE26 mice were used to investigate the potential therapeutic effects of FGF21 on DN.

Methods

Four-month-old female OVE26 mice were intraperitoneally treated with recombinant FGF21 at a dose of 100 µg/kg/day for 3 months. The diabetic and non-diabetic control mice were treated with phosphate-buffered saline at the same volume. Renal functions, pathological changes, inflammation, apoptosis, oxidative stress and fibrosis were examined in mice of all groups.

Results

The results showed that severe renal dysfunction, morphological changes, inflammation, apoptosis, and fibrosis were observed in OVE26 mice. However, all the renal abnormalities above in OVE26 mice were significantly attenuated by 3-month FGF21 treatment associated with improvement of renal adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) activity and sirtuin 1 (SIRT1) expression.

Conclusion

Therefore, this study demonstrated that FGF21 might exert therapeutic effects on DN through AMPK-SIRT1 pathway.

Citations

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Fibroblast growth factor 21 alleviates unilateral ureteral obstruction-induced renal fibrosis by inhibiting Wnt/β-catenin signaling pathway
Wenhui Zhong, Yuheng Jiang, Huizhen Wang, Xiang Luo, Tao Zeng, Huimi Huang, Ling Xiao, Nan Jia, Aiqing Li
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.2024; 1871(2): 119620. CrossRef
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Yutong Zou, Lijun Zhao, Junlin Zhang, Yiting Wang, Yucheng Wu, Honghong Ren, Tingli Wang, Yuancheng Zhao, Huan Xu, Lin Li, Nanwei Tong, Fang Liu
Acta Diabetologica.2022; 60(2): 225. CrossRef
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Basic Research
Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT: Sundong Lin, Lechu Yu, Yongqing Ni, Lulu He, Xiaolu Weng, Xuemian Lu, Chi Zhang; Diabetes Metab J. 2020;44(1):158-172. Published online October 28, 2019; DOI: https://doi.org/10.4093/dmj.2018.0235

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Background

Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study.

Methods

Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4′-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months.

Results

DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-β)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2).

Conclusion

FGF21 prevents renal fibrosis via negative regulation of the TGF-β/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.

Citations

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Sudarat Hadpech, Visith Thongboonkerd
genesis.2024;[Epub] CrossRef
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Wenhui Zhong, Yuheng Jiang, Huizhen Wang, Xiang Luo, Tao Zeng, Huimi Huang, Ling Xiao, Nan Jia, Aiqing Li
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.2024; 1871(2): 119620. CrossRef
Platelet concentrates may affect the formation of pathological scars by regulating epithelial to mesenchymal transition
Ju Tian, Dandan Shi, Chenyan Long, Jing Ding, Huimin You, Xiaoying He, Biao Cheng
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Cadherin-responsive hydrogel combined with dental pulp stem cells and fibroblast growth factor 21 promotes diabetic scald repair via regulating epithelial-mesenchymal transition and necroptosis
Wenjie Lu, Juan Zhao, Xiong Cai, Yutian Wang, Wenwei Lin, Yaoping Fang, Yunyang Wang, Jinglei Ao, Jiahui Shou, Jiake Xu, Sipin Zhu
Materials Today Bio.2024; 24: 100919. CrossRef
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Tingting Yang, Lin Li, Cai Heng, Pian Sha, Yiying Wang, Jiaming Shen, Zhenzhou Jiang, Sitong Qian, Chujing Wei, Hao Yang, Xia Zhu, Tao Wang, Mengying Wu, Jianyun Wang, Qian Lu, Xiaoxing Yin
Food & Function.2024; 15(5): 2628. CrossRef
Urinary Excretion of Biomolecules Related to Cell Cycle, Proliferation, and Autophagy in Subjects with Type 2 Diabetes and Chronic Kidney Disease
Anton I. Korbut, Vyacheslav V. Romanov, Vadim V. Klimontov
Biomedicines.2024; 12(3): 487. CrossRef
FGF21 Inhibits Hypoxia/Reoxygenation-induced Renal Tubular Epithelial Cell Injury by Regulating the PPARγ/NF-κB Signaling Pathway
Ruixue Li, Xi Liu
Cell Biochemistry and Biophysics.2024;[Epub] CrossRef
Advances in the Treatment of Kidney Disorders using Mesenchymal Stem Cells
Shivam Rajput, Rishabha Malviya, Prerna Uniyal
Current Pharmaceutical Design.2024; 30(11): 825. CrossRef
The endocrine FGFs axis: A systemic anti-fibrotic response that could prevent pulmonary fibrogenesis?
Mada Ghanem, Gabrielle Archer, Bruno Crestani, Arnaud A. Mailleux
Pharmacology & Therapeutics.2024; 259: 108669. CrossRef
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Dali Ding, Xuebin Shen, Lizhen Yu, Yueyue Zheng, Yao Liu, Wei Wang, Li Liu, Zitong Zhao, Sihui Nian, Limin Liu
Phytotherapy Research.2023; 37(7): 2787. CrossRef
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M. Ghanem, A. Mailleux, B. Crestani
Revue des Maladies Respiratoires.2023; 40(3): 239. CrossRef
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Cell Transplantation.2023; 32: 096368972311642. CrossRef
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Yuxin Shen, Yao Zhang, Xiyue Gao, Mengdi Shang, Yanfei Cai, Zhaoqi Yang
Emergent Materials.2023; 6(5): 1537. CrossRef
Downregulation of a potential therapeutic target NPAS2, regulated by p53, alleviates pulmonary fibrosis by inhibiting epithelial-mesenchymal transition via suppressing HES1
Yingying Chen, Zhong He, Bo Zhao, Rui Zheng
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Xiao Li, Doudou Chen, Bowen Ouyang, Shengnan Wang, Yawei Li, Li Li, Siquan Zhu, Guangying Zheng
Laboratory Investigation.2023; 103(11): 100226. CrossRef
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Yu Xia, Haiyue Wang, Meihua Shao, Xuemei Liu, Feng Sun
Molecular Biotechnology.2023;[Epub] CrossRef
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LiSha He, Tingting Bao, Yingying Yang, Han Wang, Chengjuan Gu, Jia Chen, Tiangang Zhai, Xinhui He, Mengyi Wu, Linhua Zhao, Xiaolin Tong
Journal of Ethnopharmacology.2022; 285: 114786. CrossRef
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Chan Gao, Xiao Fei, Ming Wang, Qi Chen, Ning Zhao
International Immunopharmacology.2022; 107: 108610. CrossRef
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Guihai Wu, Shenglin Wu, Jingyi Yan, Shanshan Gao, Jinxiu Zhu, Minghui Yue, Zexin Li, Xuerui Tan
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Mingqun Li, Yuqin Huang, Hongli Xi, Wei Zhang, Ziwu Xiang, Lingyun Wang, Xuanyu Li, Hongyan Guo
Endocrine Journal.2022; 69(9): 1067. CrossRef
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Xinghao Jiang, Qing Wu, Yeboah Kwaku Opoku, Yimeng Zou, Dan Wang, Changhui Hu, Guiping Ren
Basic & Clinical Pharmacology & Toxicology.2022; 131(6): 474. CrossRef
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Yuexian Xing, Qi Wang, Jing Zhang, Wenju Li, Aiping Duan, Jingping Yang, Zhihong Liu
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Journal of Interferon & Cytokine Research.2021; 41(8): 271. CrossRef
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Xue Zhou, Yuefeng Zhang, Ning Wang
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International Journal of Molecular Sciences.2021; 22(22): 12341. CrossRef
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Ruochen Qi, Jiyan Wang, Yamei Jiang, Yue Qiu, Ming Xu, Ruiming Rong, Tongyu Zhu
Cell Death & Disease.2021;[Epub] CrossRef
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Genetics
Severity of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Mellitus: Relationship between Nongenetic Factors and PNPLA3/HSD17B13 Polymorphisms: Mattia Bellan, Cosimo Colletta, Matteo Nazzareno Barbaglia, Livia Salmi, Roberto Clerici, Venkata Ramana Mallela, Luigi Mario Castello, Giuseppe Saglietti, Gian Piero Carnevale Schianca, Rosalba Minisini, Mario Pirisi; Diabetes Metab J. 2019;43(5):700-710. Published online July 29, 2019; DOI: https://doi.org/10.4093/dmj.2018.0201

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Background

The prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) is high, though its severity is often underestimated. Our aim is to provide an estimate of the prevalence of severe NAFLD in T2DM and identify its major predictors.

Methods

T2DM patients (n=328) not previously known to have NAFLD underwent clinical assessment, transient elastography with measure of liver stiffness (LS) and controlled attenuation parameter (CAP), and genotyping for patatin like phospholipase domain containing 3 (PNPLA3) and 17β-hydroxysteroid-dehydrogenase type 13 (HSD17B13).

Results

Median LS was 6.1 kPa (4.9 to 8.6). More than one-fourth patients had advanced liver disease, defined as LS ≥7.9 kPa (n=94/238, 29%), and had a higher body mass index (BMI) than those with a LS <7.9 kPa. Carriage of the G allele in the PNPLA3 gene was associated with higher LS, being 5.9 kPa (4.7 to 7.7) in C/C homozygotes, 6.1 kPa (5.2 to 8.7) in C/G heterozygotes, and 6.8 kPa (5.8 to 9.2) in G/G homozygotes (P=0.01). This trend was absent in patients with ≥1 mutated HSD17B13 allele. In a multiple linear regression model, BMI and PNPLA3 genotype predicted LS, while age, gender, disease duration, and glycosylated hemoglobin did not fit into the model. None of these variables was confirmed to be predictive among carriers of at least one HSD17B13 mutated allele. There was no association between CAP and polymorphisms of PNPLA3 or HSD17B13.

Conclusion

Advanced NAFLD is common among T2DM patients. LS is predicted by both BMI and PNPLA3 polymorphism, the effect of the latter being modulated by mutated HSD17B13.

Citations

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Venkata Ramana Mallela, Marie Rajtmajerová, Andriy Trailin, Václav Liška, Kari Hemminki, Filip Ambrozkiewicz
Non-coding RNA Research.2024; 9(1): 24. CrossRef
17-Beta-Hydroxysteroid Dehydrogenase 13 Loss of Function Does Not Confer Protection to Nonalcoholic Fatty Liver Disease in Indian Population
Bale Govardhan, V. Kulkarni Anand, Padaki Nagaraja Rao, P. Balachandran Menon, Sharma Mithun, Mitnala Sasikala, T.R. Sowmya, Sekaran Anuradha, C. Pawar Smita, D. Nageshwar Reddy, Vishnubhotla Ravikanth
Journal of Clinical and Experimental Hepatology.2024; 14(4): 101371. CrossRef
Review article: the role of HSD17B13 on global epidemiology, natural history, pathogenesis and treatment of NAFLD
Maral Amangurbanova, Daniel Q. Huang, Rohit Loomba
Alimentary Pharmacology & Therapeutics.2023; 57(1): 37. CrossRef
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O. V. Smirnova, D. V. Lagutinskaya
Meditsinskiy sovet = Medical Council.2023; (8): 119. CrossRef
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Elina En Li Cho, Chong Zhe Ang, Jingxuan Quek, Clarissa Elysia Fu, Lincoln Kai En Lim, Zane En Qi Heng, Darren Jun Hao Tan, Wen Hui Lim, Jie Ning Yong, Rebecca Zeng, Douglas Chee, Benjamin Nah, Cosmas Rinaldi Adithya Lesmana, Aung Hlaing Bwa, Khin Maung W
Gut.2023; 72(11): 2138. CrossRef
HSD17B13 and other liver fat-modulating genes predict development of hepatocellular carcinoma among HCV-positive cirrhotics with and without viral clearance after DAA treatment
Michela E. Burlone, Mattia Bellan, Matteo N. Barbaglia, Ginevra Mocchetti, Venkata R. Mallela, Rosalba Minisini, Cristina Rigamonti, Mario Pirisi
Clinical Journal of Gastroenterology.2022; 15(2): 301. CrossRef
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Pablo Gabriel-Medina, Roser Ferrer-Costa, Francisco Rodriguez-Frias, Andreea Ciudin, Salvador Augustin, Jesus Rivera-Esteban, Juan M. Pericàs, David Martinez Selva
Biomedicines.2022; 10(5): 1015. CrossRef
Triglyceride and glucose index is a simple and easy‐to‐calculate marker associated with nonalcoholic fatty liver disease
Kyung‐Soo Kim, Sangmo Hong, Hong‐Yup Ahn, Cheol‐Young Park
Obesity.2022; 30(6): 1279. CrossRef
Prevalence of elevated liver stiffness in patients with type 1 and type 2 diabetes: A systematic review and meta-analysis
Stefano Ciardullo, Gianluca Perseghin
Diabetes Research and Clinical Practice.2022; 190: 109981. CrossRef
Associations of Hydroxysteroid 17-beta Dehydrogenase 13 Variants with Liver Histology in Chinese Patients with Metabolic-associated Fatty Liver Disease
Wen-Yue Liu, Mohammed Eslam, Kenneth I. Zheng, Hong-Lei Ma, Rafael S. Rios, Min-Zhi Lv, Gang Li, Liang-Jie Tang, Pei-Wu Zhu, Xiao-Dong Wang, Christopher D. Byrne, Giovanni Targher, Jacob George, Ming-Hua Zheng
Journal of Clinical and Translational Hepatology.2021; 000(000): 000. CrossRef
Albuminuria Is Associated with Steatosis Burden in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease
Eugene Han, Mi Kyung Kim, Byoung Kuk Jang, Hye Soon Kim
Diabetes & Metabolism Journal.2021; 45(5): 698. CrossRef
Genetic Polymorphisms and Clinical Features in Diabetic Patients With Fatty Liver: Results From a Single-Center Experience in Southern Italy
Rosanna Villani, Grazia Pia Magnati, Giuseppe De Girolamo, Moris Sangineto, Antonino Davide Romano, Tommaso Cassano, Gaetano Serviddio
Frontiers in Medicine.2021;[Epub] CrossRef
Interplay of PNPLA3 and HSD17B13 Variants in Modulating the Risk of Hepatocellular Carcinoma among Hepatitis C Patients
Carla De Benedittis, Mattia Bellan, Martina Crevola, Elena Boin, Matteo Nazzareno Barbaglia, Venkata Ramana Mallela, Paolo Ravanini, Elisa Ceriani, Stefano Fangazio, Pier Paolo Sainaghi, Michela Emma Burlone, Rosalba Minisini, Mario Pirisi
Gastroenterology Research and Practice.2020; 2020: 1. CrossRef
Toward Genetic Prediction of Nonalcoholic Fatty Liver Disease Trajectories: PNPLA3 and Beyond
Marcin Krawczyk, Roman Liebe, Frank Lammert
Gastroenterology.2020; 158(7): 1865. CrossRef
The effect of liraglutide on nonalcoholic fatty liver disease in type 2 diabetes mellitus
Xueyang Zhang, Ran Bai, Yong Jia, Junwei Zong, Yongbo Wang, Yanan Dong
International Journal of Diabetes in Developing Countries.2020; 40(4): 491. CrossRef
Lifestyle and silymarin: a fight against liver damage in NAFLD associated - prediabetic disease
Cosimo Colletta, Alessandro Colletta, Giuseppe Placentino
Journal of Diabetes & Metabolic Disorders.2020; 19(2): 883. CrossRef

Complications
Gemigliptin Attenuates Renal Fibrosis Through Down-Regulation of the NLRP3 Inflammasome: Jung Beom Seo, Yeon-Kyung Choi, Hye-In Woo, Yun-A Jung, Sungwoo Lee, Seunghyeong Lee, Mihyang Park, In-Kyu Lee, Gwon-Soo Jung, Keun-Gyu Park; Diabetes Metab J. 2019;43(6):830-839. Published online March 5, 2019; DOI: https://doi.org/10.4093/dmj.2018.0181

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Background

The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis.

Methods

We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and in vitro in human kidney tubular epithelial human renal proximal tubule cells (HK-2) cells, we further analyzed the effect of gemigliptin on transforming growth factor-β (TGF-β)-stimulated production of profibrotic proteins.

Results

Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β, which had all been markedly increased by UUO. In line with the in vivo results, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin treatment. Furthermore, gemigliptin treatment attenuated phosphorylated nuclear factor-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells.

Conclusion

The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.

Citations

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Science of The Total Environment.2024; 926: 171817. CrossRef
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Linfeng Zheng, Wenjuan Mei, Jing Zhou, Xin Wei, Zhijuan Huang, Xiaozhen Lin, Li Zhang, Wei Liu, Qian Wu, Jinhong Li, Yan Yan
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Alexandria Journal of Medicine.2024; 60(1): 249. CrossRef
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Cell Death & Disease.2023;[Epub] CrossRef
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Cell Death & Disease.2023;[Epub] CrossRef
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Chemical Biology & Drug Design.2023; 102(6): 1409. CrossRef
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Cardiovascular Research.2022; 118(3): 785. CrossRef
The NLRP3 inflammasome in fibrosis and aging: The known unknowns
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Ageing Research Reviews.2022; 79: 101638. CrossRef
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Journal of Cellular and Molecular Medicine.2022; 26(12): 3313. CrossRef
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Complications
Renoprotective Effect of Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, in Streptozotocin-Induced Type 1 Diabetic Mice: Gwon-Soo Jung, Jae-Han Jeon, Mi Sun Choe, Sung-Woo Kim, In-Kyu Lee, Mi-Kyung Kim, Keun-Gyu Park; Diabetes Metab J. 2016;40(3):211-221. Published online March 31, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.3.211

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Abstract PDF PubReader

Background

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice.

Methods

Diabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis.

Results

Gemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation.

Conclusion

Our data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes.

Citations

Citations to this article as recorded by

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Diabetes & Metabolism Journal.2019; 43(6): 830. CrossRef
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Archives of Pharmacal Research.2019; 42(3): 252. CrossRef
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Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2019; 13(1): 754. CrossRef
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Katarina Tomovic, Jelena Lazarevic, Gordana Kocic, Marina Deljanin‐Ilic, Marko Anderluh, Andrija Smelcerovic
Medicinal Research Reviews.2019; 39(1): 404. CrossRef
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Endocrinology and Metabolism.2019; 34(1): 80. CrossRef
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Kelly R. McHugh, Adam D. DeVore, Robert J. Mentz, Daniel Edmonston, Jennifer B. Green, Adrian F. Hernandez
Clinical Cardiology.2018; 41(9): 1259. CrossRef
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Advances in Chronic Kidney Disease.2018; 25(2): 166. CrossRef
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Weiqin Yin, Shiqing Xu, Zai Wang, Honglin Liu, Liang Peng, Qing Fang, Tingting Deng, Wenjian Zhang, Jinning Lou
Biochemical and Biophysical Research Communications.2018; 495(1): 793. CrossRef
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American Journal of Physiology-Regulatory, Integrative and Comparative Physiology.2018; 314(6): R834. CrossRef
Renoprotective effect of fucoidan from Acaudina molpadioides in streptozotocin/high fat diet-induced type 2 diabetic mice
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Journal of Functional Foods.2017; 31: 123. CrossRef
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The Korean Journal of Internal Medicine.2017; 32(4): 622. CrossRef
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Diabetes, Obesity and Metabolism.2017; 19(4): 590. CrossRef
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Eun-Sol Lee, Dong-Sung Lee, Prakash Raj Pandeya, Youn-Chul Kim, Dae-Gil Kang, Ho-Sub Lee, Byung-Chul Oh, Dae Ho Lee
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Endocrinology and Metabolism.2017; 32(1): 115. CrossRef
Gemigliptin: An Update of Its Clinical Use in the Management of Type 2 Diabetes Mellitus
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Diabetes & Metabolism Journal.2016; 40(5): 339. CrossRef
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The Effects of High Glucose, Insulin and TGF-beta 1 on Proliferation and Differentiation of the Pancreatic Stellate Cells.: Oak Kee Hong, Hyuk Sang Kwon, Kyu Hyun Yeom, Marie Lee, Ji Hun Yang, Seung Hyeon Ko, Soon Jib Yoo, Hyun Sik Son, Kun Ho Yoon, Bong Yeon Cha, Kwang Woo Lee, Ho Yong Son, Sung Koo Kang; Korean Diabetes J. 2003;27(3):228-240. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Although chronic pancreatitis gives rise to fibrosis of pancreatic exocrine tissue, and type 2 diabetes is accompanied by pancreatic fibrosis, the mechanisms of fibrogenesis in the pancreas have been insufficiently studied. The activated Pancreatic stellate cells (PSC) have recently been identified in human and experimental fibrotic areas from chronic panceatitis tissues. As PSC are similar in their morphology and biochemistry to hepatic stellate cells, they are suspected to play the same role in pancreatic fibrogenesis as the hepatic stellate cells in liver fibrosis. The PSC were isolated from the rat pancreata, and mediators stimulating the proliferation and differentiation identified. METHODS: The pancreatic stellate shaped cells were isolated by a minor modification to the method described by Apte et al (ref), using a Nycodenz gradient. The isolated PSCs were confirmed by phase-contrast and by the immunofluorescence of vimentin, desmin and smooth muscle a-actin (a-SMA). The level of alpha-SMA was quantified by Western blot in the PSCs in the culture, over time, and the cell proliferation was measured by 3[H]-Thymidine incorporation. The effect of the proliferation and differentiation of the PSC were assessed in relation to D-glucose (500 mg/dL), Insulin (10 IU/mL) and TGF-beta (10 ng/mL) treatment of the culture medium. RESULTS: The stellate shaped cells from the rat pancreata grew readily in the culture. Unactivated PSCs, cultured for 3 days, had an angular appearance, contained lipid droplets, manifesting positive vitamin A autofliuorescence, and stained positively for vimentin and desmin, but negatively for alpha-SMA. Within 4~8 days of primary culturing, the PSCs were activated, the sizes and numbers of the fat droplets decreased, the cells flattened, developed long cytoplasmic extensions and expressed alpha-SMA. After 3 passages, almost 100% of the cells were positive for alpha-SMA expression, indicating a myofibroblast type of differentiation in vitro. The addition of high-glucose concentrations and insulin to the activated PSCs significantly stimulated cell proliferation (194.4+/-8.3, 175.0+/-31.0 vs. control), and when the combination of high- glucose and insulin was applied, the cell proliferation was increased to an even greater extent (247.0+/-21.8 vs. control). CONCLUSIONS: Pancreata stellate cells can be isolated, and cultured in vitro, from normal SD rats. High concentrations of glucose and insulin in culture medium activated the PSC proliferation.

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