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Metabolic Risk/Epidemiology
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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
  • 3,548 View
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  • 1 Crossref
AbstractAbstract PDFPubReader   ePub   
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.

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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
Original Articles
Basic Research
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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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  • 195 Download
AbstractAbstract PDFSupplementary MaterialPubReader   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
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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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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
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.
Basic Research
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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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  • 1 Web of Science
  • 1 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
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

Citations to this article as recorded by  
  • 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
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
  • 6,057 View
  • 280 Download
  • 15 Web of Science
  • 17 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
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

Citations to this article as recorded by  
  • Esteatosis hepática metabólica y nefropatía diabética: una llamada a la acción
    Salvador Benlloch, Francesc Moncho, Jose Luis Górriz
    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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    Amedeo Lonardo
    Metabolism and Target Organ Damage.2024;[Epub]     CrossRef
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    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
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    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
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    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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    Verena Damiani, Alessia Lamolinara, Ilaria Cicalini, Maria Concetta Cufaro, Francesco Del Pizzo, Federica Di Marco, Piero Del Boccio, Beatrice Dufrusine, Michael Hahne, Rossano Lattanzio, Damiana Pieragostino, Manuela Iezzi, Massimo Federici, Maria Cateri
    Molecular Metabolism.2023; 74: 101752.     CrossRef
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    Rudi Supriyadi, Theo Audi Yanto, Timotius Ivan Hariyanto, Ketut Suastika
    Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2023; 17(8): 102814.     CrossRef
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    Jaehyun Bae, Byung-Wan Lee
    Biomedicines.2023; 11(7): 1928.     CrossRef
  • Hepatic Fibrosis Evaluated in Patients with Type 2 Diabetes with and without Chronic Kidney Disease
    Therese Adrian, Mads Hornum, Filip Krag Knop, Karl Bang Christensen, Thomas Almdal, Peter Rossing, Lisa Í Lídaa, Niels Søndergaard Heinrich, Vincent Oltman Boer, Anouk Marsman, Esben Thade Petersen, Hartwig Roman Siebner, Bo Feldt-Rasmussen
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    Olivier Deckmyn, Thierry Poynard, Pierre Bedossa, Valérie Paradis, Valentina Peta, Raluca Pais, Vlad Ratziu, Dominique Thabut, Angelique Brzustowski, Jean-François Gautier, Patrice Cacoub, Dominique Valla
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    Yifan Sun, Liang Hong, Zhe Huang, Lihong Wang, Yanqin Xiong, Shuhang Zong, Rui Zhang, Jun Liu, Shufei Zang
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    Eugene Han
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    Ji Hye Huh
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    Da Hea Seo, So Hun Kim
    Diabetes & Metabolism Journal.2022; 46(6): 956.     CrossRef
Review
Metabolic Risk/Epidemiology
Article image
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
  • 12,409 View
  • 551 Download
  • 16 Web of Science
  • 16 Crossref
AbstractAbstract PDFPubReader   ePub   
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.

Citations

Citations to this article as recorded by  
  • 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
  • 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
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    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
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    Pervej Alom Barbhuiya, Saikat Sen, Manash Pratim Pathak
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    Youngmin A. Lee, Scott L. Friedman
    Journal of Internal Medicine.2022; 291(1): 11.     CrossRef
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    E. A. Fokina, A. O. Shpakov
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    Su-Yeon Lee, Sanghwa Kim, Inhee Choi, Yeonhwa Song, Namjeong Kim, Hyung Chul Ryu, Jee Woong Lim, Hyo Jin Kang, Jason Kim, Haeng Ran Seo
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Original Articles
Complications
Article image
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
  • 6,341 View
  • 102 Download
  • 12 Web of Science
  • 11 Crossref
AbstractAbstract PDFPubReader   ePub   
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
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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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AbstractAbstract PDFSupplementary MaterialPubReader   
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.

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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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AbstractAbstract PDFPubReader   
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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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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  • 24 Web of Science
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AbstractAbstract PDFPubReader   
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.

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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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AbstractAbstract PDFPubReader   
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

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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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AbstractAbstract 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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