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Nakamura T, Masuda A, Nakano D, Amano K, Sano T, Nakano M, Kawaguchi T. Pathogenic Mechanisms of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Associated Hepatocellular Carcinoma. Cells 2025; 14:428. [PMID: 40136677 PMCID: PMC11941585 DOI: 10.3390/cells14060428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/25/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer deaths worldwide. The etiology of HCC has now dramatically changed from viral hepatitis to metabolic dysfunction-associated steatotic liver disease (MASLD). The main pathogenesis of MASLD-related HCC is the hepatic lipid accumulation of hepatocytes, which causes chronic inflammation and the subsequent progression of hepatic fibrosis. Chronic hepatic inflammation generates oxidative stress and DNA damage in hepatocytes, which contribute to genomic instability, resulting in the development of HCC. Several metabolic and molecular pathways are also linked to chronic inflammation and HCC in MASLD. In particular, the MAPK and PI3K-Akt-mTOR pathways are upregulated in MASLD, promoting the survival and proliferation of HCC cells. In addition, MASLD has been reported to enhance the development of HCC in patients with chronic viral hepatitis infection. Although there is no approved medication for MASLD besides resmetirom in the USA, there are some preventive strategies for the onset and progression of HCC. Sodium-glucose cotransporter-2 (SGLT2) inhibitor, a class of medications, has been reported to exert anti-tumor effects on HCC by regulating metabolic reprogramming. Moreover, CD34-positive cell transplantation improves hepatic fibrosis by promoting intrahepatic angiogenesis and supplying various growth factors. Furthermore, exercise improves MASLD through an increase in energy consumption as well as changes in chemokines and myokines. In this review, we summarize the recent progress made in the pathogenic mechanisms of MASLD-associated HCC. Furthermore, we introduced new therapeutic strategies for preventing the development of HCC based on the pathogenesis of MASLD.
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Affiliation(s)
- Toru Nakamura
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, 67 Asahi-Machi, Kurume 830-0011, Japan
| | - Atsutaka Masuda
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, 67 Asahi-Machi, Kurume 830-0011, Japan
| | - Dan Nakano
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, 67 Asahi-Machi, Kurume 830-0011, Japan
| | - Keisuke Amano
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Fukuoka Consulting and Support Center for Liver Diseases, Kurume 830-0011, Japan
| | - Tomoya Sano
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Fukuoka Consulting and Support Center for Liver Diseases, Kurume 830-0011, Japan
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume 830-0011, Japan; (T.N.); (A.M.); (D.N.); (K.A.); (T.S.); (M.N.)
- Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, 67 Asahi-Machi, Kurume 830-0011, Japan
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Liu H, Hao YM, Jiang S, Baihetiyaer M, Li C, Sang GY, Li Z, Du GL. Evaluation of MASLD Fibrosis, FIB-4 and APRI Score in MASLD Combined with T2DM and MACCEs Receiving SGLT2 Inhibitors Treatment. Int J Gen Med 2024; 17:2613-2625. [PMID: 38855422 PMCID: PMC11162633 DOI: 10.2147/ijgm.s460200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 05/21/2024] [Indexed: 06/11/2024] Open
Abstract
Purpose This study aims to investigate the relationship between Sodium Glucose Co-transporter-2 inhibitors (SGLT2i) treatment and fibrosis in patients with Metabolic dysfunction-associated steatotic liver disease (MASLD) combined with Type 2 Diabetes Mellitus (T2DM) and Major Adverse Cardiovascular and Cerebrovascular Events (MACCEs). Methods A case-control study was conducted, involving 280 patients with MASLD combined with T2DM treated at the First Affiliated Hospital of Xinjiang Medical University from January 2014 to October 2023. Among these patients, 135 received SGLT2i treatment. The association between the Fibrosis-4 (FIB-4) index and the occurrence of MACCEs, as well as the association between the Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) scores and MACCEs, were evaluated. Results The FIB-4 index and APRI scores were significantly lower in the SGLT2i treatment group compared to the non-SGLT2i group (1.59 vs 1.25, P<0.001). SGLT2i treatment tended to reduce the occurrence of MACCEs compared to non-SGLT2i treatment (45.5% vs 38.5%, P=0.28). All patients who developed MACCEs in the non-SGLT2i treatment group had higher FIB-4 index (1.83 vs 1.35, P=0.003). Additionally, after SGLT2i treatment for a median duration of 22 months, patients showed significant reductions in blood glucose, APRI, and FIB-4 index. Conclusion SGLT2i treatment significantly reduces the occurrence of MACCEs and liver fibrosis in patients with MASLD combined with T2DM. The FIB-4 index may serve as a potential surrogate marker for predicting the occurrence of MACCEs.
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Affiliation(s)
- Hua Liu
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, Urumqi, Xinjiang, People’s Republic of China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Yang-Min Hao
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, Urumqi, Xinjiang, People’s Republic of China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Sheng Jiang
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, Urumqi, Xinjiang, People’s Republic of China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Maiheliya Baihetiyaer
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, Urumqi, Xinjiang, People’s Republic of China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Cheng Li
- Data Statistics and Analysis Center of Operation Management Department, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Guo-Yao Sang
- Laboratory Medicine Diagnostic Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Zhiming Li
- Department of Ultrasound, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Guo-Li Du
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, Urumqi, Xinjiang, People’s Republic of China
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
- Bazhou People’s Hospital, Korla, Xinjiang Uygur Autonomous Region, People’s Republic of China
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Makri ES, Makri E, Goulas A, Xanthopoulos K, Polyzos SA. Animal studies of sodium-glucose co-transporter 2 inhibitors in nonalcoholic fatty liver disease. Ann Gastroenterol 2024; 37:280-290. [PMID: 38779641 PMCID: PMC11107411 DOI: 10.20524/aog.2024.0884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/10/2024] [Indexed: 05/25/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered one of the most common chronic liver diseases. Modern lifestyle, characterized by increasing rates of obesity and type 2 diabetes mellitus (T2DM), has led to a "pandemic" of NAFLD that imposes a personal health and socioeconomic burden. Apart from overnutrition and insulin resistance, various metabolic aberrations, gut microbiota and genetic predispositions are involved in the pathogenesis of the disease. The multifactorial nature of NAFLD's pathogenesis makes the development of pharmacological therapies for patients with this disease challenging. Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) are antidiabetic agents that reduce blood glucose mainly by increasing its renal excretion. As T2DM is one of the major contributors to NAFLD, SGLT-2i have emerged as promising agents for the management of NAFLD. In this review, we summarize the main animal studies on SGLT-2i in models of NAFLD.
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Affiliation(s)
- Evangelia S. Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki (Evangelia S. Makri, Eleftheria Makri, Antonis Goulas, Stergios A. Polyzos)
| | - Eleftheria Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki (Evangelia S. Makri, Eleftheria Makri, Antonis Goulas, Stergios A. Polyzos)
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki (Evangelia S. Makri, Eleftheria Makri, Antonis Goulas, Stergios A. Polyzos)
| | - Konstantinos Xanthopoulos
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki (Konstantinos Xanthopoulos)
- Institute of Applied Biosciences, Centre for Research and Technology, Thessaloniki (Konstantinos Xanthopoulos), Greece
| | - Stergios A. Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki (Evangelia S. Makri, Eleftheria Makri, Antonis Goulas, Stergios A. Polyzos)
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Shakour N, Karami S, Iranshahi M, Butler AE, Sahebkar A. Antifibrotic effects of sodium-glucose cotransporter-2 inhibitors: A comprehensive review. Diabetes Metab Syndr 2024; 18:102934. [PMID: 38154403 DOI: 10.1016/j.dsx.2023.102934] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/25/2023] [Accepted: 12/20/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND AND AIMS Scar tissue accumulation in organs is the underlying cause of many fibrotic diseases. Due to the extensive array of organs affected, the long-term nature of fibrotic processes and the large number of people who suffer from the negative impact of these diseases, they constitute a serious health problem for modern medicine and a huge economic burden on society. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a relatively new class of anti-diabetic pharmaceuticals that offer additional benefits over and above their glucose-lowering properties; these medications modulate a variety of diseases, including fibrosis. Herein, we have collated and analyzed all available research on SGLT2is and their effects on organ fibrosis, together with providing a proposed explanation as to the underlying mechanisms. METHODS PubMed, ScienceDirect, Google Scholar and Scopus were searched spanning the period from 2012 until April 2023 to find relevant articles describing the antifibrotic effects of SGLT2is. RESULTS The majority of reports have shown that SGLT2is are protective against lung, liver, heart and kidney fibrosis as well as arterial stiffness. According to the results of clinical trials and animal studies, many SGLT2 inhibitors are promising candidates for the treatment of fibrosis. Recent studies have demonstrated that SGLT2is affect an array of cellular processes, including hypoxia, inflammation, oxidative stress, the renin-angiotensin system and metabolic activities, all of which have been linked to fibrosis. CONCLUSION Extensive evidence indicates that SGLT2is are promising treatments for fibrosis, demonstrating protective effects in various organs and influencing key cellular processes linked to fibrosis.
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Affiliation(s)
- Neda Shakour
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shima Karami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Adliya, Bahrain
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Noah AA, El-Mezayen NS, El-Ganainy SO, Darwish IE, Afify EA. Reversal of fibrosis and portal hypertension by Empagliflozin treatment of CCl 4-induced liver fibrosis: Emphasis on gal-1/NRP-1/TGF-β and gal-1/NRP-1/VEGFR2 pathways. Eur J Pharmacol 2023; 959:176066. [PMID: 37769984 DOI: 10.1016/j.ejphar.2023.176066] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/06/2023] [Accepted: 09/19/2023] [Indexed: 10/03/2023]
Abstract
To date, liver fibrosis has no clinically approved treatment. Empagliflozin (EMPA), a highly selective sodium-glucose-cotransporter-2 (SGLT2) inhibitor, has shown ameliorative potential in liver diseases without revealing its full mechanisms. Neuropilin-1 (NRP-1) is a novel regulator of profibrogenic signaling pathways related to hepatic stellate cells (HSCs) and hepatic sinusoidal endothelial cells (HSECs) that modulates intrahepatic profibrogenic and angiogenic pathways. Herein, EMPA's antifibrotic potentials and effects on galactin-1 (Gal-1)/NRP-1 signaling pathways have been evaluated in an experimental liver fibrosis rat model by testing different EMPA dose regimens. EMPA treatment brought a dose-dependent decrease in Gal-1/NRP-1 hepatic expression. This was coupled with suppression of major HSCs pro-fibrotic pathways; transforming growth factor-β (TGF-β)/TGF-βRI/Smad2 and platelet-derived growth factor-beta (PDGF-β) with a diminution of hepatic Col 1A1 level. In addition, EMPA prompted a protuberant suppression of the angiogenic pathway; vascular endothelial growth factor (VEGF)/VEGF-receptor-2 (VEGFR-2)/SH2-Domain Containing Adaptor Protein-B (Shb), and reversal of altered portal hypertension (PHT) markers; endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS). The amelioration of liver fibrosis was coupled with a remarkable improvement in liver aminotransferases and histologic hepatic fibrosis Ishak scores. The highest EMPA dose showed a good safety profile with minimal changes in renal function and glycemic control. Thus, the current study brought about novel findings for a potential liver fibrosis treatment modality via targeting NRP-1 signaling pathways by EMPA.
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Affiliation(s)
- Ashraf A Noah
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt; Clinical Research Administration, Alexandria Directorate of Health Affairs, Egyptian Ministry of Health and Population, Alexandria, Egypt
| | - Nesrine S El-Mezayen
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt.
| | - Samar O El-Ganainy
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Inas E Darwish
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt; Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Elham A Afify
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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Pathak M, Parveen R, Khan P, Saha N, Agarwal N. Impact of tofogliflozin on hepatic outcomes: a systematic review. Eur J Clin Pharmacol 2023; 79:1281-1290. [PMID: 37462748 DOI: 10.1007/s00228-023-03537-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 07/05/2023] [Indexed: 09/16/2023]
Abstract
PURPOSE Studies have demonstrated a high prevalence of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) patients. The aim was to review the effect of tofogliflozin on hepatic outcomes in T2DM patients. METHODS A literature search in PubMed, Science Direct and Cochrane Central Register of Controlled Trials was conducted for randomised clinical trials of tofogliflozin by applying predetermined inclusion and exclusion criteria. RESULTS A total number of four randomised clinical trials, including 226 subjects, were included in the review. There was a significant decrease in aspartate aminotransferase (AST) and alanine transaminase (ALT) levels in the tofogliflozin group as compared to the control or active comparator groups. Additionally, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) levels were also significantly decreased in the tofogliflozin group. However, no significant difference was observed in levels of adiponectin. CONCLUSION Overall, an improvement in levels of hepatic parameters was observed in T2DM patients with concurrent liver disorders. However, a large number of clinical trials are needed to prove the efficacy of tofogliflozin on hepatic outcomes in patients with T2DM.
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Affiliation(s)
- Mani Pathak
- Centre for Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Rizwana Parveen
- Centre for Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Parvej Khan
- Centre for Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Nilanjan Saha
- Centre for Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Nidhi Agarwal
- Centre for Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India.
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Schwertheim S, Alhardan M, Manka PP, Sowa JP, Canbay A, Schmidt HHJ, Baba HA, Kälsch J. Higher pNRF2, SOCS3, IRF3, and RIG1 Tissue Protein Expression in NASH Patients versus NAFL Patients: pNRF2 Expression Is Concomitantly Associated with Elevated Fasting Glucose Levels. J Pers Med 2023; 13:1152. [PMID: 37511764 PMCID: PMC10381647 DOI: 10.3390/jpm13071152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/05/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) embraces simple steatosis in non-alcoholic fatty liver (NAFL) to advanced non-alcoholic steatohepatitis (NASH) associated with inflammation, fibrosis, and cirrhosis. NAFLD patients often have metabolic syndrome and high risks of cardiovascular and liver-related mortality. Our aim was to clarify which proteins play a role in the progression of NAFL to NASH. The study investigates paraffin-embedded samples of 22 NAFL and 33 NASH patients. To detect potential candidates, samples were analyzed by immunohistochemistry for the proteins involved in innate immune regulation, autophagy, apoptosis, and antioxidant defense: IRF3, RIG-1, SOCS3, pSTAT3, STX17, SGLT2, Ki67, M30, Caspase 3, and pNRF2. The expression of pNRF2 immunopositive nuclei and SOCS3 cytoplasmic staining were higher in NASH than in NAFL (p = 0.001); pNRF2 was associated with elevated fasting glucose levels. SOCS3 immunopositivity correlated positively with RIG1 (r = 0.765; p = 0.001). Further, in NASH bile ducts showed stronger IRF3 immunostaining than in NAFL (p = 0.002); immunopositive RIG1 tissue was higher in NASH than in NAFL (p = 0.01). Our results indicate that pNRF2, SOCS3, IRF3, and RIG1 are involved in hepatic lipid metabolism. We suggest that they may be suitable for further studies to assess their potential as therapeutics.
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Affiliation(s)
- Suzan Schwertheim
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Malek Alhardan
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Paul P Manka
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
| | - Jan-Peter Sowa
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
| | - Ali Canbay
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
| | - Hartmut H-J Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Hideo A Baba
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Julia Kälsch
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
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Xie K, Sugimoto K, Tanaka M, Akasaka H, Fujimoto T, Takahashi T, Onishi Y, Minami T, Yoshida S, Takami Y, Yamamoto K, Rakugi H. Effects of luseogliflozin treatment on hyperglycemia-induced muscle atrophy in rats. J Clin Biochem Nutr 2023; 72:248-255. [PMID: 37251965 PMCID: PMC10209601 DOI: 10.3164/jcbn.22-58] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 08/04/2022] [Indexed: 10/22/2023] Open
Abstract
Diabetes mellitus is recognized as a risk factor for sarcopenia. Luseogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces inflammation and oxidative stress by improving hyperglycemia, subsequently improving hepatosteatosis or kidney dysfunction. However, the effects of SGLT2 inhibitor on the regulation of skeletal muscle mass or function in hyperglycemia are still unknown. In this study, we investigated the effects of luseogliflozin-mediated attenuation of hyperglycemia on the prevention of muscle atrophy. Twenty-four male Sprague-Dawley rats were randomly divided into four groups: control, control with SGLT2 inhibitor treatment, hyperglycemia, and hyperglycemia with SGLT2 inhibitor treatment. The hyperglycemic rodent model was established using a single injection of streptozotocin, a compound with preferential toxicity toward pancreatic beta cells. Muscle atrophy in streptozotocin-induced hyperglycemic model rats was inhibited by the suppression of hyperglycemia using luseogliflozin, which consequently suppressed hyperglycemia-mediated increase in the levels of advanced glycation end products (AGEs) and activated the protein degradation pathway in muscle cells. Treatment with luseogliflozin can restore the hyperglycemia-induced loss in the muscle mass to some degree partly through the inhibition of AGEs-induced or homeostatic disruption of mitochondria-induced activation of muscle degradation.
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Affiliation(s)
- Keyu Xie
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Ken Sugimoto
- Department of General Geriatric Medicine, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama 700-8505, Japan
| | - Minoru Tanaka
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
- Department of Rehabilitation Science, Graduate School of Health Sciences, Kobe University, 7-10-2 Tomoga-oka, Suma, Kobe, Hyogo 654-0142, Japan
- Department of Rehabilitation Science, Osaka Health Science University, 1-9-27 Tenma, Kita-ku, Osaka 530-0043, Japan
| | - Hiroshi Akasaka
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Taku Fujimoto
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
- Institute for Biogenesis Research, Department of Anatomy Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
| | - Toshimasa Takahashi
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yuri Onishi
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Tomohiro Minami
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Shino Yoshida
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yoichi Takami
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Koichi Yamamoto
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hiromi Rakugi
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
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Kawade S, Ogiso K, Shayo SC, Obo T, Arimura A, Hashiguchi H, Deguchi T, Nishio Y. Luseogliflozin and caloric intake restriction increase superoxide dismutase 2 expression, promote antioxidative effects, and attenuate aortic endothelial dysfunction in diet-induced obese mice. J Diabetes Investig 2023; 14:548-559. [PMID: 36729938 PMCID: PMC10034951 DOI: 10.1111/jdi.13981] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 01/06/2023] [Accepted: 01/11/2023] [Indexed: 02/03/2023] Open
Abstract
AIMS/INTRODUCTION The mechanisms underlying the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on aortic endothelial dysfunction in diet-induced obesity are not clearly understood. This study investigated whether SGLT2 inhibition by luseogliflozin improved free fatty acid (FFA)-induced endothelial dysfunction in high-fat diet (HFD)-induced obese mice. MATERIALS AND METHODS Mice were fed a control diet or high-fat diet for 8 weeks, and then each diet with or without luseogliflozin was provided for an additional 8 weeks under free or paired feeding. Afterward, the thoracic aortas were removed and utilized for the experiments. RESULTS Luseogliflozin treatment decreased body weight, fasting blood glucose, insulin, and total cholesterol in HFD-fed mice only under paired feeding but not under free feeding. Endothelial-dependent vasodilation under FFA exposure conditions was significantly lower in HFD-fed mice than in control diet-fed mice, and luseogliflozin treatment ameliorated FFA-induced endothelial dysfunction. Reactive oxygen species (ROS) production induced by FFA was significantly increased in HFD-induced obese mice. Luseogliflozin treatment increased the expression of superoxide dismutase 2 (SOD2), an antioxidative molecule, and reduced FFA-induced ROS production in the thoracic aorta. Superoxide dismutase reversed FFA-induced endothelial dysfunction in HFD-fed mice. CONCLUSIONS It was shown that caloric restriction is important for the effect of luseogliflozin on metabolic parameters and endothelial dysfunction. Furthermore, SGLT2 inhibition by luseogliflozin possibly ameliorates FFA-induced endothelial dysfunction by increasing SOD2 expression and decreasing reactive oxygen species production in the thoracic aorta.
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Affiliation(s)
- Shigeru Kawade
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Kazuma Ogiso
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Sigfrid Casmir Shayo
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Takahiko Obo
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Aiko Arimura
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Hiroshi Hashiguchi
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Takahisa Deguchi
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Yoshihiko Nishio
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
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10
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Licata A, Russo GT, Giandalia A, Cammilleri M, Asero C, Cacciola I. Impact of Sex and Gender on Clinical Management of Patients with Advanced Chronic Liver Disease and Type 2 Diabetes. J Pers Med 2023; 13:jpm13030558. [PMID: 36983739 PMCID: PMC10051396 DOI: 10.3390/jpm13030558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/22/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Gender differences in the epidemiology, pathophysiological mechanisms and clinical features in chronic liver diseases that may be associated with type 2 diabetes (T2D) have been increasingly reported in recent years. This sexual dimorphism is due to a complex interaction between sex- and gender-related factors, including biological, hormonal, psychological and socio-cultural variables. However, the impact of sex and gender on the management of T2D subjects with liver disease is still unclear. In this regard, sex-related differences deserve careful consideration in pharmacology, aimed at improving drug safety and optimising medical therapy, both in men and women with T2D; moreover, low adherence to and persistence of long-term drug treatment is more common among women. A better understanding of sex- and gender-related differences in this field would provide an opportunity for a tailored diagnostic and therapeutic approach to the management of T2D subjects with chronic liver disease. In this narrative review, we summarized available data on sex- and gender-related differences in chronic liver disease, including metabolic, autoimmune, alcoholic and virus-related forms and their potential evolution towards cirrhosis and/or hepatocarcinoma in T2D subjects, to support their appropriate and personalized clinical management.
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Affiliation(s)
- Anna Licata
- Internal Medicine & Hepatology Unit, University Hospital of Palermo, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Giuseppina T Russo
- Internal Medicine and Diabetology Unit, University of Messina, 98125 Messina, Italy
| | - Annalisa Giandalia
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
| | - Marcella Cammilleri
- Internal Medicine & Hepatology Unit, University Hospital of Palermo, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Clelia Asero
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
| | - Irene Cacciola
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
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11
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Plaz Torres MC, Jaffe A, Perry R, Marabotto E, Strazzabosco M, Giannini EG. Diabetes medications and risk of HCC. Hepatology 2022; 76:1880-1897. [PMID: 35239194 PMCID: PMC9790535 DOI: 10.1002/hep.32439] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus is a recognized risk factor for HCC in patients with liver disease, independent from the etiology of their liver disease. Hence, prevention and treatment of type 2 diabetes mellitus and its underlying cause, insulin resistance, should be considered a treatment target for patients with liver disease. The drug armamentarium for diabetes is wide and consists of agents with insulin-sensitizing activity, agents that stimulate insulin secretion, insulin itself, and agents that reduce gastrointestinal and urinary glucose absorption. From an endocrinology perspective, the main goal of treatment is the achievement of euglycemia; however, in patients at risk of, or with known underlying liver disease, the choice of diabetic medication as it relates to potential hepatic carcinogenesis remains complex and should be carefully considered. In the last decade, increasing evidence has suggested that metformin may reduce the risk of HCC, whereas evidence for other classes of diabetic medications, particularly some of the newer agents including the sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, is fewer and often inconsistent. In this review, we aim to summarize the current evidence on the potential effects of the most widely used diabetic agents on liver cancer tumorigenesis.
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Affiliation(s)
- Maria Corina Plaz Torres
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
| | - Ariel Jaffe
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
| | - Rachel Perry
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
- Section of EndocrinologyDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
- Department of Cellular and Molecular PhysiologyYale University School of MedicineNew HavenConnecticutUSA
| | - Elisa Marabotto
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
| | - Mario Strazzabosco
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
| | - Edoardo G. Giannini
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
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12
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Kim J, Han K, Kim B, Baek KH, Song KH, Kim MK, Kwon HS. Sodium-glucose cotransporter 2 inhibitors for non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus: A nationwide propensity-score matched cohort study. Diabetes Res Clin Pract 2022; 194:110187. [PMID: 36442545 DOI: 10.1016/j.diabres.2022.110187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 11/02/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022]
Abstract
AIMS This study was to determine the association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes. METHODS We used data from the Korean National Health Insurance Service from 2014 to 2017. New drug users were screened, dipeptidyl peptidase 4 inhibitors (DPP4i) were set as the active comparator, and the differences between the two groups were corrected through propensity score matching. NAFLD was evaluated by the fatty liver index (FLI), which was calculated using body mass index, waist circumference, triglycerides, and gamma glutamyl peptidase. RESULTS After 1:1 matching, 25,371 patients in each group who received medication for an average of 299 days were analyzed. Despite similar baseline FLI of each group, the FLI of the SGLT2i users was 44.4 ± 26.7 and the FLI of the DPP4i users was 48.9 ± 27.3 (P value < 0.001) after treatment. SGLT2i showed more significant decrements than DPP4i in all components of FLI. The more the adherence to the SGLT2i increased, the greater the decrease in FLI. CONCLUSIONS SGLT2i showed a significant reduction in FLI and its components. We suggest that SGLT2i may have beneficial effects in reducing the prevalence of NAFLD in type 2 diabetes.
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Affiliation(s)
- Jinyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Bongsung Kim
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Ki-Hyun Baek
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ki-Ho Song
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Mee Kyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Hyuk-Sang Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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13
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Zhou Y, Li Z, Xu M, Zhang D, Ling J, Yu P, Shen Y. O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease. Cells 2022; 11:cells11223637. [PMID: 36429065 PMCID: PMC9688300 DOI: 10.3390/cells11223637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/04/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD.
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Affiliation(s)
- Yicheng Zhou
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, Nanchang 330031, China
| | - Minxuan Xu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Deju Zhang
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Jitao Ling
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Peng Yu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
- Correspondence: (P.Y.); (Y.S.)
| | - Yunfeng Shen
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
- Correspondence: (P.Y.); (Y.S.)
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14
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Deng L, Yang Y, Xu G. Empagliflozin ameliorates type 2 diabetes mellitus-related diabetic nephropathy via altering the gut microbiota. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159234. [PMID: 36185030 DOI: 10.1016/j.bbalip.2022.159234] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/22/2022] [Accepted: 09/04/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND The dysregulation of gut microbiota can be found in patients with type 2 diabetes mellitus (T2DM)-related diabetic nephropathy (DN). Inhibitors of sodium-glucose co-transporter 2 (SGLT2) were reported to affect gut microbiota. This study aimed to identify whether empagliflozin (EMPA) attenuated DN via regulating gut microbiota. MATERIALS AND METHODS The high-fat diet (HFD) combining streptozocin (STZ) injection was performed to induce DN in mice. The therapeutic effects of EMPA were observed by staining of renal tissues and urine albumin/creatinine ratio (UACR). Mouse feces were collected for 16S rRNA sequencing. Fecal short-chain fatty acids (SCFAs) and fecal and serum lipopolysaccharide (LPS) were determined. An antibiotic-ablated model was established to confirm the role of the gut microbiota in the actions of EMPA. RESULTS EMPA reduced the elevation of blood glucose and UACR caused by HFD/STZ. It inhibited the thickening of the colonic crypt and restored goblet cells and the expressions of ZO-1 and Occludin. The 16S rRNA sequencing showed that the diversity of gut microbiota was reduced after HFD/STZ treatment, while it was restored after EMPA treatment. The LPS-producing bacteria, Oscillibacter, and the SCFA-producing bacteria, Bateroid and Odoribacter, were changed after EMPA administration. The therapeutic effects of EMPA on ABX-treated mice were reduced. Meanwhile, the level of fecal SCFAs was decreased, while the levels of fecal and serum LPS were elevated, in T2DM mice, and they were negated by the administration of EMPA. CONCLUSION EMPA ameliorates T2DM-related DN via altering the gut microbiota, especially reducing LPS-producing bacteria and increasing SCFA-producing bacteria.
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Affiliation(s)
- Le Deng
- Department of Nephrology, the Second Affiliated Hospital of Nanchang University, Jiangxi 330006, China
| | - Yang Yang
- Department of Nephrology, the Second Affiliated Hospital of Nanchang University, Jiangxi 330006, China
| | - Gaosi Xu
- Department of Nephrology, the Second Affiliated Hospital of Nanchang University, Jiangxi 330006, China.
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15
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Shaaban HH, Alzaim I, El-Mallah A, Aly RG, El-Yazbi AF, Wahid A. Metformin, pioglitazone, dapagliflozin and their combinations ameliorate manifestations associated with NAFLD in rats via anti-inflammatory, anti-fibrotic, anti-oxidant and anti-apoptotic mechanisms. Life Sci 2022; 308:120956. [PMID: 36103959 DOI: 10.1016/j.lfs.2022.120956] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an important health threat that is strongly linked to components of metabolic syndrome, particularly the low-grade inflammatory changes. Significantly, several of the available anti-diabetic drug classes demonstrate a considerable anti-inflammatory effect, and hence might be of benefit for NAFLD patients. In this study, we used a rat model of diet-induced NAFLD to examine the potential effect of metformin, pioglitazone, dapagliflozin and their combinations on NAFLD manifestations. Rats were fed an atherogenic diet containing 1.25 % cholesterol, 0.5 % cholic acid and 60 % cocoa butter for 6 weeks causing a number of metabolic and hepatic alterations including insulin resistance, dyslipidemia, systemic inflammation, increased hepatic oxidative stress and lipid peroxidation, hepatic steatosis, lobular inflammation, as well as increased markers of liver inflammation and hepatocyte apoptosis. Drug treatment, which started at the third week of NAFLD induction and continued for three weeks, not only ameliorated the observed metabolic impairment, but also functional and structural manifestations of NAFLD. Specifically, anti-diabetic drug treatment reversed markers of systemic and hepatic inflammation, oxidative stress, hepatic fibrosis, and hepatocyte apoptosis. Our findings propose that anti-diabetic drugs with a potential anti-inflammatory effect can ameliorate the manifestations of NAFLD, and thus may provide a therapeutic option for such a condition that is closely associated with metabolic diseases. The detailed pharmacology of these classes in aspects linked to the observed impact on NAFLD requires to be further investigated and translated into clinical studies for tailored therapy specifically targeting NAFLD.
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Affiliation(s)
- Hager H Shaaban
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
| | - Ibrahim Alzaim
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine the American University of Beirut, Beirut, Lebanon; Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ahmed El-Mallah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt
| | - Rania G Aly
- Department of Pathology, Faculty of Medicine, Alexandria University, Egypt
| | - Ahmed F El-Yazbi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt; Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Faculty of Pharmacy, Al-Alamein International University, Alamein, Egypt.
| | - Ahmed Wahid
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
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16
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Wang Z, Ye M, Zhang XJ, Zhang P, Cai J, Li H, She ZG. Impact of NAFLD and its pharmacotherapy on lipid profile and CVD. Atherosclerosis 2022; 355:30-44. [PMID: 35872444 DOI: 10.1016/j.atherosclerosis.2022.07.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 06/16/2022] [Accepted: 07/13/2022] [Indexed: 11/21/2022]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Increasing evidence suggests that, in addition to traditional metabolic risk factors such as obesity, hypercholesterolemia, hypertension, diabetes mellitus, and insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD) is an emerging driver of ASCVD via multiple mechanisms, mainly by disrupting lipid metabolism. The lack of pharmaceutical treatment has spurred substantial investment in the research and development of NAFLD drugs. However, many reagents with promising therapeutic potential for NAFLD also have considerable impacts on the circulating lipid profile. In this review, we first summarize the mechanisms linking lipid dysregulation in NAFLD to the progression of ASCVD. Importantly, we highlight the potential risks of/benefits to ASCVD conferred by NAFLD pharmaceutical treatments and discuss potential strategies and next-generation drugs for treating NAFLD without the unwanted side effects.
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Affiliation(s)
- Zhenya Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China
| | - Mao Ye
- Department of Cardiology, Huanggang Central Hospital, HuBei Province, China; Huanggang Institute of Translational Medicine, Huanggang, China
| | - Xiao-Jing Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China; School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Peng Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China; School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jingjing Cai
- Institute of Model Animal, Wuhan University, Wuhan, China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Huanggang Institute of Translational Medicine, Huanggang, China.
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China.
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17
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Lingli X, Wenfang X. Characteristics and molecular mechanisms through which SGLT2 inhibitors improve metabolic diseases: A mechanism review. Life Sci 2022; 300:120543. [PMID: 35421452 DOI: 10.1016/j.lfs.2022.120543] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 11/26/2022]
Abstract
Metabolic diseases, such as diabetes, gout and hyperlipidemia are global health challenges. Among them, diabetes has been extensively investigated. Type 2 diabetes mellitus (T2DM), which is characterized by hyperglycemia, is a complex metabolic disease that is associated with various metabolic disorders. The newly developed oral hypoglycemic agent, sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been associated with glucose-lowering effects and it affects metabolism in various ways. However, the potential mechanisms of SGLT2 inhibitors in metabolic diseases have not fully reviewed. Many of the effects beyond glycemic control must be considered off-target effects. Therefore, we reviewed the effects of SGLT2 inhibitors on metabolic diseases such as obesity, hypertension, hyperlipidemia, hyperuricemia, fatty liver disease, insulin resistance, osteoporosis and fractures. Moreover, we elucidated their molecular mechanisms to provide a theoretical basis for metabolic disease treatment.
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Affiliation(s)
- Xie Lingli
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China
| | - Xia Wenfang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China.
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18
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Li N, Zhou H. Sodium-glucose Cotransporter Type 2 Inhibitors: A New Insight into the Molecular Mechanisms of Diabetic Nephropathy. Curr Pharm Des 2022; 28:2131-2139. [PMID: 35718973 DOI: 10.2174/1381612828666220617153331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 03/15/2022] [Indexed: 11/22/2022]
Abstract
Diabetic nephropathy is one of the chronic microvascular complications of diabetes and is a leading cause of end-stage renal disease. Fortunately, clinical trials have demonstrated that sodium-glucose cotransporter type 2 inhibitors could decrease proteinuria and improve renal endpoints and are promising agents for the treatment of diabetic nephropathy. The renoprotective effects of sodium-glucose cotransporter type 2 inhibitors cannot be simply attributed to their advantages in aspects of metabolic benefits, such as glycemic control, lowering blood pressure, and control of serum uric acid, or improving hemodynamics associated with decreased glomerular filtration pressure. Some preclinical evidence suggests that sodium-glucose cotransporter type 2 inhibitors exert their renoprotective effects by multiple mechanisms, including attenuation of oxidative and endoplasmic reticulum stresses, anti-fibrosis and anti-inflammation, protection of podocytes, suppression of megalin function, improvement of renal hypoxia, restored mitochondrial dysfunction and autophagy, as well as inhibition of sodium-hydrogen exchanger 3. In the present study, the detailed molecular mechanisms of sodium-glucose cotransporter type 2 inhibitors with the actions of diabetic nephropathy were reviewed, with the purpose of providing the basis for drug selection for the treatment of diabetic nephropathy.
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Affiliation(s)
- Na Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hong Zhou
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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19
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Ding C, Tang Y, Zhu W, Huang P, Lian P, Ran J, Huang X. Sodium-glucose cotransporter protein-2 inhibitors and glucagon-like peptide-1 receptor agonists versus thiazolidinediones for non-alcoholic fatty liver disease: A network meta-analysis. Acta Diabetol 2022; 59:519-533. [PMID: 34988690 DOI: 10.1007/s00592-021-01830-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023]
Abstract
AIMS Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disorders worldwide. Some hypoglycemic drugs can improve NAFLD. However, it is unclear which of these types of hypoglycemic drugs are more effective for NAFLD. Therefore, we conducted a network meta-analysis to determine the effect of thiazolidinediones (TZDs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists on NAFLD patients. METHODS A literature search of PubMed, EMBASE, the Cochrane Library, and Medline was conducted, and the literature from database inception up to April 30, 2021 was obtained. Liver function tests, lipid profiles, body mass index (BMI) and glycemic parameters were obtained from randomized controlled trials. Weighted mean differences (WMDs), relative risks and 95% confidence intervals (CIs) were calculated for continuous outcomes, and the I2 statistic was used to evaluate the heterogeneity of the studies. RESULTS In total, 22 trials, including 1361 patients, were selected. In direct meta-analysis, GLP-1 receptor agonists were superior to TZDs in decreasing alanine aminotransferase (WMD, -0.40, 95% CI: -0.60 to -0.20), γ-glutamyl transferase (WMD, -5.00, 95% CI: -6.47 to -3.53), BMI (WMD, -4.10, 95%CI: -6.55 to -1.65) and triglycerides (WMD, - 0.50, 95% CI: -0.68 to -0.32). Based on Bayesian network meta-analysis, the effect of SGLT-2 inhibitors on weight loss was superior to that of TZDs (WMD, -1.80, 95%CI: -3.30 to -0.41). CONCLUSIONS GLP-1 receptor agonists and SGLT-2 inhibitors improved liver enzymes, BMI, blood lipid, blood glucose and insulin resistance in NAFLD patients.
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Affiliation(s)
- Chen Ding
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yaxin Tang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Wenqiang Zhu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Piaopiao Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Pingan Lian
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Juanli Ran
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Xiansheng Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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20
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Barritt AS, Marshman E, Noureddin M. Review article: role of glucagon-like peptide-1 receptor agonists in non-alcoholic steatohepatitis, obesity and diabetes-what hepatologists need to know. Aliment Pharmacol Ther 2022; 55:944-959. [PMID: 35266164 PMCID: PMC9310586 DOI: 10.1111/apt.16794] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/13/2022] [Accepted: 01/14/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) is characterised by hepatic lipid accumulation, cell injury, inflammation and fibrosis. Insulin resistance, a hallmark of type 2 diabetes (T2D) and obesity, is a key pathogenic driver of NASH. Other than difficult-to-maintain lifestyle changes, there are no approved treatments for NASH. Due to their effects on multiple pathophysiological processes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been tested in disorders related to insulin resistance and metabolic defects. AIMS To summarise studies of GLP-1RAs relevant to the treatment of NASH. METHODS PubMed searches were performed and results were compiled. RESULTS Large trials with GLP-1RAs in T2D demonstrate highly effective glucose lowering, with body weight loss, and in some cases, reduced cardiovascular events and improved liver transaminases. The GLP-1RAs, liraglutide and semaglutide, were associated with clinically relevant, sustained body weight reduction in individuals with overweight or obesity and without T2D. In a phase II trial in NASH, liraglutide reduced metabolic dysfunction, insulin resistance and lipotoxicity in key organs associated with NASH pathogenesis. Furthermore, liraglutide and semaglutide led to histological resolution of NASH in ~40% to 60% of patients, although a statistically significant effect on fibrosis has not been confirmed. Regarding safety, GLP-1RAs are associated with gastrointestinal and gallbladder-related adverse events, with the latter perhaps related to weight loss. Meta-analyses do not indicate increased risk of acute pancreatitis, pancreatic cancer or other malignancies with GLP-1RAs. CONCLUSIONS These studies support the use of GLP-1RAs for the improvement of underlying metabolic dysfunction observed in NASH and suggest further long-term phase III trials are warranted.
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Affiliation(s)
- A. Sidney Barritt
- Division of Gastroenterology and Hepatology, UNC Liver CenterUniversity of North Carolina at Chapel HillChapel HillNCUSA
| | | | - Mazen Noureddin
- Department of MedicineCedars‐Sinai Medical CenterLos AngelesCAUSA
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21
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SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection. Int J Mol Sci 2022; 23:ijms23063107. [PMID: 35328527 PMCID: PMC8953901 DOI: 10.3390/ijms23063107] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/03/2022] [Accepted: 03/09/2022] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.
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22
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Rajesh N, Drishya L, Ambati MMR, Narayanan AL, Alex M, R KK, Abraham JJ, Vijayakumar T. Safety and Efficacy of Saroglitazar in Nonalcoholic Fatty Liver Patients With Diabetic Dyslipidemia-A Prospective, Interventional, Pilot Study. J Clin Exp Hepatol 2022; 12:61-67. [PMID: 35068786 PMCID: PMC8766544 DOI: 10.1016/j.jceh.2021.03.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 03/28/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Saroglitazar-a unique dual peroxisome proliferator-activated receptor agonist was approved marketing authorization in India in 2013 for diabetic dyslipidemia. Postmarketing studies have additionally shown improvement in liver parameters in diabetic dyslipidemia patients with nonalcoholic fatty liver disease (NAFLD) who received saroglitazar. AIM The aim of this study was to evaluate the effect of saroglitazar on liver function test, liver fibrosis score by FibroScan, lipid profiles, HbA1c in NAFLD patients with diabetic dyslipidemia in southern India. METHODOLOGY A prospective, interventional, pilot study was performed to study the safety and efficacy of saroglitazar in NAFLD patients having type 2 diabetes mellitus. About 97 patients were screened, of which 85 patients were involved in the study based on the inclusion criteria. The clinical parameters and liver stiffness were measured at the baseline and also after 12 weeks of treatment with administration of saroglitazar 4 mg once daily. The change in the parameters at the baseline and after the end of the treatment was measured and was subjected to statistical analysis using SPSS software. RESULTS The recruited patients received saroglitazar and were followed up for a period of 12 weeks. The clinical parameters such as fasting blood sugar, postprandial blood sugar, HbA1c, total cholesterol, triglycerides, SGPT, and liver stiffness showed significant difference after 12 weeks of treatment when compared with the baseline values. No adverse drug reaction was reported in patients receiving saroglitazar during the study. CONCLUSION Saroglitazar was found to show significant improvement in liver parameters in NAFLD patients with a significant reduction in liver fibrosis and triglycerides level.
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Key Words
- AACE, American Associaton of Clinical Endocrinologists
- ADR, Adverse Drug Reaction
- ALT, Alanine Transaminase
- BMI, Body Mass Index
- CDSCO, Central Drugs Standard Control Organisation
- CT Scan, Computed Tomography Scan
- DBP, Diastolic Blood Pressure
- DCGI, Drug Controller General of India
- FBS, Fasting Blood Sugar
- GLP1Ra, Glucagon Like Peptide 1 Receptor agonist
- HCV, Hepatitis - C Virus
- HDL, High Density Lipoprotein
- HbA1C, Glycated Hemoglobin
- IHEC, Institutional Human Ethics Committee
- LDL-C, Low Density Lipoprotein Cholesterol
- LSM, Liver Stiffness Measurement
- MRI, Magnetic Resonance Imaging
- NAFLD, Nonalcoholic Fatty Liver Disease
- NASH, Non-Alcoholic Steatohepatitis
- NPV, Negative Predictive Value
- Na2EDTA, Sodium Ethylenedinitrilotetraacetic acid
- PPAR, Peroxisome Proliferator Activated Receptor
- PPBS, Post Prandial Blood Sugar
- SBP, Systolic Blood Pressure
- SDB, Serum Direct Bilirubin
- SGLT2i, Sodium Glucose Co-Transporter-2 Inhibitor
- SGOT, Serum Glutamate Oxaloacetic Transaminase
- SGPT, Serum Glutamate Pyruvic Transaminase
- SPSS, Statistical Package for the Social Sciences
- STB, Serum Total Bilirubin
- T2DM, Type 2 Diabetes Mellitus
- TC, Total Cholesterol
- TG, Triglycerides
- TZD, Thiazolidinediones
- USG, Ultra Sonography
- VLDL, Very Low Density Lipoprotein
- diabetic dyslipidemia
- fibrosis level
- non-alcoholic fatty liver disease
- saroglitazar
- ultrasound
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Affiliation(s)
- N.A. Rajesh
- Department of Medical Gastroenterology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India
| | - L. Drishya
- Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India
| | - Murali Mohan Raju Ambati
- Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India
| | - Athi L. Narayanan
- Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India
| | - Maria Alex
- Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India
| | - Kiran Kumar R
- Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India
| | - Justin J. Abraham
- Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India
| | - T.M. Vijayakumar
- Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603 203, India
- Address for correspondence: Dr. T.M. Vijayakumar, M.Pharm, Ph.D., Associate Professor & Head, Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603 203, India. Tel.: +91 44 2745 3160, +91 44 2745 5718; Fax: +91 44 2745 5734.
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23
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Han T, Fan Y, Gao J, Fatima M, Zhang Y, Ding Y, Bai L, Wang C. Sodium glucose cotransporter 2 inhibitor dapagliflozin depressed adiposity and ameliorated hepatic steatosis in high-fat diet induced obese mice. Adipocyte 2021; 10:446-455. [PMID: 34550043 PMCID: PMC8475578 DOI: 10.1080/21623945.2021.1979277] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
With the increasing obesity prevalence, the rates of obesity-related diseases, including type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases, have increased dramatically. Dapagliflozin, one of the sodium glucose cotransporter inhibitors, not only exerts hypoglycaemic effects through increasing urinary glucose excretion but alsoreprograms the metabolic system, leading to benefits in metabolic and cardiovascular diseases. In this study, pre-established obese mice on a high-fat diet were given dapagliflozin by gavage for fourweeks. It showed that dapagliflozin can enhance fat utilization and browning of adipose tissue and improve local oxidative stress, thus inhibiting fat accumulation and hepatic steatosis without disturbance in body weight or plasma glycolipid level. Overall, our study highlights the potential clinical application of SGLT2 inhibition in the prevention of obesity and related metabolic diseases, such as insulin resistance, NAFLD, and diabetes.
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Affiliation(s)
- Tuo Han
- Department of Cardiology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Laboratory Animal Center, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China
| | - Yajie Fan
- Department of Cardiology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Jie Gao
- Laboratory Animal Center, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China
| | - Mahreen Fatima
- Laboratory Animal Center, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China
| | - Yali Zhang
- Laboratory Animal Center, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China
| | - Yiming Ding
- Laboratory Animal Center, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China
| | - Liang Bai
- Laboratory Animal Center, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China
| | - Congxia Wang
- Department of Cardiology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
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Phrueksotsai S, Pinyopornpanish K, Euathrongchit J, Leerapun A, Phrommintikul A, Buranapin S, Chattipakorn N, Thongsawat S. The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2021; 36:2952-2959. [PMID: 34129252 DOI: 10.1111/jgh.15580] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/25/2021] [Accepted: 06/12/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Sodium-glucose cotransporter 2 inhibitors have shown excellent results in glucose control in type 2 diabetes mellitus (T2DM) patients, while also promoting weight loss. These mechanisms may be beneficial in the treatment of non-alcoholic fatty liver disease (NAFLD). Our study aims to investigate the effect of dapagliflozin on hepatic and visceral fat contents and related biochemical markers in T2DM with NAFLD patients. METHODS This is a double-blinded placebo-controlled randomized, single-center study. Non-insulin-dependent T2DM patients with NAFLD were prospectively enrolled and randomly assigned to receive either dapagliflozin (10 mg/day) or placebo for 12 weeks. The primary end-point was the changes in intrahepatic lipid contents, evaluated by the liver attenuation index. RESULTS Of 40 patients enrolled, 38 patients completed the study (dapagliflozin group, n = 18; placebo group, n = 20). Baseline demographic and laboratory findings were similar in both groups. After 12 weeks of treatment, dapagliflozin significantly decreased intrahepatic lipid contents demonstrated by an increase in liver attenuation index in comparison with the placebo treatment (5.8 ± 5.1 vs 0.5 ± 6.1 Hounsfield units, P = 0.006). Significant reduction in bodyweight, bodyfat, visceral fat/subcutaneous fat ratio, hemoglobin A1c, and alanine aminotransferase were also observed in the dapagliflozin-treated group as compared with the placebo group (all P < 0.05). There was no significant difference in adipokines including adiponectin, leptin, and tumor necrosis factor-α changes between the dapagliflozin-treated group and the placebo group (all P = nonsignificant). CONCLUSION Dapagliflozin treatment for 12 weeks is associated with improvement in hepatic fat content, a decrease in visceral fat and bodyweight, enhanced glycemic control, and improved liver biochemistry among T2DM patients with NAFLD.
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Affiliation(s)
- Susrichit Phrueksotsai
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Kanokwan Pinyopornpanish
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Juntima Euathrongchit
- Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Apinya Leerapun
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Arintaya Phrommintikul
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Supawan Buranapin
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Satawat Thongsawat
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Padda J, Khalid K, Khedr A, Tasnim F, Al-Ewaidat OA, Cooper AC, Jean-Charles G. Non-Alcoholic Fatty Liver Disease and Its Association With Diabetes Mellitus. Cureus 2021; 13:e17321. [PMID: 34557367 PMCID: PMC8449987 DOI: 10.7759/cureus.17321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2021] [Indexed: 11/29/2022] Open
Abstract
There is a bidirectional relationship between non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). The liver has a vital role in the pathophysiology of both diseases as it leads to the development of insulin resistance (IR), which in turn results in NAFLD and T2DM. It has been shown that T2DM increases the risk of NAFLD progression. Furthermore, the presence of NAFLD raises the probability of T2DM complications, which explains the increased rates of NAFLD screening in patients with T2DM. In addition, there are common management options for the two diseases. Lifestyle changes can play a role in the initial management of both diseases. Medications that are used to treat T2DM are also used in the management of NAFLD, such as metformin, thiazolidinediones (TZD), glucagon-like peptide-1 (GLP-1) analogues, and dipeptidyl peptidase-4 (DPP4) inhibitors. Bariatric surgery is often used as a last resort and has shown promising results. Lifestyle interventions with diet and exercise are important postoperatively to maintain the weight loss. There are many novel treatments that are being investigated for the treatment of NAFLD, targeting multiple pathophysiologic pathways. This review aims to shed some light on the intricate relationship between NAFLD and T2DM and how IR links both diseases. We also try to raise awareness among clinicians about this relationship and how the presence of one disease should raise a high index of suspicion for the existence of the other.
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Affiliation(s)
| | | | - Anwar Khedr
- Internal Medicine, JC Medical Center, Orlando, USA
| | | | | | | | - Gutteridge Jean-Charles
- Internal Medicine, JC Medical Center, Orlando, USA.,Internal Medicine, Advent Health & Orlando Health Hospital, Orlando, USA
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26
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Makri ES, Goulas A, Polyzos SA. Sodium-glucose co-transporter 2 inhibitors in nonalcoholic fatty liver disease. Eur J Pharmacol 2021; 907:174272. [PMID: 34147478 DOI: 10.1016/j.ejphar.2021.174272] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 06/03/2021] [Accepted: 06/14/2021] [Indexed: 12/15/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered the most prevalent chronic hepatic disease, as it has been estimated that one of four individuals in the general population has been affected by NAFLD. The evolution of the referred entity, which includes nonalcoholic steatohepatitis (NASH) and hepatic fibrosis, may have crucial and even fatal consequences, leading to cirrhosis and hepatocellular carcinoma. Although NAFLD has also been linked with cardiovascular and renal diseases, and all-cause mortality increment, pharmacological therapy is as yet an unfulfilled demand. Since NAFLD is closely associated with type 2 diabetes mellitus (T2DM), a variety of anti-diabetic drugs have been investigated for their effectiveness towards NAFLD. Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) improve blood glucose levels through increasing renal glucose excretion and they are recommended as one of standard therapeutic categories for T2DM patients. Based on preclinical animal studies, SGLT-2i have shown a beneficial effect on NAFLD, inducing histologically proven amelioration of hepatic steatosis, inflammation and fibrosis. Promising data have been also derived by clinical trials, which have indicated a potentially beneficial effect of SGLT-2i on NAFLD, at least in terms of liver function tests and imaging. Thus, it is not strange that there are many ongoing trials on the effect of various SGLT-2i in NAFLD. In conclusion, current evidence concerning the effect of SGLT-2i on NAFLD is encouraging; however, data from ongoing clinical trials with histological endpoints are awaited.
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Affiliation(s)
- Evangelia S Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
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27
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Smati S, Canivet CM, Boursier J, Cariou B. Anti-diabetic drugs and NASH: from current options to promising perspectives. Expert Opin Investig Drugs 2021; 30:813-825. [PMID: 34214406 DOI: 10.1080/13543784.2021.1951701] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Accumulating evidence supports a bidirectional association between nonalcoholic steatohepatitis (NASH) and type 2 diabetes (T2D). There is a clinical challenge to consider pharmaceutical strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis.Areas covered: By using PubMed, we performed a literature search to review the potential beneficial effect of anti-diabetic and metabolic investigational drugs on NASH.Expert opinion: Since insulin resistance is central in the pathophysiology of both T2D and NASH, there is an urgent need for new insulin sensitizers. Peroxisome proliferator-activated receptor (PPAR) agonists, especially PPARγ and pan-PPARs agonists, have shown some beneficial effects on both NASH and liver fibrosis, but their routine use should be limited by their safety profile. Incretin-based therapies, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and the polyagonists (GLP-1, GIP, glucagon) under development are the most promising anti-diabetic drugs for NASH treatment, mainly due to their action on body weight loss. Preliminary, preclinical and early phase studies suggest that SGLT2 inhibitors and fibroblast growth factor (FGF)19 and FGF21-based therapies are promising targets for NASH and T2D treatment. The common weakness for all of these drugs is their limited effect on liver fibrosis, potentially due to short-term trial design.
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Affiliation(s)
- Sarra Smati
- Department of Endocrinology, Université De Nantes, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, Nantes, France
| | - Clémence M Canivet
- Hepato-Gastroenterology department, University Hospital, Angers, France.,HIFIH Laboratory, EA 3859, University of Angers, Angers, France
| | - Jérôme Boursier
- Hepato-Gastroenterology department, University Hospital, Angers, France.,HIFIH Laboratory, EA 3859, University of Angers, Angers, France
| | - Bertrand Cariou
- Department of Endocrinology, Université De Nantes, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, Nantes, France
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28
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Chrysavgis L, Papatheodoridi AM, Chatzigeorgiou A, Cholongitas E. The impact of sodium glucose co-transporter 2 inhibitors on non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2021; 36:893-909. [PMID: 33439540 DOI: 10.1111/jgh.15202] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/29/2020] [Accepted: 07/23/2020] [Indexed: 12/13/2022]
Abstract
Affecting one fourth of the global population, non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disorder. It encompasses the simple liver fat accumulation to more progressive steatosis, inflammation, and fibrosis characterized as non-alcoholic steatohepatitis (NASH) and in some cases cirrhosis and hepatocellular carcinoma. NAFLD regularly coexists with metabolic disorders, such as obesity and mostly type 2 diabetes mellitus (T2DM). A relatively new class of antidiabetic drugs, the sodium glucose co-transporter 2 (SGLT2) inhibitors exert their action by increasing the urinary glucose and calorie excretion leading to ameliorated plasma glucose levels and lower bodyweight. Recently, several animal studies and human clinical trial have emphasized the possible beneficial impact of SGLT2 inhibitors on NAFLD and its progression to NASH. In this present review, we summarize the current literature regarding the efficacy of the aforementioned category of drugs on anthropometric, laboratory, and histological features of patients with NAFLD. Conclusively, as SGLT2 inhibitors seem to be an appealing therapeutic opportunity for NAFLD management, we identify the open issues and questions to be addressed in order to clarify the impact in choosing antidiabetic medication to treat NAFLD patients associated with T2DM.
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Affiliation(s)
- Lampros Chrysavgis
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | | | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School of National and Kapodistrian University, General Hospital of Athens "Laiko", Athens, Greece
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29
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Seino H. Efficacy and Safety of Luseogliflozin in Patients with Type 2 Diabetes Complicated by Hepatic Dysfunction: A Single-Site, Single-Arm, Open-Label, Exploratory Trial. Diabetes Ther 2021; 12:863-877. [PMID: 33594581 PMCID: PMC7947107 DOI: 10.1007/s13300-021-01014-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/27/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Improvements in glycemic control and hepatic function are clinically important goals in the treatment of patients with type 2 diabetes mellitus (T2DM) complicated by hepatic dysfunction. The favorable effects of the sodium-glucose co-transporter inhibitor luseogliflozin on hepatic dysfunction were anticipated for humans. Nevertheless, few clinical studies have confirmed its real-world efficacy on hepatic dysfunction. This trial assessed the efficacy and safety of luseogliflozin in patients with T2DM complicated by hepatic dysfunction. METHODS This prospective, single-site, single-arm, open-label, exploratory trial included 55 subjects with T2DM complicated by hepatic dysfunction. Subjects were administered luseogliflozin and observed for 52 weeks. The primary endpoints were the change in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), and hemoglobin A1c (HbA1c) from baseline to week 52. The secondary endpoints included body weight, body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose (FPG), homeostatic model assessment beta (HOMA-β), homeostatic model assessment of insulin resistance (HOMA-IR), ferritin, Mac-2 binding protein (M2-BP), fatty liver index (FLI), fibrosis-4 (FIB-4) index, type IV collagen 7S domain, nonalcoholic fatty liver disease (NAFLD) fibrosis score, high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6). RESULTS AST, ALT, γ-GTP, and HbA1c significantly decreased from baseline to week 52. Body weight, BMI, waist circumference, and FPG also significantly decreased. HOMA-IR significantly decreased but HOMA-β was unchanged. FLI, ferritin, M2-BP, and NAFLD fibrosis scores significantly decreased whereas the FIB-4 index and type IV collagen 7S domain did not significantly change. The hs-CRP and IL-6 levels did not significantly change. CONCLUSION Luseogliflozin administration in patients with T2DM complicated by hepatic dysfunction was well tolerated, did not worsen the hepatic condition, and might even be beneficial to improve hepatic function, reduce liver fat, and attenuate liver injury and fibrosis. TRIAL REGISTRATION This study was registered under the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) (No. UMIN000025808) and the Japan Registry of Clinical Trials (jRCT) (No. jRCTs021180017).
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Affiliation(s)
- Hiroaki Seino
- Seino Internal Medical Clinic, Kaisei, Koriyama, Fukushima, Japan.
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Fu ZD, Cai XL, Yang WJ, Zhao MM, Li R, Li YF. Novel glucose-lowering drugs for non-alcoholic fatty liver disease. World J Diabetes 2021; 12:84-97. [PMID: 33520110 PMCID: PMC7807257 DOI: 10.4239/wjd.v12.i1.84] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/22/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The efficacy of novel glucose-lowering drugs in treating non-alcoholic fatty liver disease (NAFLD) is unknown.
AIM To evaluate the efficacy of glucose-lowering drugs dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors in treating NAFLD and to perform a comparison between these treatments.
METHODS Electronic databases were systematically searched. The inclusion criteria were: Randomized controlled trials comparing DPP-4 inhibitors, GLP-1 RAs, or SGLT2 inhibitors against placebo or other active glucose-lowering drugs in NAFLD patients, with outcomes of changes in liver enzyme [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] from baseline.
RESULTS Nineteen studies were finally included in this meta-analysis. Compared with placebo or other active glucose-lowering drug treatment, treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors all led to a significant decrease in ALT change and AST change from baseline. The difference between the DPP-4 inhibitor and SGLT2 inhibitor groups in ALT change was significant in favor of DPP-4 inhibitor treatment (P < 0.05). The trends of reduction in magnetic resonance imaging proton density fat fraction and visceral fat area changes were also observed in all the novel glucose-lowering agent treatment groups.
CONCLUSION Treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors resulted in improvements in serum ALT and AST levels and body fat composition, indicating a beneficial effect in improving liver injury and reducing liver fat in NAFLD patients.
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Affiliation(s)
- Zuo-Di Fu
- Department of Endocrinology, Beijing Friendship Hospital Pinggu Campus, Beijing 101200, China
| | - Xiao-Ling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Wen-Jia Yang
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Ming-Ming Zhao
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100079, China
| | - Ran Li
- Sport Science School, Beijing Sport University, Beijing 100078, China
| | - Yu-Feng Li
- Department of Endocrinology, Beijing Friendship Hospital Pinggu Campus, Capital Medical University, Beijing 101200, China
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Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE (-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis. Int J Mol Sci 2021; 22:818. [PMID: 33467546 PMCID: PMC7829901 DOI: 10.3390/ijms22020818 ] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
AIMS/HYPOTHESIS SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis. METHODS Five-week old ApoE(-/-) mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of Fasn, Screbp-1, Scd-1, Ppar-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Χbp1, Ire1α, Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2α, EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting. RESULTS Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (Fasn, Screbp-1c and Pck-1) and inflammatory molecules (Mcp-1 and F4/80), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules Grp78, Ire1α, Xbp1, Elf2α, Atf4, Atf6, Chop, P62(Sqstm1) and Grp94; whilst activating autophagy via increased AMPK phosphorylation, decreased mTOR and increased LC3B expression. Finally, empagliflozin increased the Bcl2/Bax ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results. CONCLUSION These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE(-/-) mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis.
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Nasiri-Ansari N, Nikolopoulou C, Papoutsi K, Kyrou I, Mantzoros CS, Kyriakopoulos G, Chatzigeorgiou A, Kalotychou V, Randeva MS, Chatha K, Kontzoglou K, Kaltsas G, Papavassiliou AG, Randeva HS, Kassi E. Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE (-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis. Int J Mol Sci 2021; 22:818. [PMID: 33467546 PMCID: PMC7829901 DOI: 10.3390/ijms22020818] [Citation(s) in RCA: 202] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 12/11/2022] Open
Abstract
AIMS/HYPOTHESIS SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis. METHODS Five-week old ApoE(-/-) mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of Fasn, Screbp-1, Scd-1, Ppar-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Χbp1, Ire1α, Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2α, EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting. RESULTS Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (Fasn, Screbp-1c and Pck-1) and inflammatory molecules (Mcp-1 and F4/80), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules Grp78, Ire1α, Xbp1, Elf2α, Atf4, Atf6, Chop, P62(Sqstm1) and Grp94; whilst activating autophagy via increased AMPK phosphorylation, decreased mTOR and increased LC3B expression. Finally, empagliflozin increased the Bcl2/Bax ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results. CONCLUSION These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE(-/-) mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis.
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Affiliation(s)
- Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Chrysa Nikolopoulou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Katerina Papoutsi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK;
- Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, UK
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Christos S. Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;
- Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA 02215, USA
| | - Georgios Kyriakopoulos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
- Department of Pathology, Evangelismos Hospital, 10676 Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Vassiliki Kalotychou
- 1st Department of Internal Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Manpal S. Randeva
- Human Metabolism Research Unit, WISDEM Centre, NHS Trust, Coventry CV2 2DX, UK;
| | - Kamaljit Chatha
- Department of Biochemistry & Immunology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK;
| | - Konstantinos Kontzoglou
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Gregory Kaltsas
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK;
- Human Metabolism Research Unit, WISDEM Centre, NHS Trust, Coventry CV2 2DX, UK;
- Division of Translational and Experimental Medicine-Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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Wei Q, Xu X, Guo L, Li J, Li L. Effect of SGLT2 Inhibitors on Type 2 Diabetes Mellitus With Non-Alcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne) 2021; 12:635556. [PMID: 34220701 PMCID: PMC8247927 DOI: 10.3389/fendo.2021.635556] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 05/26/2021] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVE Clinical trials showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors can improve non-alcoholic fatty liver disease (NAFLD). In this work, a meta-analysis of randomized controlled trials was conducted to evaluate the effect of SGLT2 inhibitors on type 2 diabetes mellitus (T2DM) with NAFLD. METHODS PubMed, Embase, Web of Science, and Cochrane Libraries were used for the systematic literature review to determine eligible studies. A randomized effect model was adapted to perform a meta-analysis on these eligible studies to estimate the combined effect sizes. Differences were expressed as the weighted average difference (WMD) of the continuous results and the 95% confidence interval (CI). RESULTS Ten randomized controlled trials with 573 participants were included. SGLT2 inhibitors significantly reduced the levels of alanine transaminase (WMD -5.36 [95% CI: -8.86, -1.85], p = 0.003) and Aspartate Transaminase (WMD -2.56 [95% CI: -3.83, -1.29], p <0.0001). In terms of body composition, liver proton density fat fraction (WMD -2.20 [95% CI: -3.67, -0.74], p = 0.003), visceral fat mass area (WMD -20.71 [95% CI: -28.19, -13.23], p <0.00001), subcutaneous fat areas (WMD -14.68 [95% CI: -26.96, -2.40], p = 0.02) were also significantly reduced. CONCLUSION SGLT2 inhibitors can remarkably reduce hepatic enzymes, hepatic fat and improve body composition. Thus, they may become a new treatment option for NAFLD. SYSTEMATIC REVIEW REGISTRATION PROSPERO, identifier CRD42020215570.
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Affiliation(s)
- Qiong Wei
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
- Institute of Pancreas, Southeast University, Nanjing, China
| | - Xinyue Xu
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
- Institute of Pancreas, Southeast University, Nanjing, China
| | - Li Guo
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
- Institute of Pancreas, Southeast University, Nanjing, China
| | - Jia Li
- Department of Ultrasonography, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
- *Correspondence: Ling Li, ; Jia Li,
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
- Institute of Pancreas, Southeast University, Nanjing, China
- *Correspondence: Ling Li, ; Jia Li,
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Xing B, Zhao Y, Dong B, Zhou Y, Lv W, Zhao W. Effects of sodium-glucose cotransporter 2 inhibitors on non-alcoholic fatty liver disease in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. J Diabetes Investig 2020; 11:1238-1247. [PMID: 32083798 PMCID: PMC7477503 DOI: 10.1111/jdi.13237] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 02/04/2020] [Accepted: 02/19/2020] [Indexed: 12/11/2022] Open
Abstract
AIMS/INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is increasingly common in patients with type 2 diabetes mellitus. Currently, some studies have found that sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new hypoglycemic drug, can improve non-alcoholic fatty liver in addition to its hypoglycemic effect. Thus, we undertook a meta-analysis of randomized controlled trials to evaluate the efficacy of SGLT2 inhibitors on the treatment of NAFLD. MATERIALS AND METHODS PubMed, Embase and the Cochrane Library were searched for randomized controlled trials of SGLT2 inhibitors in patients with NAFLD and type 2 diabetes mellitus up to 1 October 2019. Differences were expressed as weight mean difference (WMD) with 95% confidence interval (CI) for continuous outcomes. The I2 statistic was applied to evaluate the heterogeneity of studies. RESULTS A total of six trials including 309 patients were selected into our meta-analysis. SGLT2 inhibitors could reduce alanine aminotransferase (WMD -11.05 IU/L, 95% CI -19.85, -2.25, P = 0.01) and magnetic resonance imaging proton density fat fraction (WMD -2.07%, 95% CI -3.86, -0.28, P = 0.02). However, SGLT2 inhibitors did not reduce aspartate aminotransferase (WMD -1.11 IU/L, 95% CI -2.39, 0.17, P = 0.09). In addition, secondary outcomes, such as bodyweight and visceral fat area, were also reduced (WMD -1.62 kg, 95% CI -2.02, -1.23, P < 0.00001; WMD -19.98 cm2 , 95% CI -27.18, -12.79, P < 0.00001, respectively). CONCLUSIONS SGLT2 inhibitors can significantly decrease alanine aminotransferase and liver fat, accompanied with weight loss, which might have a positive effect on fatty liver in patients with type 2 diabetes mellitus. The limitation is that the sample size of the studies was small. Therefore, more large randomized controlled trials specified on NAFLD are required to evaluate these results.
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Affiliation(s)
- Baodi Xing
- Department of Endocrine and Metabolic Diseasesthe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Yuhang Zhao
- Department of Endocrine and Metabolic Diseasesthe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Bingzi Dong
- Department of Endocrine and Metabolic Diseasesthe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Yue Zhou
- Department of Endocrine and Metabolic Diseasesthe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Wenshan Lv
- Department of Endocrine and Metabolic Diseasesthe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Wenjuan Zhao
- Department of Endocrine and Metabolic Diseasesthe Affiliated Hospital of Qingdao UniversityQingdaoChina
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Ribeiro Dos Santos L, Baer Filho R. Treatment of nonalcoholic fatty liver disease with dapagliflozin in non-diabetic patients. Metabol Open 2020; 5:100028. [PMID: 32812927 PMCID: PMC7424832 DOI: 10.1016/j.metop.2020.100028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 01/07/2020] [Accepted: 01/30/2020] [Indexed: 12/25/2022] Open
Abstract
Steatosis, a condition characterized by excessive lipid deposition. Although usually a benign condition, steatosis mays progress to cirrhosis or hepatocellular carcinoma. Recent evidence suggests that SGLT2 inhibitors suppress the development of nonalcoholic steatohepatitis in humans, as well as in rodent models and that SGLT2 inhibitors alleviate hepatic steatosis or steatohepatitis in obese type 2 diabetic rats or mice. 14 Patients with nonalcoholic fatty liver disease used a fixed dose of 10 mg of dapagliflozin for an average of 75 days. ALT, AST, GGT, insulin, HOMA-IR, and weight levels were significantly lower after treatment. There was no significant correlation between the reduction in HOMA and the reduction in ALT values or weight reduction obtained during treatment and ALT values.
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Affiliation(s)
| | - Ricardo Baer Filho
- Lusíada University Center, Faculty of Medical Sciences of Santos, Brazil
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Kim KS, Lee BW. Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease. Clin Mol Hepatol 2020; 26:430-443. [PMID: 32791578 PMCID: PMC7641556 DOI: 10.3350/cmh.2020.0137] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder and is associated with various metabolic diseases, including type 2 diabetes mellitus. There are no approved drugs for NAFLD, and the only approved treatment option is weight reduction. As insulin resistance plays an important role in the development of NAFLD, many anti-diabetic drugs have been evaluated for the treatment of NAFLD. Improvement of liver enzymes has been demonstrated by many anti-diabetic drugs, but histological assessment still remains insufficient. Pioglitazone could become the first-line therapy for T2DM patients with NAFLD, based on evidence of histological improvement in patients with biopsy-proven nonalcoholic steatohepatitis (NASH). Liraglutide, another promising alternative, is not yet recommended in patients with NAFLD/NASH due to limited evidence. Therefore, well-designed randomized controlled trials should be performed in the near future to demonstrate if and how anti-diabetic drugs can play a role in the treatment of NAFLD.
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Affiliation(s)
- Kyung-Soo Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Mittag‐Roussou V, Wagenpfeil S, Lammert F, Stokes CS. Noninvasive monitoring of liver fat during treatment with GLP-1 analogues and SGLT-2 inhibitors in a real-world setting. Endocrinol Diabetes Metab 2020; 3:e00131. [PMID: 32704556 PMCID: PMC7375113 DOI: 10.1002/edm2.131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 03/10/2020] [Accepted: 03/14/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Patients with NAFLD have a two-fold increased risk of diabetes, and conversely, NAFLD affects up to 80% of patients with type 2 diabetes. Due to the co-occurrence of both diseases and the lack of approved pharmacotherapy for NAFLD, the anti-steatogenic potential of diabetes-related drugs is being explored. In this study, we aim to monitor liver fat noninvasively during treatment with SGLT-2 inhibitors or GLP-1 analogues in a real-world setting. METHODS Overall, 39 patients (49% women, age 57.7 ± 10.9 years) with type 2 diabetes and hepatic steatosis (defined by controlled attenuation parameter [CAP] values ≥ 215 dB/m) were observed for 6 months and routinely monitored with respect to hepatic fat contents and liver stiffness (VCTE); body composition (BIA); and blood biochemistry, including liver function tests (LFTs), serum lipids and glucose metabolism markers. RESULTS Median liver fat contents were significantly (P = .026) reduced by 9% in patients taking either SGLT-2 (n = 22) or GLP-1 (n = 17) for 6 months (absolute median CAP decrease: -32 dB/m [-58 to 32 dB/m]). In parallel, serum ALT and γ-GT activities decreased significantly (P = .002 and P = .049, respectively). These improvements were accompanied by significant (P < .0001) changes to body weight and BMI (-2.5 ± 3.3 kg and -0.9 ± 1.2 kg/m2, respectively) and glucose homeostasis, with significant reductions in HbA1c and fasting plasma glucose (FDG) (both P < .0001). Of note, significant reductions of intrahepatic lipid contents occured in patients receiving SGLT-2 inhibitors only. CONCLUSIONS In this real-world observational evaluation of fatty liver monitored noninvasively in patients with type 2 diabetes treated with either SGLT2 or GLP-1, improvements in measures of hepatic steatosis, glucose and weight parameters were observed after 6 months, with significant reductions of intrahepatic lipid contents seen specifically in the SGLT2 subgroup.
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Affiliation(s)
- Vasiliki Mittag‐Roussou
- Department of Medicine II (Gastroenterology and Endocrinology)Saarland University Medical CenterSaarland UniversityHomburgGermany
| | - Stefan Wagenpfeil
- Institute of Medical Biometry, Epidemiology and Medical InformaticsSaarland UniversityHomburgGermany
| | - Frank Lammert
- Department of Medicine II (Gastroenterology and Endocrinology)Saarland University Medical CenterSaarland UniversityHomburgGermany
| | - Caroline S. Stokes
- Department of Medicine II (Gastroenterology and Endocrinology)Saarland University Medical CenterSaarland UniversityHomburgGermany
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Sano R, Shinozaki Y, Ohta T. Sodium-glucose cotransporters: Functional properties and pharmaceutical potential. J Diabetes Investig 2020; 11:770-782. [PMID: 32196987 PMCID: PMC7378437 DOI: 10.1111/jdi.13255] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/06/2020] [Accepted: 03/13/2020] [Indexed: 02/06/2023] Open
Abstract
Glucose is the most abundant monosaccharide, and an essential source of energy for most living cells. Glucose transport across the cell membrane is mediated by two types of transporters: facilitative glucose transporters (gene name: solute carrier 2A) and sodium-glucose cotransporters (SGLTs; gene name: solute carrier 5A). Each transporter has its own substrate specificity, distribution, and regulatory mechanisms. Recently, SGLT1 and SGLT2 have attracted much attention as therapeutic targets for various diseases. This review addresses the basal and functional properties of glucose transporters and SGLTs, and describes the pharmaceutical potential of SGLT1 and SGLT2.
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Affiliation(s)
- Ryuhei Sano
- Biological/Pharmacological Research LaboratoriesCentral Pharmaceutical Research InstituteJapan Tobacco IncTakatsukiJapan
| | - Yuichi Shinozaki
- Biological/Pharmacological Research LaboratoriesCentral Pharmaceutical Research InstituteJapan Tobacco IncTakatsukiJapan
| | - Takeshi Ohta
- Laboratory of Animal Physiology and Functional AnatomyGraduate School of AgricultureKyoto UniversityKyotoJapan
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Smeuninx B, Boslem E, Febbraio MA. Current and Future Treatments in the Fight Against Non-Alcoholic Fatty Liver Disease. Cancers (Basel) 2020; 12:E1714. [PMID: 32605253 PMCID: PMC7407591 DOI: 10.3390/cancers12071714] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/24/2020] [Accepted: 06/25/2020] [Indexed: 02/06/2023] Open
Abstract
Obesity is recognised as a risk factor for many types of cancers, in particular hepatocellular carcinoma (HCC). A critical factor in the development of HCC from non-alcoholic fatty liver disease (NAFLD) is the presence of non-alcoholic steatohepatitis (NASH). Therapies aimed at NASH to reduce the risk of HCC are sparse and largely unsuccessful. Lifestyle modifications such as diet and regular exercise have poor adherence. Moreover, current pharmacological treatments such as pioglitazone and vitamin E have limited effects on fibrosis, a key risk factor in HCC progression. As NAFLD is becoming more prevalent in developed countries due to rising rates of obesity, a need for directed treatment is imperative. Numerous novel therapies including PPAR agonists, anti-fibrotic therapies and agents targeting inflammation, oxidative stress and the gut-liver axis are currently in development, with the aim of targeting key processes in the progression of NASH and HCC. Here, we critically evaluate literature on the aetiology of NAFLD-related HCC, and explore the potential treatment options for NASH and HCC.
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Affiliation(s)
| | | | - Mark A. Febbraio
- Cellular & Molecular Metabolism Laboratory, Monash Institute of Pharmacological Sciences, Monash University, Parkville, VIC 3052, Australia; (B.S.); (E.B.)
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Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med 2020; 7:22. [PMID: 32158768 PMCID: PMC7052117 DOI: 10.3389/fcvm.2020.00022] [Citation(s) in RCA: 742] [Impact Index Per Article: 148.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 02/10/2020] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue plays essential roles in maintaining lipid and glucose homeostasis. To date several types of adipose tissue have been identified, namely white, brown, and beige, that reside in various specific anatomical locations throughout the body. The cellular composition, secretome, and location of these adipose depots define their function in health and metabolic disease. In obesity, adipose tissue becomes dysfunctional, promoting a pro-inflammatory, hyperlipidemic and insulin resistant environment that contributes to type 2 diabetes mellitus (T2DM). Concurrently, similar features that result from adipose tissue dysfunction also promote cardiovascular disease (CVD) by mechanisms that can be augmented by T2DM. The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissue depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review. The impact that various T2DM and CVD treatment strategies have on adipose tissue function and body weight also will be discussed.
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Affiliation(s)
- Alan Chait
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Laura J den Hartigh
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
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Cusi K. Time to Include Nonalcoholic Steatohepatitis in the Management of Patients With Type 2 Diabetes. Diabetes Care 2020; 43:275-279. [PMID: 31959644 DOI: 10.2337/dci19-0064] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Kenneth Cusi
- Division of Endocrinology, Diabetes & Metabolism, University of Florida, Gainesville, FL .,Malcom Randall Veterans Affairs Medical Center, Gainesville, FL
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Lai LL, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus. Dig Dis Sci 2020; 65:623-631. [PMID: 30684076 DOI: 10.1007/s10620-019-5477-1] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 01/17/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of drugs that lower glucose by inducing renal glycosuria. We aimed to explore whether SGLT2 inhibitor added to the usual care for patients with type 2 diabetes mellitus (T2DM) and biopsy-proven nonalcoholic steatohepatitis (NASH) will benefit NASH histology. METHODS In this investigator-initiated, single-arm, open-label, pilot study, nine biopsy-proven NASH patients with T2DM were given empagliflozin 25 mg daily for 24 weeks. Liver biopsy was repeated at the end of treatment. The histological outcomes were compared with the placebo group of a previous 48-week clinical trial. RESULTS There was a significant reduction in body mass index (median change, Δ = -0.7 kg per m2, p = 0.011), waist circumference (Δ = -3 cm, p = 0.033), systolic blood pressure (Δ = -9 mmHg, p = 0.024), diastolic blood pressure (Δ = -6 mmHg, p = 0.033), fasting blood glucose (Δ = -1.7 mmol/L, p = 0.008), total cholesterol (Δ = -0.5 mmol/L, p = 0.011), gamma glutamyl transpeptidase (Δ = -19 U/L, p = 0.013), volumetric liver fat fraction (Δ = -7.8%, p = 0.017), steatosis (Δ = -1, p = 0.014), ballooning (Δ = -1, p = 0.034), and fibrosis (Δ = 0, p = 0.046). All histological components either remained unchanged or improved, except in one patient who had worsening ballooning. Empagliflozin resulted in significantly greater improvements in steatosis (67% vs. 26%, p = 0.025), ballooning (78% vs. 34%, p = 0.024), and fibrosis (44% vs. 6%, p = 0.008) compared with historical placebo. CONCLUSION This pilot study provides primary histological evidence that empagliflozin may be useful for the treatment of NASH. This preliminary finding should prompt larger clinical trials to assess the effectiveness of empagliflozin and other SGLT2 inhibitors for the treatment of NASH in T2DM patients. Trial registry number ClincialTrials.gov number, NCT02964715.
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Affiliation(s)
- Lee-Lee Lai
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Shireene Ratna Vethakkan
- Endocrine Unit, Department of Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
| | | | - Sanjiv Mahadeva
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
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David-Silva A, Esteves JV, Morais MRPT, Freitas HS, Zorn TM, Correa-Giannella ML, Machado UF. Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice. Diabetes Metab Syndr Obes 2020; 13:739-751. [PMID: 32231437 PMCID: PMC7085338 DOI: 10.2147/dmso.s242282] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/29/2020] [Indexed: 12/11/2022] Open
Abstract
PURPOSE NAFLD is a hepatic component of type 2 diabetes mellitus (T2D), in which impaired hepatic glucose production plays an important role. Inhibitors of sodium glucose transporter 2 (SGLT2) reduce glycemia and exert beneficial effects on diabetic complications. Recently, dual SGLT1/2 inhibition has been proposed to be more effective in reducing glycemia. We hypothesized that improving hepatic glucose metabolism induced by SGLT1/2 inhibition could be accompanied by beneficial effects on NAFLD progression. METHODS Glycemic homeostasis, hepatic glucose production and NAFLD features were investigated in obese T2D mice, treated with SGLT1/2 inhibitor phlorizin for 1 week. RESULTS T2D increased glycemia; insulinemia; hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and glucose transporter 2 (Slc2a2 gene); hepatocyte nuclear factors 1A/4A/3B-binding activity in Slc2a2; endogenous glucose production; liver weight, plasma transaminase concentration as well as hepatic inflammation markers, and induced histological signals of non-alcoholic steatohepatitis (NASH, according to NASH-CRN Pathology Committee System). Phlorizin treatment restored all these parameters (mean NASH score reduced from 5.25 to 2.75 P<0.001); however, plasma transaminase concentration was partially reverted and some hepatic inflammation markers remained unaltered. CONCLUSION NAFLD accompanies altered hepatic glucose metabolism in T2D mice and that greatly ameliorated through short-term treatment with the dual SGLT1/2 inhibitor. This suggests that altered hepatic glucose metabolism participates in T2D-related NAFLD and highlights the pharmacological inhibition of SGLTs as a useful approach not only for controlling glycemia but also for mitigating development and/or progression of NAFLD.
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Affiliation(s)
- Aline David-Silva
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - João Victor Esteves
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Mychel Raony P T Morais
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Helayne Soares Freitas
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Telma Maria Zorn
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Maria Lucia Correa-Giannella
- Laboratório de Carboidratos e Radioimunoensaio, LIM-18, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Ubiratan Fabres Machado
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Correspondence: Ubiratan Fabres Machado Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, São Paulo, SP05508-900, BrazilTel +55 11 30917494 Email
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Ganguli S, DeLeeuw P, Satapathy SK. A Review Of Current And Upcoming Treatment Modalities In Non-Alcoholic Fatty Liver Disease And Non-Alcoholic Steatohepatitis. Hepat Med 2019; 11:159-178. [PMID: 31814783 PMCID: PMC6863115 DOI: 10.2147/hmer.s188991] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 10/03/2019] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the West. Non-alcoholic steatohepatitis (NASH) is the progressive form of NAFLD and can lead to cirrhosis, hepatocellular carcinoma, and is associated with increased cardiovascular risks. Multiple components and risk factors are thought to be involved in the pathogenesis of NAFLD and NASH. Optimal therapy has not yet been found, but many advances have been made with the discovery of potential therapeutic options. In this paper, we aim to provide a comprehensive review of approved, studied, and upcoming treatment options for NAFLD and NASH. Non-pharmacologic therapy (lifestyle modifications and bariatric surgery) and pharmacologic therapy are both reviewed. Pharmacologic therapy target components thought to be involved in the pathogenesis of this disease process including insulin resistance, oxidative stress, inflammation, lipid metabolism, and fibrosis are reviewed in this paper. Results of the emerging treatment targets in phase 2 and 3 clinical trials are also included.
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Affiliation(s)
- Surosree Ganguli
- Division of Internal Medicine, University of Louisville, Louisville, KY40202, USA
| | - Peter DeLeeuw
- Division of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN38163, USA
| | - Sanjaya K Satapathy
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Manhasset, NY11030, USA
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45
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Patel BM, Goyal RK. Liver and insulin resistance: New wine in old bottle!!! Eur J Pharmacol 2019; 862:172657. [DOI: 10.1016/j.ejphar.2019.172657] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 09/02/2019] [Accepted: 09/05/2019] [Indexed: 12/20/2022]
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Jojima T, Wakamatsu S, Kase M, Iijima T, Maejima Y, Shimomura K, Kogai T, Tomaru T, Usui I, Aso Y. The SGLT2 Inhibitor Canagliflozin Prevents Carcinogenesis in a Mouse Model of Diabetes and Non-Alcoholic Steatohepatitis-Related Hepatocarcinogenesis: Association with SGLT2 Expression in Hepatocellular Carcinoma. Int J Mol Sci 2019; 20:ijms20205237. [PMID: 31652578 PMCID: PMC6829338 DOI: 10.3390/ijms20205237] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 10/08/2019] [Accepted: 10/17/2019] [Indexed: 02/06/2023] Open
Abstract
The aim of the present study is to investigate the effects of canagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, on non-alcoholic steatohepatitis (NASH) and NASH-related hepatocellular carcinoma (HCC) in a mouse model of diabetes and NASH-HCC. First, mice aged five weeks were divided into two groups (vehicle group and canagliflozin group) and were treated for three weeks. Then, mice aged five weeks were divided into three groups of nine animals each: the vehicle group, early canagliflozin group (treated from five to nine weeks), and continuous canagliflozin group (treated from five to 16 weeks). Canagliflozin was administered at a dose of 30 mg/kg in these experiments. In addition, the in vitro effects of canagliflozin were investigated using HepG2 cells, a human HCC cell line. At the age of eight or 16 weeks, the histological non-alcoholic fatty liver disease activity score was lower in the canagliflozin-treated mice than in vehicle-treated mice. There were significantly fewer hepatic tumors in the continuous canagliflozin group than in the vehicle group. Immunohistochemistry showed significantly fewer glutamine synthetase-positive nodules in the continuous canagliflozin group than in the vehicle group. Expression of α-fetoprotein mRNA, a marker of HCC, was downregulated in the continuous canagliflozin group when compared with the vehicle group. At 16 weeks, there was diffuse SGLT1 expression in the hepatic lobules and strong expression by hepatocytes in the vehicle group, while SGLT2 expression was stronger in liver tumors than in the lobules. In the in vitro study, canagliflozin (10 μM) suppressed the proliferation of HepG2 cells. Flow cytometry showed that canagliflozin reduced the percentage of HepG2 cells in the G2/M phase due to arrest in the G1 phase along with decreased expression of cyclin D and Cdk4 proteins, while it increased the percentage of cells in the G0/1 phase. Canagliflozin also induced apoptosis of HepG2 cells via activation of caspase 3. In this mouse model of diabetes and NASH/HCC, canagliflozin showed anti-steatotic and anti-inflammatory effects that attenuated the development of NASH and prevented the progression of NASH to HCC, partly due to the induction of cell cycle arrest and/or apoptosis as well as the reduction of tumor growth through the direct inhibition of SGLT2 in tumor cells.
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Affiliation(s)
- Teruo Jojima
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi 321-0293, Japan.
| | - Sho Wakamatsu
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi 321-0293, Japan.
| | - Masato Kase
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi 321-0293, Japan.
| | - Toshie Iijima
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi 321-0293, Japan.
| | - Yuko Maejima
- Department of Pharmacology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
| | - Kenju Shimomura
- Department of Pharmacology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
| | - Takahiko Kogai
- Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Tochigi 321-0293, Japan.
| | - Takuya Tomaru
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi 321-0293, Japan.
| | - Isao Usui
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi 321-0293, Japan.
| | - Yoshimasa Aso
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi 321-0293, Japan.
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Imprialos K, Stavropoulos K, Papademetriou V. Sodium-Glucose Cotransporter-2 Inhibitors, Reverse J-Curve Pattern, and Mortality in Heart Failure. Heart Fail Clin 2019; 15:519-530. [PMID: 31472887 DOI: 10.1016/j.hfc.2019.06.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The prevalence of diabetes mellitus and heart failure is increasing. The novel sodium-glucose cotransporters 2 inhibitors offer multidimensional ameliorating effects on cardiovascular and heart failure risk factors. Several studies have assessed the impact on cardiovascular events, with data suggesting beneficial effects on cardiovascular events in high-risk patients with diabetes in patients with heart failure. The reverse J-curve pattern between blood pressure levels and mortality has emerged as an important topic in the field of heart failure. There is no significant evidence to propose any potential effect of sodium-glucose co-transporter 2 inhibitors on the J-shape-suggested mortality in patients with heart failure.
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48
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Leng W, Wu M, Pan H, Lei X, Chen L, Wu Q, Ouyang X, Liang Z. The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:429. [PMID: 31700865 DOI: 10.21037/atm.2019.09.03] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Diabetes mellitus (DM) is considered as a risk factor for the progress of liver diseases. After tissue damage, there is the highest amplitude of ubiquitously sterile inflammatory response in the liver, resulting in a major clinical consequence concerning a high prevalence of steatohepatitis in DM patients. This study aimed to investigate the inhibitory efficacy of dapagliflozin (DAPA), a sodium glucose cotransporter-2 (SGLT2) inhibitor, on experimental steatohepatitis with DM. Methods DM-steatohepatitis model was established by dual intraperitoneal injection of streptozotocin (STZ) and feeding with the high-fat diet (HFD) in apolipoprotein E-deficient (ApoE-/-) mice (n=40). The mice were concurrently treated with DAPA (1 mg/kg/d) by gavage for 12 weeks. Results In ApoE-/- mice, dual HFD/STZ dramatically induced hepatic damage and inflammation as compared with HFD alone. DAPA treatment was effective to protect from hepatic damage and inflammation in dual HFD/STZ treated ApoE-/- mice. DAPA also significantly the probability decreased the blood glucose, hepatic lipid accumulation, liver steatosis, and fibrotic response in dual HFD/STZ treated ApoE-/- mice. Further mechanistic investigations indicated that the protection of DAPA on diabetic liver injury was associated with the suppressed production of hepatic reactive oxygen species (ROS) and malondialdehyde (MDA) and the inhibited activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Conclusions These data demonstrate the efficacy of DAPA for protecting liver damage, inflammation and steatosis from experimental steatohepatitis with DM, and indicate a possible involvement of the inhibited activity of ROS-NLRP3 inflammasome.
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Affiliation(s)
- Weiling Leng
- Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Mingxia Wu
- Health Management Center, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hang Pan
- Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Xiaotian Lei
- Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Liu Chen
- Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Qinan Wu
- Department of Endocrine Nephropathy, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400038, China
| | - Xinshou Ouyang
- Section of Digestive Diseases, Yale University of Medicine, New Haven, CT, USA
| | - Ziwen Liang
- Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
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Katsiki N, Perakakis N, Mantzoros C. Effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Ex quo et quo vadimus? Metabolism 2019; 98:iii-ix. [PMID: 31301336 DOI: 10.1016/j.metabol.2019.07.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Accepted: 07/08/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Niki Katsiki
- Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America
| | - Nikolaos Perakakis
- Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America
| | - Christos Mantzoros
- Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America.
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Dokmak A, Almeqdadi M, Trivedi H, Krishnan S. Rise of sodium-glucose cotransporter 2 inhibitors in the management of nonalcoholic fatty liver disease. World J Hepatol 2019; 11:562-573. [PMID: 31388398 PMCID: PMC6669193 DOI: 10.4254/wjh.v11.i7.562] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/12/2019] [Accepted: 06/27/2019] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the Western world. It is more prevalent in male gender, and with increasing age, obesity, and insulin resistance. Besides weight loss, there are limited treatment options. The use of anti-diabetic medications has been studied with mixed results. In this review, we discuss the use of anti-diabetic medications in the management of NAFLD with a specific focus on sodium-glucose cotransporter 2 inhibitors. We shed light on the evidence supporting their use in detail and discuss limitations and future directions.
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Affiliation(s)
- Amr Dokmak
- Division of Medicine, St. Elizabeth’s Medical Center, Brighton, MA 02135, United States
- Tufts University School of Medicine, Boston, MA 02111, United States
| | - Mohammad Almeqdadi
- Division of Medicine, St. Elizabeth’s Medical Center, Brighton, MA 02135, United States
- Tufts University School of Medicine, Boston, MA 02111, United States
| | - Hirsh Trivedi
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
| | - Sandeep Krishnan
- Tufts University School of Medicine, Boston, MA 02111, United States
- Division of Gastroenterology, St. Elizabeth’s Medical Center, Brighton, MA 02135, United States
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