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Cagigas ML, De Ciutiis I, Masedunskas A, Fontana L. Dietary and pharmacological energy restriction and exercise for healthspan extension. Trends Endocrinol Metab 2025:S1043-2760(25)00076-1. [PMID: 40318928 DOI: 10.1016/j.tem.2025.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 03/30/2025] [Accepted: 04/02/2025] [Indexed: 05/07/2025]
Abstract
Extending healthspan - the years lived in optimal health - holds transformative potential to reduce chronic diseases and healthcare costs. Dietary restriction (DR), particularly when combined with nutrient-rich diets and exercise, is among the most effective, evidence-based strategies for enhancing metabolic health and longevity. By targeting fundamental pathways, it mitigates the onset and progression of obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), neurodegeneration, and cancer. This review synthesizes human data on the impact of DR and exercise on metabolic and age-related diseases, while emphasizing key biological mechanisms such as nutrient sensing, insulin sensitivity, inflammation, mitochondrial function, and gut microbiota. We also examine the emerging role of pharmacologically induced DR, focusing on glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) that partially mimic DR and present opportunities for chronic disease prevention.
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Affiliation(s)
- Maria Lastra Cagigas
- Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Isabella De Ciutiis
- Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Andrius Masedunskas
- Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Luigi Fontana
- Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
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2
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Konings LAM, Miguelañez‐Matute L, Boeren AMP, van de Luitgaarden IAT, Dirksmeier F, de Knegt RJ, Tushuizen ME, Grobbee DE, Holleboom AG, Cabezas MC. Pharmacological treatment options for metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus: A systematic review. Eur J Clin Invest 2025; 55:e70003. [PMID: 39937036 PMCID: PMC11891831 DOI: 10.1111/eci.70003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 01/24/2025] [Indexed: 02/13/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to type 2 diabetes mellitus (T2DM) through a common root in insulin resistance. The more severe stage, metabolic dysfunction-associated steatohepatitis (MASH), increases the risk for cardiovascular complications, liver cirrhosis and hepatocellular carcinoma. Several trials investigating established antidiabetic-drugs in patients with T2DM and MASLD have yielded promising results. Therefore, we aimed to systematically review the effect of T2DM-drug treatment on MALSD parameters. METHODS Medical databases were searched until January 2025 for controlled trials in patients with T2DM and MASLD/MASH. Studies that evaluated the effect of T2DM-medication on the severity of MASLD/MASH in T2DM patients were included. The quality of the studies was assessed by three independent reviewers using a set of Cochrane risk-of-bias tools. RESULTS Of 1748 references, 117 studies fulfilled the inclusion-criteria and were assessed for eligibility in full-text. Fifty-two articles were included. Data included a total of 64.708 patients and study populations ranged from 9 to 50.742. Heterogeneity in study-design and analysis hampered the comparability of the results. Most evidence was present for GLP-1 receptor agonists, SGLT2-inhibitors and PPAR-γ-agonists for regression of liver fibrosis and MASH. CONCLUSION Studies on the value of T2DM-drug treatment in the improvement of MASLD vary significantly in study design, size and quality. GLP-1 receptor agonists, PPAR-γ-agonists, SGLT2-inhibitors may all be preferred pharmacological interventions for patients with MASLD/MASH and T2DM. Newer agents like dual GLP-1/GIP or triple GLP-1/GIP/Glucagon agonists will likely play an important role in the treatment of MASLD/MASH in the near future.
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Affiliation(s)
- Laura A. M. Konings
- Department of Internal MedicineFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
- Department of Internal Medicine and EndocrinologyErasmus MCRotterdamthe Netherlands
| | | | - Anna M. P. Boeren
- Department of Internal MedicineFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
| | | | - Femme Dirksmeier
- Department of Gastroenterology and HepatologyFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
| | - Rob J. de Knegt
- Department of Gastroenterology and HepatologyErasmus MCRotterdamthe Netherlands
| | | | | | | | - Manuel Castro Cabezas
- Department of Internal MedicineFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
- Department of Internal Medicine and EndocrinologyErasmus MCRotterdamthe Netherlands
- Julius ClinicalZeistthe Netherlands
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Misra A, Kumar A, Kuchay MS, Ghosh A, Gulati S, Choudhary NS, Dutta D, Sharma P, Vikram NK. Consensus guidelines for the diagnosis and management of metabolic dysfunction-associated steatotic liver disease in adult Asian Indians with type 2 diabetes. Diabetes Metab Syndr 2025; 19:103209. [PMID: 40222341 DOI: 10.1016/j.dsx.2025.103209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 02/14/2025] [Accepted: 02/17/2025] [Indexed: 04/15/2025]
Affiliation(s)
- Anoop Misra
- Fortis CDOC Center of Excellence for Diabetes, Metabolic Diseases and Endocrinology, New Delhi, India; National Diabetes Obesity and Cholesterol Foundation (N-DOC), New Delhi, India; Diabetes Foundation India, New Delhi, India.
| | - Ashish Kumar
- Gastroenterology & Hepatology,Sir Ganga Ram Hospital, Rajinder Nagar New Delhi, India
| | - Mohammad Shafi Kuchay
- Division of Endocrinology and Diabetes, Medanta, The Medicity, Gurugram, 122001, Haryana, India
| | - Amerta Ghosh
- Fortis CDOC Center of Excellence for Diabetes, Metabolic Diseases and Endocrinology, New Delhi, India; National Diabetes Obesity and Cholesterol Foundation (N-DOC), New Delhi, India
| | - Seema Gulati
- National Diabetes Obesity and Cholesterol Foundation (N-DOC), New Delhi, India; Diabetes Foundation India, New Delhi, India
| | | | - Deep Dutta
- Department of Endocrinology, Center for Endocrinology, Diabetes, Arthritis & Rheumatism (CEDAR) Super speciality Clinics, New Delhi, India
| | - Praveen Sharma
- Gastroenterology & Hepatology,Sir Ganga Ram Hospital, Rajinder Nagar New Delhi, India
| | - Naval K Vikram
- Department of Internal Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
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Wang MW, Lu LG. Current Status of Glucagon-like Peptide-1 Receptor Agonists in Metabolic Dysfunction-associated Steatotic Liver Disease: A Clinical Perspective. J Clin Transl Hepatol 2025; 13:47-61. [PMID: 39801787 PMCID: PMC11712088 DOI: 10.14218/jcth.2024.00271] [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: 08/07/2024] [Revised: 10/13/2024] [Accepted: 10/24/2024] [Indexed: 01/16/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a pressing public health issue associated with adverse outcomes such as cirrhosis, malignancy, transplantation, and mortality. Lifestyle modifications constitute the most effective and fundamental management approach, but they often pose challenges in sustaining long-term clinical benefits. Hence, there is a critical need to enhance our understanding through pharmacological management, which unfortunately remains limited. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a leading treatment in the fields of diabetes and obesity, with recent preclinical and clinical studies indicating significant benefits in the management and treatment of MASLD. Our article begins by reviewing the beneficial therapeutic components of GLP-1RAs in MASLD. Subsequently, from a clinical research perspective, we concluded with the liver outcomes of current primary GLP-1RAs and co-agonists. Finally, we presented our insights on clinical concerns such as appropriate trial endpoints, management of comorbidities, and future developments. In conclusion, the benefits of GLP-1RAs in MASLD are promising, and background therapy involving metabolic modulation may represent one of the future therapeutic paradigms.
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Affiliation(s)
- Ming-Wang Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lun-Gen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Du M, Yue J, Qi Y, He S, Lu X, Yang M, Wang L, Lu Q, Ma J. Effects of liraglutide on abdominal fat distribution and glucose metabolism in Chinese subjects with obesity. Diabetol Metab Syndr 2024; 16:307. [PMID: 39707524 DOI: 10.1186/s13098-024-01540-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/27/2024] [Indexed: 12/23/2024] Open
Abstract
AIMS To observe the effects of liraglutide on abdominal fat distribution in Chinese subjects with obesity in 12 weeks, and further to explore the correlation between abdominal fat content and glucose metabolism after monotherapy. METHODS This study recruited 71 obese subjects. All the subjects have received liraglutide monotherapy (0.6 mg-1.8 mg/d) for 12 weeks. Clinical assessment, laboratory assays and magnetic resonance imaging (MRI) examination were accessed at baseline and after 12 weeks treatment. MRI was applied to measure abdominal fat distribution, calculated by proton-density fat fraction (PDFF). RESULTS After 12 weeks of liraglutide monotherapy, body weight in the obese participants decreased significantly (P < 0.001). Fasting blood glucose (FBG) levels, 2 h post-load blood glucose (2hPBG) levels, and glycosylated hemoglobin (HbA1c) were remarkably improved after liraglutide monotherapy (all P < 0.001). Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were significantly reduced after liraglutide monotheraphy (both P < 0.001). There was a notable reduction in liver fat content (LFC) after liraglutide monotherapy (P < 0.001). In the further analysis, LFC was greater in obese subjects with impaired glucose regulation (IGR) at baseline compared to those with normal glucose tolerance (NGT) (P = 0.002). The LFC reduction in IGR group was significantly greater than those in NGT group after liraglutide treatment (P < 0.001). Pearson correlation analysis showed that reduction of LFC was significantly correlated with improvement of FBG (r = 0.587, P < 0.001) and HbA1c (r = 0.607, P < 0.001) in obese patients. CONCLUSION LFC was significantly reduced after liraglutide monotherapy for 12 weeks in subjects with obesity. The LFC reduction is likely to be associated with IGR remission in obese subjects.
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Affiliation(s)
- Mengyang Du
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Shanghai, 200127, China
| | - Jiang Yue
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Shanghai, 200127, China
| | - Yicheng Qi
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Shanghai, 200127, China
| | - Shengyun He
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Shanghai, 200127, China
| | - Xiaobing Lu
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Shanghai, 200127, China
| | - Minglan Yang
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Shanghai, 200127, China
| | - Lihua Wang
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Shanghai, 200127, China.
| | - Qing Lu
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Shanghai, 200127, China.
| | - Jing Ma
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Shanghai, 200127, China.
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Amorim R, Soares P, Chavarria D, Benfeito S, Cagide F, Teixeira J, Oliveira PJ, Borges F. Decreasing the burden of non-alcoholic fatty liver disease: From therapeutic targets to drug discovery opportunities. Eur J Med Chem 2024; 277:116723. [PMID: 39163775 DOI: 10.1016/j.ejmech.2024.116723] [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: 05/30/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/22/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) presents a pervasive global pandemic, affecting approximately 25 % of the world's population. This grave health issue not only demands urgent attention but also stands as a significant economic concern on a global scale. The genesis of NAFLD can be primarily attributed to unhealthy dietary habits and a sedentary lifestyle, albeit certain genetic factors have also been recorded to contribute to its occurrence. NAFLD is characterized by fat accumulation in more than 5 % of hepatocytes according to histological analysis, or >5.6 % of lipid volume fraction in total liver weight in patients. The pathophysiology of NAFLD/non-alcoholic steatohepatitis (NASH) is multifactorial and the mechanisms underlying the progression to advanced forms remain unclear, thereby representing a challenge to disease therapy. Despite the substantial efforts from the scientific community and the large number of pre-clinical and clinical trials performed so far, only one drug was approved by the Food and Drug Administration (FDA) to treat NAFLD/NASH specifically. This review provides an overview of available information concerning emerging molecular targets and drug candidates tested in clinical studies for the treatment of NAFLD/NASH. Improving our understanding of NAFLD pathophysiology and pharmacotherapy is crucial not only to explore new molecular targets, but also to potentiate drug discovery programs to develop new therapeutic strategies. This knowledge endeavours scientific efforts to reduce the time for achieving a specific and effective drug for NAFLD or NASH management and improve patients' quality of life.
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Affiliation(s)
- Ricardo Amorim
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Pedro Soares
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Daniel Chavarria
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Sofia Benfeito
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Fernando Cagide
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - José Teixeira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Paulo J Oliveira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal.
| | - Fernanda Borges
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
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7
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Riedinger CJ, Sakach J, Maples JM, Fulton J, Chippior J, O'Donnell B, O'Malley DM, Chambers LM. Glucagon-like peptide-1 (GLP-1) receptor agonists for weight management: A review for the gynecologic oncologist. Gynecol Oncol 2024; 190:1-10. [PMID: 39116625 DOI: 10.1016/j.ygyno.2024.07.008] [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: 05/07/2024] [Revised: 07/04/2024] [Accepted: 07/15/2024] [Indexed: 08/10/2024]
Abstract
The use of glucagon-like peptide-1 receptor agonists (GLP-1RA) has experienced rapid growth amidst the obesity epidemic in the United States. While originally developed for glucose control in Type 2 Diabetes Mellitus, the scope of these agents now extends to encompass weight loss and cardiovascular risk reduction. GLP-1RAs have the potential to induce significant weight loss, in combination with lifestyle modifications, among adults who are overweight or obese. Furthermore, these agents demonstrate efficacy in ameliorating hyperglycemia, enhancing insulin sensitivity, regulating blood pressure, improving cardiometabolic parameters, mitigating kidney dysfunction, and potentially reducing the risk of several obesity-related cancers. Drug-related toxicity is primarily gastrointestinal and active management can prevent drug discontinuation. Obesity is associated both with an increased incidence of malignancy but also with decreased survival. More research is needed to evaluate the potential use of GLP-1RA to modify the endocrine function of adipocytes, regulate the chronic inflammatory state associated with obesity, and prospective applications in oncology. These agents can impact patients with gynecologic malignancies both through their direct mechanism of action as well as potential drug toxicity.
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Affiliation(s)
- Courtney J Riedinger
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH, USA
| | - Julia Sakach
- Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Jill M Maples
- Department of Obstetrics and Gynecology, The University of Tennessee Graduate School of Medicine, Knoxville, TN, USA
| | - Jessica Fulton
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH, USA
| | - Jessica Chippior
- Department of Internal Medicine, Division of Endocrinology Diabetes and Metabolism, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Benjamin O'Donnell
- Department of Internal Medicine, Division of Endocrinology Diabetes and Metabolism, The Ohio State University College of Medicine, Columbus, OH, USA
| | - David M O'Malley
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH, USA
| | - Laura M Chambers
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH, USA.
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Xie Z, Li Y, Cheng L, Huang Y, Rao W, Shi H, Li J. Potential therapeutic strategies for MASH: from preclinical to clinical development. LIFE METABOLISM 2024; 3:loae029. [PMID: 39872142 PMCID: PMC11749562 DOI: 10.1093/lifemeta/loae029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/16/2024] [Accepted: 07/05/2024] [Indexed: 01/03/2025]
Abstract
Current treatment paradigms for metabolic dysfunction-associated steatohepatitis (MASH) are based primarily on dietary restrictions and the use of existing drugs, including anti-diabetic and anti-obesity medications. Given the limited number of approved drugs specifically for MASH, recent efforts have focused on promising strategies that specifically target hepatic lipid metabolism, inflammation, fibrosis, or a combination of these processes. In this review, we examined the pathophysiology underlying the development of MASH in relation to recent advances in effective MASH therapy. Particularly, we analyzed the effects of lipogenesis inhibitors, nuclear receptor agonists, glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, fibroblast growth factor mimetics, and combinatorial therapeutic approaches. We summarize these targets along with their preclinical and clinical candidates with the ultimate goal of optimizing the therapeutic prospects for MASH.
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Affiliation(s)
- Zhifu Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yufeng Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Long Cheng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yidan Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wanglin Rao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
| | - Honglu Shi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jingya Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
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Njei B, Al-Ajlouni Y, Lemos SY, Ugwendum D, Ameyaw P, Njei LP, Boateng S. Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cureus 2024; 16:e71366. [PMID: 39534801 PMCID: PMC11556413 DOI: 10.7759/cureus.71366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2024] [Indexed: 11/16/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a major global health challenge. glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential therapeutic benefits for MASLD patients, including improvements in liver function, inflammation, and fibrosis. This study aims to systematically review and meta-analyze randomized controlled trials (RCTs) to evaluate the efficacy and safety of GLP-1RAs in MASLD patients, focusing on hepatic outcomes, cardiovascular outcomes, anthropometric measurements, and mortality. Following PRISMA guidelines, a comprehensive database search was conducted to include RCTs assessing GLP-1RAs' effects on MASLD. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool. Our meta-analysis used a random-effects model, calculating standardized mean differences for continuous outcomes to determine the agents' efficacy and safety. Additionally, funnel plots were generated to assess publication bias, ensuring the integrity of our meta-analytical findings. The review included 27 trials, revealing GLP-1RAs significantly improved hepatic function markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and liver fat content) and cardiovascular risk factors (fasting blood sugar, HbA1c levels, lipid profiles). Additionally, GLP-1RAs were associated with significant reductions in body weight, BMI, subcutaneous fat, and waist circumference. GLP-1RAs demonstrate a promising therapeutic role in managing MASLD, offering benefits that extend to improving liver function, mitigating cardiovascular risk, and promoting weight loss. Further research is needed to confirm these findings and optimize GLP-1RAs' usage in MASLD treatment.
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Affiliation(s)
- Basile Njei
- Department of Medicine, Yale School of Medicine, New Haven, USA
| | | | - Samira Y Lemos
- Department of Diabetes and Endocrinology, Yaoundé General Hospital, Yaoundé, CMR
| | - Derek Ugwendum
- Department of Internal Medicine, Richmond University Medical Center Affiliated with Mount Sinai Health System and Icahn School of Medicine at Mount Sinai, Staten Island, USA
| | - Prince Ameyaw
- Department of Internal Medicine, Bridgeport Hospital, Yale New Haven Health, Bridgeport, USA
| | - Lea-Pearl Njei
- Department of Biological Science, University of Maryland Baltimore County, Baltimore, USA
| | - Sarpong Boateng
- Department of Medicine, Bridgeport Hospital, Bridgeport, USA
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Ishikawa T, Terai N, Sato R, Jimbo R, Kobayashi Y, Sato T, Iwanaga A, Sano T, Yokoyama J, Honma T. Clinical Efficacy and Body Composition Changes with Sodium Glucose Cotransporter 2 Inhibitor/Glucagon-like Peptide-1 Antagonist Combination Therapy in Patients with Type 2 Diabetes Mellitus-associated Nonalcoholic Fatty Liver Disease. Intern Med 2024; 63:2491-2497. [PMID: 38346734 PMCID: PMC11473285 DOI: 10.2169/internalmedicine.3259-23] [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: 11/24/2023] [Accepted: 12/14/2023] [Indexed: 09/18/2024] Open
Abstract
Objective Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) treatment guidelines recommend sodium glucose cotransporter 2 inhibitor (SGLT2I) and glucagon-like peptide-1 agonist (GLP-1A) therapy in patients with type 2 diabetes mellitus (T2DM). SGLT2I improves the pathological condition of NAFLD/NASH in T2DM patients. However, cases of rebound during long-term SGLT2I treatment have been reported. This study investigated the efficacy of SGLT2I and GLP-1A combination therapy in diabetic patients with NAFLD by examining changes in computed tomography (CT)-based body composition and clinical outcomes. Methods Fifteen patients (5 men/10 women) with T2DM-associated NAFLD who had not responded to SGLT2I treatment and were being treated with GLP-1A combination therapy were included. Changes in the liver function, visceral adipose tissue index (VATI), and subcutaneous adipose tissue index (SATI) were compared using CT to evaluate the body composition. Results SGLT2I significantly improved alanine aminotransferase (28.0 to 13.0 IU/L), alkaline phosphatase (250.0 to 77.0 IU/L), and gamma glutamyl transpeptidase (23.0 to 12.0 IU/L) levels. The body mass index (BMI) decreased from 25.7 to 25.2 kg/m2. A CT-based analysis showed a significant improvement in SATI (80.9 to 66.1, p=0.002), with no significant change in VATI (53.2 to 51.5). GLP-1A addition improved the BMI (25.2 to 23.5 kg/m2) and hemoglobin A1c (6.5% to 6.2%, p=0.001). A further analysis revealed additional improvement in SATI (66.1 to 56.6, p=0.007) and a significant decrease in VATI (51.5 to 48.3, p=0.001). Conclusion SGLT2I and GLP-1A combination therapy improved the liver function, body composition, and glycemic control in diabetic patients with NAFLD/NASH, as well as SATI and VATI. The optimal timing of combination therapy remains to be determined.
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Affiliation(s)
- Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Nanako Terai
- Department of Radiographer, Saiseikai Niigata Hospital, Japan
| | - Ryo Sato
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Ryo Jimbo
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Yuji Kobayashi
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Toshifumi Sato
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Akito Iwanaga
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Tomoe Sano
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Junji Yokoyama
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Terasu Honma
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
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Janez A, Muzurovic E, Bogdanski P, Czupryniak L, Fabryova L, Fras Z, Guja C, Haluzik M, Kempler P, Lalic N, Mullerova D, Stoian AP, Papanas N, Rahelic D, Silva-Nunes J, Tankova T, Yumuk V, Rizzo M. Modern Management of Cardiometabolic Continuum: From Overweight/Obesity to Prediabetes/Type 2 Diabetes Mellitus. Recommendations from the Eastern and Southern Europe Diabetes and Obesity Expert Group. Diabetes Ther 2024; 15:1865-1892. [PMID: 38990471 PMCID: PMC11330437 DOI: 10.1007/s13300-024-01615-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 06/20/2024] [Indexed: 07/12/2024] Open
Abstract
The increasing global incidence of obesity and type 2 diabetes mellitus (T2D) underscores the urgency of addressing these interconnected health challenges. Obesity enhances genetic and environmental influences on T2D, being not only a primary risk factor but also exacerbating its severity. The complex mechanisms linking obesity and T2D involve adiposity-driven changes in β-cell function, adipose tissue functioning, and multi-organ insulin resistance (IR). Early detection and tailored treatment of T2D and obesity are crucial to mitigate future complications. Moreover, personalized and early intensified therapy considering the presence of comorbidities can delay disease progression and diminish the risk of cardiorenal complications. Employing combination therapies and embracing a disease-modifying strategy are paramount. Clinical trials provide evidence confirming the efficacy and safety of glucagon-like peptide 1 receptor agonists (GLP-1 RAs). Their use is associated with substantial and durable body weight reduction, exceeding 15%, and improved glucose control which further translate into T2D prevention, possible disease remission, and improvement of cardiometabolic risk factors and associated complications. Therefore, on the basis of clinical experience and current evidence, the Eastern and Southern Europe Diabetes and Obesity Expert Group recommends a personalized, polymodal approach (comprising GLP-1 RAs) tailored to individual patient's disease phenotype to optimize diabetes and obesity therapy. We also expect that the increasing availability of dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists will significantly contribute to the modern management of the cardiometabolic continuum.
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Affiliation(s)
- Andrej Janez
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia.
| | - Emir Muzurovic
- Department of Internal Medicine, Endocrinology Section, Clinical Centre of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica, Montenegro
| | - Pawel Bogdanski
- Department of Treatment of Obesity, Metabolic Disorders and Clinical Dietetics, University of Medical Sciences, Poznan, Poland
| | - Leszek Czupryniak
- Department of Diabetology and Internal Medicine, Medical University of Warsaw, Warszawa, Poland
| | - Lubomira Fabryova
- MetabolKLINIK sro, Department for Diabetes and Metabolic Disorders, Lipid Clinic, MED PED Centre, Biomedical Research Centre of Slovak Academy of Sciences, Slovak Health University, Bratislava, Slovak Republic
| | - Zlatko Fras
- Preventive Cardiology Unit, Division of Medicine, University Medical Centre Ljubljana and Chair of Internal Medicine, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Cristian Guja
- Clinic of Diabetes, Nutrition and Metabolic Diseases, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Martin Haluzik
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Vídeňská 1958/9, 140 21, Prague 4, Czech Republic
| | - Peter Kempler
- Department of Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Nebojsa Lalic
- Faculty of Medicine, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia
| | - Dana Mullerova
- Faculty of Medicine in Pilsen, Department of Public Health and Preventive Medicine and Faculty Hospital in Pilsen, 1st Internal Clinic, Charles University, Pilsen, Czech Republic
| | - Anca Pantea Stoian
- Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dario Rahelic
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Zagreb, Croatia
- Catholic University of Croatia School of Medicine, Zagreb, Croatia
- Josip Juraj Strossmayer, University of Osijek School of Medicine, Osijek, Croatia
| | - José Silva-Nunes
- NOVA Medical School, New University of Lisbon, Lisbon, Portugal
- Department of Endocrinology, Diabetes and Metabolism, Unidade Local de Saúde São José, Lisbon, Portugal
| | - Tsvetalina Tankova
- Department of Endocrinology, Faculty of Medicine, Medical University, Sofia, Bulgaria
| | - Volkan Yumuk
- Division of Endocrinology, Metabolism and Diabetes, Istanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, Istanbul, Turkey
| | - Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), School of Medicine, University of Palermo, Palermo, Italy
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Lee HY, Ko SH, Park S, Kim K, Kim SY, Cho IJ, Cho EJ, Kim HC, Park JH, Ryu SK, Moon MK, Ihm SH. The role of glucagon-like peptide-1 receptor agonists (GLP1-RAs) in the management of the hypertensive patient with metabolic syndrome: a position paper from the Korean society of hypertension. Clin Hypertens 2024; 30:24. [PMID: 39217384 PMCID: PMC11366170 DOI: 10.1186/s40885-024-00279-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 06/16/2024] [Indexed: 09/04/2024] Open
Abstract
Obesity is the one of the most important components of metabolic syndrome. Because obesity related hypertension accounts for two thirds of essential hypertension, managing obesity and metabolic syndrome is a crucial task in the management of hypertension. However, the current non-pharmacological therapies have limitations for achieving or maintaining ideal body weight. Recently, glucagon-like peptide-1 receptor agonists (GLP1-RAs) have demonstrated excellent weight control effects, accompanied by corresponding reductions in blood pressure. GLP1-RAs have shown cardiovascular and renal protective effects in cardiovascular outcome trials both in primary and secondary prevention. In this document, the Korean Society of Hypertension intends to remark the current clinical results of GLP1-RAs and recommend the government and health-policy makers to define obesity as a disease and to establish forward-looking policies for GLP1-RA treatment for obesity treatment, including active reimbursement policies.
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Affiliation(s)
- Hae Young Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung-Hyun Ko
- Department of Internal Medicine, Division of Endocrinology and Metabolism, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sungjoon Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyuho Kim
- Department of Internal Medicine, Division of Endocrinology and Metabolism, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Song-Yi Kim
- Department of Internal Medicine, Division of Cardiology, Jeju National University Hospital, Jeju, Republic of Korea
| | - In-Jeong Cho
- Department of Internal Medicine, Division of Cardiology, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Eun Joo Cho
- Department of Internal Medicine, Division of Cardiology, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyeon Chang Kim
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Hyeong Park
- Department of Cardiology in Internal Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Sung Kee Ryu
- Wellness Healthcare Center, Ewha Womans University Seoul Hospital, Seoul, Republic of Korea
| | - Min Kyong Moon
- Department of Internal Medicine, Division of Endocrinology & Metabolism, Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sang-Hyun Ihm
- Department of Internal Medicine, Division of Cardiology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Eagle SR, Henry RJ. Applying Dynamical Systems Theory to Improve Personalized Medicine Following Mild Traumatic Brain Injury. Neurotrauma Rep 2024; 5:671-679. [PMID: 39071984 PMCID: PMC11271149 DOI: 10.1089/neur.2024.0040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024] Open
Abstract
A sizable proportion of patients with mild traumatic brain injury (mTBI) have persistent symptoms and functional impairments months to years following injury. This phenomenon is continually observed despite an explosion of research and interest in improving mTBI clinical outcomes over the last two decades. All pharmacological clinical trials to date have failed to demonstrate improved outcomes for mTBI. One possible explanation for these continued failures is an overly myopic approach to treating mTBI (i.e., testing the effect of a single drug with a specific mechanism on a group of people with highly heterogenous injuries). Clinical presentation and prognosis of mTBI vary considerably between patients, and yet we continue to assess group-level effects of a homogenized treatment. We need to utilize an equally complex treatment approach to match the extraordinary complexity of the human brain. Dynamical systems theory has been used to describe systems composed of multiple subsystems who function somewhat independently but are ultimately interconnected. This theory was popularized in the motor control literature as an overarching framework for how the mind and body connect to interact and move through the environment. However, the human body can be viewed as a dynamical system composed of multiple subsystems (i.e., organ systems) who have isolated functions, which are also codependent on the health and performance of other interconnected organ systems. In this perspective piece, we will use the example of mTBI in the obese patient to demonstrate how broadening our approach to treatment of the individual (and not necessarily the injury) may ultimately yield improved outcomes. Furthermore, we will explore clinical and pre-clinical evidence demonstrating multiple system interactions in the context of obesity and TBI and discuss how expanding our understanding of the mechanistic interplay between multiple organ systems may ultimately provide a more personalized treatment approach for this mTBI patient subpopulation.
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Affiliation(s)
- Shawn R. Eagle
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Ito H, Someya R, Ando S, Araki R, Tsugami E, Matsumoto S, Inoue H, Antoku S, Yamasaki T, Mori T, Togane M. The change in Fibrosis-4 index in Japanese patients with type 2 diabetes treated by a fixed-ratio combination therapy of insulin degludec and liraglutide: A retrospective observational study. Hepatol Res 2024; 54:513-524. [PMID: 38141029 DOI: 10.1111/hepr.14002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 11/30/2023] [Accepted: 12/16/2023] [Indexed: 12/24/2023]
Abstract
AIM The efficacy of titratable fixed-ratio combination therapy by a combination preparation of insulin degludec and liraglutide (IDegLira) in Japanese patients with type 2 diabetes, focusing particularly on the change in Fibrosis-4 index (FIB-4), a noninvasive method for the evaluation of liver fibrosis, was investigated. METHODS As the full analysis set, 113 patients were treated with IDegLira. The patients were categorized into two groups according to the absence (GLP-1RA-naïve group, n = 72) or presence (GLP-1RA-treated group, n = 41) of glucagon-like peptide-1 receptor agonist (GLP-1RA) use before starting IDegLira. The clinical parameters were retrospectively determined over 6 months. RESULTS The glycated hemoglobin value was significantly reduced in both groups. The bodyweight significantly decreased from 67.4 ± 11.0 kg at baseline to 66.4 ± 11.6 kg at 6 months in the GLP-1RA-naïve group, although it slightly increased in the GLP-1RA-treated group. FIB-4 significantly decreased from 1.60 ± 0.84 at baseline to 1.49 ± 0.74 at 6 months in the GLP-1RA-naïve group. Although FIB-4 significantly increased in the GLP-1RA-treated group, it remained within the low-risk level for liver fibrosis. CONCLUSION Fixed-ratio combination therapy using IDegLira for the treatment of type 2 diabetes is useful for glycemic control and weight management. In particular, IDegLira may be more effective for lowering FIB-4 than adding unused oral antidiabetic agents or increasing the dose of insulin in GLP-1RA-naïve patients.
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Affiliation(s)
- Hiroyuki Ito
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
| | - Ryota Someya
- Department of Pharmacy, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
| | - Shigenori Ando
- Department of Pharmacy, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
| | - Rie Araki
- Department of Pharmacy, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
| | - Emiko Tsugami
- Department of Pharmacy, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
| | - Suzuko Matsumoto
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
| | - Hideyuki Inoue
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
| | - Shinichi Antoku
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
| | - Tomoko Yamasaki
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
| | - Toshiko Mori
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
| | - Michiko Togane
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa-Ku, Tokyo, Japan
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Vidal-Cevallos P, Sorroza-Martínez AP, Chávez-Tapia NC, Uribe M, Montalvo-Javé EE, Nuño-Lámbarri N. The Relationship between Pathogenesis and Possible Treatments for the MASLD-Cirrhosis Spectrum. Int J Mol Sci 2024; 25:4397. [PMID: 38673981 PMCID: PMC11050641 DOI: 10.3390/ijms25084397] [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: 03/12/2024] [Revised: 04/04/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a term that entails a broad spectrum of conditions that vary in severity. Its development is influenced by multiple factors such as environment, microbiome, comorbidities, and genetic factors. MASLD is closely related to metabolic syndrome as it is caused by an alteration in the metabolism of fatty acids due to the accumulation of lipids because of an imbalance between its absorption and elimination in the liver. Its progression to fibrosis is due to a constant flow of fatty acids through the mitochondria and the inability of the liver to slow down this metabolic load, which generates oxidative stress and lipid peroxidation, triggering cell death. The development and progression of MASLD are closely related to unhealthy lifestyle habits, and nutritional epigenetic and genetic mechanisms have also been implicated. Currently, lifestyle modification is the first-line treatment for MASLD and nonalcoholic steatohepatitis; weight loss of ≥10% produces resolution of steatohepatitis and fibrosis regression. In many patients, body weight reduction cannot be achieved; therefore, pharmacological treatment should be offered in particular populations.
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Affiliation(s)
- Paulina Vidal-Cevallos
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (P.V.-C.); (N.C.C.-T.); (M.U.); (E.E.M.-J.)
| | | | - Norberto C. Chávez-Tapia
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (P.V.-C.); (N.C.C.-T.); (M.U.); (E.E.M.-J.)
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico;
| | - Misael Uribe
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (P.V.-C.); (N.C.C.-T.); (M.U.); (E.E.M.-J.)
| | - Eduardo E. Montalvo-Javé
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (P.V.-C.); (N.C.C.-T.); (M.U.); (E.E.M.-J.)
- Department of Surgery, Faculty of Medicine, Universidad Nacional Autónoma de Mexico, Mexico City 04360, Mexico
- Hepatopancreatobiliary Clinic, Department of Surgery, Hospital General de Mexico “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico
| | - Natalia Nuño-Lámbarri
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico;
- Department of Surgery, Faculty of Medicine, Universidad Nacional Autónoma de Mexico, Mexico City 04360, Mexico
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Deng Y, Hu M, Huang S, Fu N. Molecular mechanism and therapeutic significance of essential amino acids in metabolically associated fatty liver disease. J Nutr Biochem 2024; 126:109581. [PMID: 38219809 DOI: 10.1016/j.jnutbio.2024.109581] [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: 08/02/2023] [Revised: 01/01/2024] [Accepted: 01/06/2024] [Indexed: 01/16/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD), also known as metabolically associated fatty liver disease (MAFLD), is a systemic metabolic disease characterized by lipid accumulation in the liver, lipid toxicity, insulin resistance, intestinal dysbiosis, and inflammation that can progress from simple steatosis to nonalcoholic steatohepatitis (NASH) and even cirrhosis or cancer. It is the most prevalent illness threatening world health. Currently, there are almost no approved drug interventions for MAFLD, mainly dietary changes and exercise to control weight and regulate metabolic disorders. Meanwhile, the metabolic pathway involved in amino acid metabolism also influences the onset and development of MAFLD in the body, and most amino acid metabolism takes place in the liver. Essential amino acids are those amino acids that must be supplemented from outside the diet and that cannot be synthesized in the body or cannot be synthesized at a rate sufficient to meet the body's needs, including leucine, isoleucine, valine (collectively known as branched-chain amino acids), tryptophan, phenylalanine (which are aromatic amino acids), histidine, methionine, threonine and lysine. The metabolic balance of the body is closely linked to these essential amino acids, and essential amino acids are closely linked to the pathophysiological process of MAFLD. In this paper, we will focus on the metabolism of essential amino acids in the body and further explore the therapeutic strategies for MAFLD based on the studies conducted in recent years.
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Affiliation(s)
- Yuting Deng
- The Affiliated Nanhua Hospital, Department of Gastroenterology, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421002, China
| | - Mengsi Hu
- The Affiliated Nanhua Hospital, Department of Gastroenterology, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421002, China
| | - Shufang Huang
- The Affiliated Nanhua Hospital, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421002, China.
| | - Nian Fu
- The Affiliated Nanhua Hospital, Department of Gastroenterology, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421002, China; The Affiliated Nanhua Hospital, Institute of Clinical Research, Hengyang Medical School, University of South China, Hengyang, Hunan, 421002, China.
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Adeghate EA. GLP-1 receptor agonists in the treatment of diabetic non-alcoholic steatohepatitis patients. Expert Opin Pharmacother 2024; 25:223-232. [PMID: 38458647 DOI: 10.1080/14656566.2024.2328796] [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: 01/22/2024] [Accepted: 03/06/2024] [Indexed: 03/10/2024]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease affecting almost 30% of the world population. Approximately 25% of people with NAFLD develop nonalcoholic steatohepatitis (NASH), the fulminant version of the disease. Diabetes mellitus is present in 22.5% of people with NAFLD and 44.60% of individuals with NASH. This review was undertaken to examine the current contribution of glucagon-like peptide 1 (GLP-1) receptor agonists to the pharmacotherapy of diabetic nonalcoholic steatohepatitis. AREAS COVERED The author analyzed the current status of GLP-1 receptor agonists for pharmacotherapy of diabetic NASH. Research data and literature reports were taken from the database and or websites of Diabetes UK, American Diabetes Association, ClinicalTrials.gov, PubMed, and Scopus. The keywords utilized included type 2 diabetes, GLP-1, NASH, NAFLD, and clinical trials. EXPERT OPINION Since diabetic NASH is associated with obesity, diabetes mellitus, oxidative stress and inflammation, drugs capable of mitigating all of these conditions simultaneously, are most ideal for the treatment of diabetic NASH. These drugs include (in order of relevance), GLP-1 receptor agonists, GLP-1 and GIP dual receptor agonists, sodium-glucose co-transporter-2 (SGLT2) inhibitors, and pioglitazone. The future, FDA-approved drug for diabetic NASH treatment will likely be GLP-1 agonist, which could be used as monotherapy or in combination with other drugs.
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Affiliation(s)
- Ernest A Adeghate
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Centre for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Lenharo M. Obesity drugs have another superpower: taming inflammation. Nature 2024; 626:246. [PMID: 38278941 DOI: 10.1038/d41586-024-00118-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2024]
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Melander SA, Kayed A, Andreassen KV, Karsdal MA, Henriksen K. OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes. Eur J Pharmacol 2024; 962:176215. [PMID: 38056618 DOI: 10.1016/j.ejphar.2023.176215] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/08/2023] [Accepted: 11/16/2023] [Indexed: 12/08/2023]
Abstract
OBJECTIVE Dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonists are therapeutic agents with an interesting liver-specific mode of action suitable for metabolic complications. In this study, dual GLP-1 and glucagon receptor agonist OXM-104 is compared head-to-head with the once-daily dual GLP-1 and glucagon receptor agonist cotadutide and GLP-1 receptor agonist semaglutide to explore the metabolic efficacy of OXM-104. METHODS The in vitro potencies of OXM-104, cotadutide and semaglutide were assessed using reporter assays. In addition, in vivo efficacy was investigated using mouse models of diet-induced obesity (DIO mice), diabetes (db/db mice) and diet-induced NASH mice (MS-NASH). RESULTS OXM-104 was found to only activate the GLP-1 and glucagon with no cross-reactivity at the (GIP) receptor. Cotadutide was also found to activate the GLP-1 and glucagon receptors, whereas semaglutide only showed activity at the GLP-1 receptor. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrotic biomarkers, were more prominent with OXM-104 and cotadutide than those seen with semaglutide, demonstrated by an improved NAFLD activity score (NAS) by OXM-104 and cotadutide, underlining the importance of the glucagon receptor. CONCLUSION These results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH.
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Affiliation(s)
| | | | | | | | - Kim Henriksen
- Nordic Bioscience, 2730 Herlev, Denmark; KeyBioscience AG, Stans, Switzerland
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Zachou M, Flevari P, Nasiri-Ansari N, Varytimiadis C, Kalaitzakis E, Kassi E, Androutsakos T. The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review. Eur J Clin Pharmacol 2024; 80:127-150. [PMID: 37938366 PMCID: PMC10781828 DOI: 10.1007/s00228-023-03586-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 10/19/2023] [Indexed: 11/09/2023]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease, affecting 30% of the global population. NAFLD prevalence is particularly high in obese individuals and patients with type 2 diabetes mellitus (T2DM). NAFLD ranges from simple fat deposition in the liver to necroinflammation and fibrosis (non-alcoholic steatohepatitis (NASH)), NASH-cirrhosis, and/or hepatocellular carcinoma. Insulin resistance plays a key role in NAFLD pathogenesis, alongside dysregulation of adipocytes, mitochondrial dysfunction, genetic factors, and changes in gut microbiota. Since insulin resistance is also a major predisposing factor of T2DM, the administration of anti-diabetic drugs for the management of NAFLD seems reasonable. METHODS In this review we provide the NAFLD-associated mechanisms of action of some of the most widely used anti-diabetic drugs, namely metformin, pioglitazone, sodium-glucose transport protein-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor analogs (GLP1 RAs), and dipeptyl-peptidase-4 inhibitors (DPP4i) and present available data regarding their use in patients with NAFLD, with and without T2DM. RESULTS Both metformin and DPP4i have shown rather contradictory results, while pioglitazone seems to benefit patients with NASH and is thus the only drug approved for NASH with concomitant significant liver fibrosis by all major liver societies. On the other hand, SGLT2i and GLP1 RAs seem to be beneficiary in patients with NAFLD, showing both remarkable results, with SGLT2i proving to be more efficient in the only head-to-head study so far. CONCLUSION In patients with NAFLD and diabetes, pioglitazone, GLP1 RAs, and SGLT2i seem to be logical treatment options. Larger studies are needed before these drugs can be recommended for non-diabetic individuals.
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Affiliation(s)
- Maria Zachou
- Gastroenterology Department, "Sismanoglio" General Hospital, 151 26, Athens, Greece
| | - Pagona Flevari
- Expertise Center in Rare Haematological Diseases-Haemoglobinopathies, "Laiko" General Hospital, 115 27, Athens, Greece
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | | | - Evangelos Kalaitzakis
- Department of Gastroenterology, University Hospital of Heraklion, University of Crete, 715 00, Heraklion, Greece
| | - Eva Kassi
- Unit of Molecular Endocrinology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, "Laiko" Hospital, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27, Athens, Greece.
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Jiang H, Zang L. GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD. Curr Pharm Des 2024; 30:100-114. [PMID: 38532322 DOI: 10.2174/0113816128283153231226103218] [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: 10/12/2023] [Accepted: 12/14/2023] [Indexed: 03/28/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a global public health concern. Currently, the cornerstone of NAFLD treatment is lifestyle modification and, if necessary, weight loss. However, compliance is a challenge, and this approach alone may not be sufficient to halt and treat the more serious disease development, so medication is urgently needed. Nevertheless, no medicines are approved to treat NAFLD. Glucagon-like peptide-1 (GLP-1) is an enteropeptide hormone that inhibits glucagon synthesis, promotes insulin secretion, and delays gastric emptying. GLP-1 has been found in recent studies to be beneficial for the management of NAFLD, and the marketed GLP-1 agonist drugs have different degrees of effectiveness for NAFLD while lowering blood glucose. In this article, we review GLP-1 and its physiological roles, the pathogenesis of NAFLD, the correlation between NAFLD and GLP-1 signaling, and potential strategies for GLP-1 treatment of NAFLD.
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Affiliation(s)
- Haoran Jiang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Linquan Zang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
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Zhang W, Lang R. Macrophage metabolism in nonalcoholic fatty liver disease. Front Immunol 2023; 14:1257596. [PMID: 37868954 PMCID: PMC10586316 DOI: 10.3389/fimmu.2023.1257596] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 09/19/2023] [Indexed: 10/24/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH), have emerged as significant contributors to hepatic morbidity worldwide. The pathophysiology of NAFLD/NASH is multifaceted, variable, and remains incompletely understood. The pivotal role of liver-resident and recruited macrophages in the pathogenesis of NAFLD and NASH is widely acknowledged as a crucial factor in innate immunity. The remarkable plasticity of macrophages enables them to assume diverse activation and polarization states, dictated by their immunometabolism microenvironment and functional requirements. Recent studies in the field of immunometabolism have elucidated that alterations in the metabolic profile of macrophages can profoundly influence their activation state and functionality, thereby influencing various pathological processes. This review primarily focuses on elucidating the polarization and activation states of macrophages, highlighting the correlation between their metabolic characteristics and the transition from pro-inflammatory to anti-inflammatory phenotypes. Additionally, we explore the potential of targeting macrophage metabolism as a promising therapeutic approach for the management of NAFLD/NASH.
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Affiliation(s)
| | - Ren Lang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
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23
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Baer B, Putz ND, Riedmann K, Gonski S, Lin J, Ware LB, Toki S, Peebles RS, Cahill KN, Bastarache JA. Liraglutide pretreatment attenuates sepsis-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 2023; 325:L368-L384. [PMID: 37489855 PMCID: PMC10639010 DOI: 10.1152/ajplung.00041.2023] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/28/2023] [Accepted: 07/23/2023] [Indexed: 07/26/2023] Open
Abstract
There are no effective targeted therapies to treat acute respiratory distress syndrome (ARDS). Recently, the commonly used diabetes and obesity medications, glucagon-like peptide-1 (GLP-1) receptor agonists, have been found to have anti-inflammatory properties. We, therefore, hypothesized that liraglutide pretreatment would attenuate murine sepsis-induced acute lung injury (ALI). We used a two-hit model of ALI (sepsis+hyperoxia). Sepsis was induced by intraperitoneal injection of cecal slurry (CS; 2.4 mg/g) or 5% dextrose (control) followed by hyperoxia [HO; fraction of inspired oxygen ([Formula: see text]) = 0.95] or room air (control; [Formula: see text] = 0.21). Mice were pretreated twice daily with subcutaneous injections of liraglutide (0.1 mg/kg) or saline for 3 days before initiation of CS+HO. At 24-h post CS+HO, physiological dysfunction was measured by weight loss, severity of illness score, and survival. Animals were euthanized, and bronchoalveolar lavage (BAL) fluid, lung, and spleen tissues were collected. Bacterial burden was assessed in the lung and spleen. Lung inflammation was assessed by BAL inflammatory cell numbers, cytokine concentrations, lung tissue myeloperoxidase activity, and cytokine expression. Disruption of the alveolar-capillary barrier was measured by lung wet-to-dry weight ratios, BAL protein, and epithelial injury markers (receptor for advanced glycation end products and sulfated glycosaminoglycans). Histological evidence of lung injury was quantified using a five-point score with four parameters: inflammation, edema, septal thickening, and red blood cells (RBCs) in the alveolar space. Compared with saline treatment, liraglutide improved sepsis-induced physiological dysfunction and reduced lung inflammation, alveolar-capillary barrier disruption, and lung injury. GLP-1 receptor activation may hold promise as a novel treatment strategy for sepsis-induced ARDS. Additional studies are needed to better elucidate its mechanism of action.NEW & NOTEWORTHY In this study, pretreatment with liraglutide, a commonly used diabetes medication and glucagon-like peptide-1 (GLP-1) receptor agonist, attenuated sepsis-induced acute lung injury in a two-hit mouse model (sepsis + hyperoxia). Septic mice who received the drug were less sick, lived longer, and displayed reduced lung inflammation, edema, and injury. These therapeutic effects were not dependent on weight loss. GLP-1 receptor activation may hold promise as a new treatment strategy for sepsis-induced acute respiratory distress syndrome.
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Affiliation(s)
- Brandon Baer
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Nathan D Putz
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Kyle Riedmann
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Samantha Gonski
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Jason Lin
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Lorraine B Ware
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Shinji Toki
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - R Stokes Peebles
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- United States Department of Veterans Affairs, Nashville, Tennessee, United States
| | - Katherine N Cahill
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Julie A Bastarache
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
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24
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Lee WH, Najjar SM, Kahn CR, Hinds TD. Hepatic insulin receptor: new views on the mechanisms of liver disease. Metabolism 2023; 145:155607. [PMID: 37271372 PMCID: PMC10330768 DOI: 10.1016/j.metabol.2023.155607] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 05/26/2023] [Accepted: 05/28/2023] [Indexed: 06/06/2023]
Abstract
Over 65 % of people with obesity display the metabolic-associated fatty liver disease (MAFLD), which can manifest as steatohepatitis, fibrosis, cirrhosis, or liver cancer. The development and progression of MAFLD involve hepatic insulin resistance and reduced insulin clearance. This review discusses the relationships between altered insulin signaling, hepatic insulin resistance, and reduced insulin clearance in the development of MAFLD and how this provides the impetus for exploring the use of insulin sensitizers to curb this disease. The review also explores the role of the insulin receptor in hepatocytes and hepatic stellate cells and how it signals in metabolic and end-stage liver diseases. Finally, we discuss new research findings that indicate that advanced hepatic diseases may be an insulin-sensitive state in the liver and deliberate whether insulin sensitizers should be used to manage late-stage liver diseases.
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Affiliation(s)
- Wang-Hsin Lee
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Sonia M Najjar
- Department of Biomedical Sciences and the Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - C Ronald Kahn
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA; Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
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25
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Tsiampali C, Papaioannidou P, Goulas A, Polyzos SA. The role of glucagon-like peptide-1 receptor agonists in nonalcoholic fatty liver disease. Expert Rev Clin Pharmacol 2023; 16:1063-1072. [PMID: 37864548 DOI: 10.1080/17512433.2023.2274536] [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: 07/17/2023] [Accepted: 10/19/2023] [Indexed: 10/23/2023]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease, associated with obesity, type 2 diabetes mellitus and dyslipidemia, which can lead to liver cirrhosis and hepatocellular carcinoma in some patients. Apart from lifestyle modifications, which are the cornerstone for its management, several drugs are under evaluation, including glucagon-like peptide-1 receptor agonists (GLP-R1RAs). In this review, we summarized major clinical data concerning the effects of GLP-1RAs on NAFLD, trying to highlight existing knowledge and to elucidate areas of uncertainty, thus providing clues to potential clinical implications and research. AREAS COVERED Selected clinical studies on GLP-R1As in NAFLD are presented in this narrative review. EXPERT OPINION There is evidence that treatment with GLP-R1As in NAFLD has beneficial effects on NAFLD, i.e. improvement in liver function tests and histological improvement in hepatic steatosis and inflammation, but not fibrosis. Further research is required toward the early use of GLP-R1Αs, i.e. in NAFLD patients without fibrosis to evaluate whether they may prevent the progression to fibrosis, or in patients with advanced disease in combination with other medications, which may have additive or even synergistic effects on NAFLD.
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Affiliation(s)
- Chara Tsiampali
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paraskevi Papaioannidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
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26
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Huang X, Chen H, Wen S, Dong M, Zhou L, Yuan X. Therapeutic Approaches for Nonalcoholic Fatty Liver Disease: Established Targets and Drugs. Diabetes Metab Syndr Obes 2023; 16:1809-1819. [PMID: 37366486 PMCID: PMC10290856 DOI: 10.2147/dmso.s411400] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/16/2023] [Indexed: 06/28/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), as a multisystemic disease, is the most prevalent chronic liver disease characterized by extremely complex pathogenic mechanisms and multifactorial etiology, which often develops as a consequence of obesity, metabolic syndrome. Pathophysiological mechanisms involved in the development of NAFLD include diet, obesity, insulin resistance (IR), genetic and epigenetic determinants, intestinal dysbiosis, oxidative/nitrosative stress, autophagy dysregulation, hepatic inflammation, gut-liver axis, gut microbes, impaired mitochondrial metabolism and regulation of hepatic lipid metabolism. Some of the new drugs for the treatment of NAFLD are introduced here. All of them achieve therapeutic objectives by interfering with certain pathophysiological pathways of NAFLD, including fibroblast growth factors (FGF) analogues, peroxisome proliferator-activated receptors (PPARs) agonists, glucagon-like peptide-1 (GLP-1) agonists, G protein-coupled receptors (GPCRs), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), farnesoid X receptor (FXR), fatty acid synthase inhibitor (FASNi), antioxidants, etc. This review describes some pathophysiological mechanisms of NAFLD and established targets and drugs.
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Affiliation(s)
- Xiaojing Huang
- Graduate School of Fudan University, Shanghai, People’s Republic of China
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Huiling Chen
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Song Wen
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Meiyuan Dong
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Ligang Zhou
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Xinlu Yuan
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
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Shinozaki S, Tahara T, Miura K, Lefor AK, Yamamoto H. Effectiveness of One-Year Pemafibrate Therapy on Non-Alcoholic Fatty Liver Disease Refractory to Long-Term Sodium Glucose Cotransporter-2 Inhibitor Therapy: A Pilot Study. Life (Basel) 2023; 13:1327. [PMID: 37374110 DOI: 10.3390/life13061327] [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: 04/12/2023] [Revised: 06/02/2023] [Accepted: 06/03/2023] [Indexed: 06/29/2023] Open
Abstract
Background: Both pemafibrate and sodium glucose cotransporter-2 (SGLT2) inhibitor can decrease serum transaminase levels in patients with non-alcoholic fatty liver disease (NAFLD) complicated with dyslipidemia and type 2 diabetes mellitus (T2DM), respectively. However, the effectiveness of combined therapy has been rarely reported. Methods: This is a two-center retrospective observational study. NAFLD patients complicated with T2DM treated with pemafibrate for >1 year were included, in whom prior treatment with SGLT2 inhibitor > 1 year failed to normalize serum alanine aminotransferase (ALT) levels. Hepatic inflammation, function, and fibrosis were assessed by ALT, albumin-bilirubin (ALBI) score, and Mac-2 binding protein glycosylation isomer (M2BPGi) levels, respectively. Results: Seven patients were included. The median duration of prior treatment with SGLT2 inhibitors was 2.3 years. During the one year before starting pemafibrate therapy, the therapy did not significantly change hepatic enzymes. All patients received pemafibrate 0.1 mg twice daily without dose escalations. During one year of pemafibrate therapy, triglyceride, aspartate aminotransferase, ALT, γ-glutamyl transpeptidase, ALBI score, and M2BPGi levels significantly improved (p < 0.05), although weight or hemoglobin A1c did not significantly change. Conclusions: One year of pemafibrate therapy improves markers of hepatic inflammation, function, and fibrosis in NAFLD patients in whom long-term SGLT2 inhibitor therapy failed to normalize serum ALT.
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Affiliation(s)
- Satoshi Shinozaki
- Shinozaki Medical Clinic, Utsunomiya 321-3223, Japan
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Tochigi 329-0431, Japan
| | - Toshiyuki Tahara
- Saiseikai Utsunomiya Hospital, 911-1 Takebayashi, Utsunomiya 321-0974, Japan
| | - Kouichi Miura
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Tochigi 329-0431, Japan
| | - Alan Kawarai Lefor
- Department of Surgery, Jichi Medical University, Tochigi 329-0431, Japan
| | - Hironori Yamamoto
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Tochigi 329-0431, Japan
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Arvanitakis K, Koufakis T, Popovic D, Maltese G, Mustafa O, Doumas M, Giouleme O, Kotsa K, Germanidis G. GLP-1 Receptor Agonists in Obese Patients with Inflammatory Bowel Disease: from Molecular Mechanisms to Clinical Considerations and Practical Recommendations for Safe and Effective Use. Curr Obes Rep 2023; 12:61-74. [PMID: 37081371 DOI: 10.1007/s13679-023-00506-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/09/2023] [Indexed: 04/22/2023]
Abstract
PURPOSE OF REVIEW To discuss current literature and provide practical recommendations for the safe and effective use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in people with inflammatory bowel disease (IBD) and type 2 diabetes (T2D) and/or obesity. The molecular mechanisms that justify the potential benefits of GLP-1 RA in IBD and the links between IBD, obesity, and cardiovascular disease are also discussed. RECENT FINDINGS Preliminary data suggest that GLP-1 RA can modulate crucial pathways in the pathogenesis of IBD, such as chronic inflammation circuits, intestinal tight junctions, and gut microbiome dysbiosis, setting the stage for human trials to investigate the role of these agents in the treatment of IBD among people with or without diabetes and obesity. However, gastrointestinal side effects related to GLP-1 RA need appropriate clinical management to mitigate risks and maximize the benefits of therapy in people with IBD. GLP-1 RA originally emerged as drugs for the treatment of hyperglycemia and are currently licensed for the management of T2D and/or overweight/obesity. However, their wealth of pleiotropic actions soon raised expectations that they might confer benefits on non-metabolic disorders. Future studies are expected to clarify whether GLP-1 RA deserve an adjunct place in the arsenal of drugs against IBD.
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Affiliation(s)
- Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Djordje Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Giuseppe Maltese
- Department of Diabetes and Endocrinology, Epsom & St Helier University Hospitals, Surrey, SM5 1AA, UK
- Unit for Metabolic Medicine, Cardiovascular Division, Faculty of Life Sciences & Medicine, King's College, London, UK
| | - Omar Mustafa
- Department of Diabetes, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK
- King's College London, London, UK
| | - Michael Doumas
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Olga Giouleme
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece.
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece.
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Alomari M, Rashid MU, Chadalavada P, Ragheb J, Zafar H, Suarez ZK, Khazaaleh S, Gonzalez AJ, Castro FJ. Comparison between metabolic-associated fatty liver disease and nonalcoholic fatty liver disease: From nomenclature to clinical outcomes. World J Hepatol 2023; 15:477-496. [PMID: 37206648 PMCID: PMC10190689 DOI: 10.4254/wjh.v15.i4.477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/04/2023] [Accepted: 03/22/2023] [Indexed: 04/20/2023] Open
Abstract
As a result of the obesity epidemic, Nonalcoholic fatty liver disease (NAFLD) and its complications have increased among millions of people. Consequently, a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis; metabolic-associated fatty liver disease (MAFLD). This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD. This article discusses the rationale behind the nomenclature change, the main differences, and its clinical implications.
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Affiliation(s)
- Mohammad Alomari
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States.
| | - Mamoon Ur Rashid
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Pravallika Chadalavada
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Jonathan Ragheb
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Hammad Zafar
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Zoilo Karim Suarez
- Department of Internal Medicine, Florida Atlantic University Charles E Schmidt College of Medicine, Boca Raton, FL 33431, United States
| | - Shrouq Khazaaleh
- Department of Internal Medicine, Cleveland Clinic Fairview Hospital, Cleveland, OH 44126, United States
| | - Adalberto Jose Gonzalez
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Fernando J Castro
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
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30
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Tian Q, Liu Y, Yuan P, Liu J, Li H, Han X, Pan C, Wu Y, Zhou Z, Liu S, Li Y, Duan S, Xia K. Glucagon-like peptide-1 receptor mediates the improvement in glycolipid metabolism disorder via AKT and AMPK signalling pathways in L02 cells with insulin resistance. J Mol Struct 2023. [DOI: 10.1016/j.molstruc.2022.134328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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31
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Yu X, Wang Y, Lai J, Song T, Duan J. Comparative efficacy of exercise training processes in improving nonalcoholic fatty liver disease: a systematic review and meta-analysis. Ir J Med Sci 2023; 192:131-142. [PMID: 35366201 DOI: 10.1007/s11845-022-02988-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023]
Abstract
OBJECTIVES This systematic review and meta-analysis aimed to evaluate the efficacy of exercise training in patients with nonalcoholic fatty liver disease (NAFLD). METHODS We searched PubMed, Cochrane Library, Web of Science, and Embase for relevant research from January 2001 to December 2021. The efficacy of exercise training was analyzed. RESULTS A total of 21 articles, involving 1733 patients, were included. Exercise training, including resistance training, aerobic exercise training, and high-intensity training, showed the efficacy in reducing weight (MD = 3.46, 95% CI [1.94, 4.98]), BMI (MD = 0.89, 95% CI [0.17, 1.61]), and ALT (MD = 6.66, 95% CI [3.27, 10.04]) and AST (MD = 3.14, 95% CI [0.35, 5.93]) levels in patients with NAFLD. When the exercise training lasted for ≥ 20 weeks, the total cholesterol (TC) (MD = 0.13, 95% CI [0.04, 0.22]), triglyceride (TG) (MD = 0.29, 95% CI [0.12, 0.47]), and blood glucose (GLU) (MD = - 0.18, 95% CI [0.10, 0.26]) levels significantly reduced. Compared with the exercise training group, the exercise training combined with probiotics group showed more efficiency in reducing the ALT, AST, TG, and TC levels. However, the exercise training combined with a hypoglycemic agent group showed no obvious efficiency compared with the exercise training group. CONCLUSION Exercise training can improve NAFLD. The improvement was more obvious when exercise was performed for ≥ 20 weeks. Probiotics may enhance the efficiency of exercise training.
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Affiliation(s)
- Xue Yu
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Fushun road, no 9, Shandong Province, 266033, China
| | - Yan Wang
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Fushun road, no 9, Shandong Province, 266033, China
| | - Jianming Lai
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Fushun road, no 9, Shandong Province, 266033, China
| | - Ting Song
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Fushun road, no 9, Shandong Province, 266033, China
| | - Jianping Duan
- Department of Hepatology, The Sixth People's Hospital of Qingdao, Fushun road, no 9, Shandong Province, 266033, China.
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Liraglutide Attenuates Hepatic Oxidative Stress, Inflammation, and Apoptosis in Streptozotocin-Induced Diabetic Mice by Modulating the Wnt/ β-Catenin Signaling Pathway. Mediators Inflamm 2023; 2023:8974960. [PMID: 36756089 PMCID: PMC9899592 DOI: 10.1155/2023/8974960] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/19/2022] [Accepted: 12/27/2022] [Indexed: 02/01/2023] Open
Abstract
Liraglutide has been extensively applied in the treatment of type 2 diabetes mellitus and also has hepatoprotective effects. However, the role of liraglutide treatment on liver injury in a mouse model of type 1 diabetes mellitus (T1DM) induced by streptozotocin (STZ) and its underlying mechanisms remain to be elucidated. In the present study, diabetes was initiated in experimental animals by single-dose intraperitoneal inoculation of STZ. Forty female C57BL/6J mice were equally assigned into five groups: diabetic group, insulin+diabetic group, liraglutide+diabetic group, insulin+liraglutide+diabetic group, and control group for eight weeks. Diabetic mice exhibited a significantly elevated blood glucose level and decreased body weight, and morphological changes of increased steatosis and apoptosis were observed in the liver compared with the control. Furthermore, a significant increase in the levels of malondialdehyde and inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin 1β (IL-1β) and the proapoptotic proteins caspase-3 and Bax were observed in the livers of diabetic mice, together with marked increases in antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPX) as well as antiapoptotic protein Bcl-2, all of which were significantly mitigated by treatment with liraglutide, insulin, and their combinations. Interestingly, liraglutide monotherapy showed better efficacy in ameliorating liver injury in T1DM mice than insulin monotherapy, similar to the combined drug therapy. Furthermore, the expression of Wnt/β-catenin signaling pathway-associated molecules was upregulated in the liver of mice treated with liraglutide or insulin. The results of the present study suggested that liraglutide improves T1DM-induced liver injury and may have important implications for the treatment of nonalcoholic fatty liver disease (NAFLD) in patients with T1DM.
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GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci 2023; 24:ijms24021703. [PMID: 36675217 PMCID: PMC9865319 DOI: 10.3390/ijms24021703] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.
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Wasim R, Ansari TM, Siddiqui MH, Ahsan F, Shamim A, Singh A, Shariq M, Anwar A, Siddiqui AR, Parveen S. Repurposing of Drugs for Cardiometabolic Disorders: An Out and Out Cumulation. Horm Metab Res 2023; 55:7-24. [PMID: 36599357 DOI: 10.1055/a-1971-6965] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cardiometabolic disorders (CMD) is a constellation of metabolic predisposing factors for atherosclerosis such as insulin resistance (IR) or diabetes mellitus (DM), systemic hypertension, central obesity, and dyslipidemia. Cardiometabolic diseases (CMDs) continue to be the leading cause of mortality in both developed and developing nations, accounting for over 32% of all fatalities globally each year. Furthermore, dyslipidemia, angina, arrhythmia, heart failure, myocardial infarction (MI), and diabetes mellitus are the major causes of death, accounting for an estimated 19 million deaths in 2012. CVDs will kill more than 23 million individuals each year by 2030. Nonetheless, new drug development (NDD) in CMDs has been increasingly difficult in recent decades due to increased costs and a lower success rate. Drug repositioning in CMDs looks promising in this scenario for launching current medicines for new therapeutic indications. Repositioning is an ancient method that dates back to the 1960s and is mostly based on coincidental findings during medication trials. One significant advantage of repositioning is that the drug's safety profile is well known, lowering the odds of failure owing to undesirable toxic effects. Furthermore, repositioning takes less time and money than NDD. Given these facts, pharmaceutical corporations are becoming more interested in medication repositioning. In this follow-up, we discussed the notion of repositioning and provided some examples of repositioned medications in cardiometabolic disorders.
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Affiliation(s)
| | | | | | - Farogh Ahsan
- Pharmacology, Integral University, Lucknow, India
| | | | - Aditya Singh
- Pharmaceutics, Integral University, Lucknow, India
| | | | - Aamir Anwar
- Pharmacy, Integral University, Lucknow, India
| | | | - Saba Parveen
- Pharmacology, Integral University, Lucknow, India
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Josloff K, Beiriger J, Khan A, Gawel RJ, Kirby RS, Kendrick AD, Rao AK, Wang RX, Schafer MM, Pearce ME, Chauhan K, Shah YB, Marhefka GD, Halegoua-DeMarzio D. Comprehensive Review of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease. J Cardiovasc Dev Dis 2022; 9:419. [PMID: 36547416 PMCID: PMC9786069 DOI: 10.3390/jcdd9120419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 11/16/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) is a growing global phenomenon, and its damaging effects in terms of cardiovascular disease (CVD) risk are becoming more apparent. NAFLD is estimated to affect around one quarter of the world population and is often comorbid with other metabolic disorders including diabetes mellitus, hypertension, coronary artery disease, and metabolic syndrome. In this review, we examine the current evidence describing the many ways that NAFLD itself increases CVD risk. We also discuss the emerging and complex biochemical relationship between NAFLD and its common comorbid conditions, and how they coalesce to increase CVD risk. With NAFLD's rising prevalence and deleterious effects on the cardiovascular system, a complete understanding of the disease must be undertaken, as well as effective strategies to prevent and treat its common comorbid conditions.
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Affiliation(s)
- Kevan Josloff
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jacob Beiriger
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Adnan Khan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard J. Gawel
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard S. Kirby
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Aaron D. Kendrick
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Abhinav K. Rao
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Roy X. Wang
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Michelle M. Schafer
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Margaret E. Pearce
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Kashyap Chauhan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Yash B. Shah
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Gregary D. Marhefka
- Department of Internal Medicine, Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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Arvanitakis K, Koufakis T, Kotsa K, Germanidis G. How Far beyond Diabetes Can the Benefits of Glucagon-like Peptide-1 Receptor Agonists Go? A Review of the Evidence on Their Effects on Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14194651. [PMID: 36230573 PMCID: PMC9562923 DOI: 10.3390/cancers14194651] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 09/20/2022] [Accepted: 09/22/2022] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of diabetes, but have also been shown to alleviate cardiorenal risk. Furthermore, they have demonstrated a wide range of extraglycemic effects that led to their evaluation as potential therapies for a variety of diseases beyond diabetes, such as obesity, neurogenerative disorders and nonalcoholic fatty liver disease. Given the presence of the GLP-1 receptor in hepatocytes, animal data suggest that GLP-1 RAs could regulate molecular pathways that are deeply involved in the genesis and progression of HCC, including inflammatory responses, tumor cell proliferation and oxidative stress, through direct and indirect effects on liver cells. However, future studies must assess several aspects of the benefit-to-risk ratio of the use of GLP-1 RAs in patients with HCC, including co-administration with approved systemic therapies, the incidence of gastrointestinal side effects in a high-risk population, and weight loss management in individuals with poor nutritional status and high rates of cancer cachexia. In this narrative review, we discuss the potential role of GLP-1 analogs in the treatment of HCC, focusing on the molecular mechanisms that could justify a possible benefit, but also referring to the potential clinical implications and areas for future research.
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Affiliation(s)
- Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- Basic and Translational Research Unit (BTRU) of Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, AHEPA University Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, AHEPA University Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- Basic and Translational Research Unit (BTRU) of Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- Correspondence: ; Tel.: +30-231-330-3156; Fax: +30-231-099-4638
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Tsankof A, Neokosmidis G, Koureta E, Veneti S, Cholongitas E, Tziomalos K. Which is the optimal antiobesity agent for patients with nonalcoholic fatty liver disease? Front Endocrinol (Lausanne) 2022; 13:984041. [PMID: 36120448 PMCID: PMC9478023 DOI: 10.3389/fendo.2022.984041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and affects a considerable proportion of the general population worldwide. Obesity is a major risk factor for development and progression of NAFLD and weight loss is an effective intervention for the management of NAFLD. However, few patients achieve substantial and sustained weight loss with lifestyle measures. Therefore, antiobesity agents are frequently considered in patients with NAFLD but there are limited data on their safety and efficacy. In the present review, we discuss the role of antiobesity agents in the management of NAFLD. All approved antiobesity agents appear to reduce transaminase levels and to improve steatosis in patients with NAFLD. However, their effects on fibrosis are less well studied and whether they affect liver-related outcomes, including progression to cirrhosis and hepatocellular cancer, is unknown. The glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, appear to represent a first-line option in obese patients with NAFLD and type 2 diabetes mellitus (T2DM) since they induce considerable weight loss and have been extensively studied in patients with T2DM. However, more studies are needed to evaluated their effects on liver-related and cardiovascular outcomes in patients with NAFLD, particularly in those without T2DM.
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Affiliation(s)
- Alexandra Tsankof
- First Propedeutic Department of Internal Medicine, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Georgios Neokosmidis
- First Propedeutic Department of Internal Medicine, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Evgenia Koureta
- Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavroula Veneti
- First Propedeutic Department of Internal Medicine, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Evangelos Cholongitas
- Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
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Rizzo M, Cosentino F, Mantzoros C. Biosimilar and generic formulations of novel antidiabetic drugs: the role of liraglutide in clinical pharmacology of type 2 diabetes. Expert Rev Clin Pharmacol 2022; 15:795-797. [PMID: 35924858 DOI: 10.1080/17512433.2022.2108400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Manfredi Rizzo
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (Promise), School of Medicine, University of Palermo, Palermo, Italy
| | - Francesco Cosentino
- Division of Cardiology, Department of Medicine, Karolinska Institute and Karolinska University Hospital, University of Stockholm, Stockholm, Sweden
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.,Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
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Arai T, Atsukawa M, Tsubota A, Ono H, Kawano T, Yoshida Y, Okubo T, Hayama K, Nakagawa‐Iwashita A, Itokawa N, Kondo C, Nagao M, Iwakiri K. Efficacy and safety of oral semaglutide in patients with non‐alcoholic fatty liver disease complicated by type 2 diabetes mellitus: A pilot study. JGH Open 2022; 6:503-511. [PMID: 35822119 PMCID: PMC9260206 DOI: 10.1002/jgh3.12780] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/27/2022] [Accepted: 06/05/2022] [Indexed: 12/13/2022]
Abstract
Background and Aim This study aimed to clarify the efficacy and safety of oral semaglutide treatment in patients with non‐alcoholic fatty liver disease (NAFLD) complicated by type 2 diabetes mellitus (T2DM). Methods This was a single‐arm, open‐label pilot study. Sixteen patients with NAFLD who received oral semaglutide for T2DM were included in the analysis. Oral semaglutide was initiated at a dose of 3 mg once daily, and the dose was sequentially increased to 7 mg at 4 weeks and 14 mg at 8 weeks (maintenance dose) until the end of the 24‐week trial. Results Body weight and levels of liver‐related biochemistry, plasma glucose, and hemoglobin A1c decreased significantly from baseline to 12 weeks. These significant decreases were maintained until the end of the trial. Additionally, levels of the homeostasis model assessment‐insulin resistance and triglyceride significantly decreased at 24 weeks. Controlled attenuation parameter (CAP) values significantly decreased from baseline to 24 weeks. Changes in body weight were correlated with those in levels of alanine aminotransferase (r = 0.52) and CAP (r = 0.72). As for liver fibrosis markers, significant decreases from baseline to 24 weeks in levels of the fibrosis‐4 index, ferritin, and type IV collagen 7 s were found; however, the liver stiffness measurement did not significantly decrease. Most adverse events were grade 1–2 transient gastrointestinal disorders. Conclusions Oral semaglutide treatment in patients with NAFLD complicated by T2DM improved impaired liver function, hypertriglyceridemia, insulin resistance, and hepatic steatosis, as well as improving diabetic status and reducing body weight.
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Affiliation(s)
- Taeang Arai
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Sciences The Jikei University School of Medicine Tokyo Japan
| | - Hirotaka Ono
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Tadamichi Kawano
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Yuji Yoshida
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Tomomi Okubo
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Korenobu Hayama
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | | | - Norio Itokawa
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Chisa Kondo
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Mototsugu Nagao
- Division of Endocrinology, Diabetes and Metabolism Nippon Medical School Tokyo Japan
| | - Katsuhiko Iwakiri
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
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Mitsala A, Tsalikidis C, Romanidis K, Pitiakoudis M. Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing? Curr Oncol 2022; 29:4478-4510. [PMID: 35877216 PMCID: PMC9325209 DOI: 10.3390/curroncol29070356] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 12/02/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.
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Moon JS, Hong JH, Jung YJ, Ferrannini E, Nauck MA, Lim S. SGLT-2 inhibitors and GLP-1 receptor agonists in metabolic dysfunction-associated fatty liver disease. Trends Endocrinol Metab 2022; 33:424-442. [PMID: 35491295 DOI: 10.1016/j.tem.2022.03.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/22/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic condition that affects nearly one billion people globally, characterized by triacylglycerol accumulation in the liver as a consequence of metabolic abnormalities (obesity and impaired glucose regulation). Low-grade inflammation, oxidative stress, mitochondrial dysfunction, and dysbiosis in gut microbiota are involved in the etiology of MAFLD, and both cardiovascular events and hepatic complications are the long-term consequences. In the absence of approved therapies for this condition, sodium-glucose cotransporter 2 inhibitors (SGLT-2 Is) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have the specific advantage of lowering body weight and providing cardiovascular benefits. Here, we discuss potential roles for SGLT-2 Is and GLP-1 RAs in the prevention and treatment of intrahepatic triacylglycerol accumulation and associated inflammation and/or fibrosis.
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Affiliation(s)
- Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Jun Hwa Hong
- Department of Internal Medicine, Eulji University Hospital, School of Medicine, Daejeon, Republic of Korea
| | - Yong Jin Jung
- Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | - Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital (Ruhr-University, Bochum), Bochum, Germany.
| | - Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
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Shi YW, Fan JG. Current status and challenges in the drug treatment for fibrotic nonalcoholic steatohepatitis. Acta Pharmacol Sin 2022; 43:1191-1199. [PMID: 34907360 PMCID: PMC9061812 DOI: 10.1038/s41401-021-00822-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022]
Abstract
Currently, nonalcoholic steatohepatitis (NASH) is one of the most common forms of chronic hepatitis, increasing the burden of health care worldwide. In patients with NASH, the fibrosis stage is the most predictive factor of long-term events. However, there are still no drugs approved by the Food and Drug Administration of the United States for treating biopsy-proven NASH with fibrosis or cirrhosis. Although some novel drugs have shown promise in preclinical studies and led to improvement in terms of hepatic fat content and steatohepatitis, a considerable proportion of them have failed to achieve histological endpoints of fibrosis improvement. Due to the large number of NASH patients and adverse clinical outcomes, the search for novel drugs is necessary. In this review, we discuss current definitions for the evaluation of treatment efficacy in fibrosis improvement for NASH patients, and we summarize novel agents in the pipeline from different mechanisms and phases of trial. We also critically review the challenges we face in the development of novel agents for fibrotic NASH and NASH cirrhosis.
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Affiliation(s)
- Yi-Wen Shi
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, 200092, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, 200092, China.
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Lavynenko O, Abdul-Ghani M, Alatrach M, Puckett C, Adams J, Abdelgani S, Alkhouri N, Triplitt C, Clarke GD, Vasquez JA, Li J, Cersosimo E, Gastaldelli A, DeFronzo RA. Combination therapy with pioglitazone/exenatide/metformin reduces the prevalence of hepatic fibrosis and steatosis: The efficacy and durability of initial combination therapy for type 2 diabetes (EDICT). Diabetes Obes Metab 2022; 24:899-907. [PMID: 35014145 DOI: 10.1111/dom.14650] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/05/2022] [Accepted: 01/06/2022] [Indexed: 12/11/2022]
Abstract
AIM To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin → glipizide → glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naïve patients with type 2 diabetes. METHODS Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat. RESULTS At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P = .0006). Twenty-seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P = .0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P = .04). Conventional therapy subjects had more liver fat (MRI-PDFF) than triple therapy (12.9% vs. 8.8%, P = .03). The severity of steatosis (CAP) (r = 0.42, P < .001) and fibrosis (LSM) (r = -0.48, P < .001) correlated inversely with the Matsuda Index of insulin sensitivity, but not with percentage body fat. Aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), non-alcoholic fatty liver disease fibrosis score (NFS), plasma AST, and alanine aminotransferase (ALT) all decreased significantly with triple therapy, but only the decrease in plasma AST and ALT correlated with the severity of steatosis and fibrosis at EOS. CONCLUSIONS At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis-4, and AST/ALT ratio) have limited value in predicting response to therapy.
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Affiliation(s)
- Olga Lavynenko
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Muhammad Abdul-Ghani
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Mariam Alatrach
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Curtiss Puckett
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - John Adams
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Siham Abdelgani
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Naim Alkhouri
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Curtis Triplitt
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Geoffrey D Clarke
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Juan A Vasquez
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Jinqi Li
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Eugenio Cersosimo
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Amalia Gastaldelli
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Ralph A DeFronzo
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
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Morishita A, Tadokoro T, Fujihara S, Iwama H, Oura K, Fujita K, Tani J, Takuma K, Nakahara M, Shi T, Haba R, Okano K, Nishiyama A, Ono M, Himoto T, Masaki T. Ipragliflozin attenuates non-alcoholic steatohepatitis development in an animal model. PLoS One 2022; 17:e0261310. [PMID: 35192632 PMCID: PMC8863244 DOI: 10.1371/journal.pone.0261310] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/30/2021] [Indexed: 01/02/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 μg/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.
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Affiliation(s)
- Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa, Japan
- * E-mail:
| | | | | | | | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Tingting Shi
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | | | - Keiichi Okano
- Department of Gastroenterological Surgery, Kagawa, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University Faculty of Medicine, Kagawa, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectual University of Health Sciences, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa, Japan
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45
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Koo BK, Lim S. Metabolic Syndrome and Metabolic Dysfunction‐Associated Fatty Liver Disease. CLINICAL OBESITY IN ADULTS AND CHILDREN 2022:159-177. [DOI: 10.1002/9781119695257.ch13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Kuchay MS, Misra A. Role of diabetologists in the management of nonalcoholic fatty liver disease: Primary prevention and screening/management of fibrosis and cirrhosis. Diabetes Metab Syndr 2022; 16:102446. [PMID: 35259705 DOI: 10.1016/j.dsx.2022.102446] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 02/24/2022] [Accepted: 02/26/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is a common condition, especially among individuals with type 2 diabetes (T2D). Presence of T2D increases the risk of progression of simple steatosis to more severe liver conditions, such as nonalcoholic steatohepatitis (NASH) and fibrosis (NASH-fibrosis). Since majority of patients with T2D are managed by diabetologists (including physicians and endocrinologists), their roles in the management of coexisting NAFLD are not well defined, partly due to lack of unambiguous guidelines. METHODS A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till January 2022, using relevant keywords (nonalcoholic fatty liver disease and diabetologist; screening of NASH; management of NASH) to extract relevant studies describing prevention and screening of NAFLD/NASH, especially in people with T2D. RESULTS Diabetologists have two main roles for the management of patients with T2D and coexisting NAFLD. The most important role is to prevent the development of NASH-fibrosis in patients with simple steatosis (primary prevention). This can be achieved by reinforcing the importance of lifestyle measures, and by early use of glucose-lowering agents with beneficial effects on the liver. The second important role of diabetologists is to screen all patients with T2D for liver fibrosis and compensated cirrhosis, and provide appropriate referral for timely management of complications (secondary prevention). CONCLUSION Diabetologists can play a central role in mitigating the epidemic of NAFLD in individuals with T2D. However, diabetologists need to be aware about their roles in NASH-fibrosis prevention and screening. Furthermore, longitudinal studies should explore the role of newer glucose-lowering drugs in the primary prevention of NASH-fibrosis in individuals with coexisting T2D and simple steatosis.
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Affiliation(s)
- Mohammad Shafi Kuchay
- Division of Endocrinology and Diabetes, Medanta The Medicity Hospital, Gurugram, 122001, Haryana, India.
| | - Anoop Misra
- Fortis CDOC Hospital for Diabetes and Allied Sciences, New Delhi, India; National Diabetes Obesity and Cholesterol Foundation (NDOC) and Diabetes Foundation, India.
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Borodavkin P, Sheridan W, Coelho C, Oštarijaš E, Zaïr ZM, Miras AD, McGowan B, le Roux CW, Vincent RP, Dimitriadis GK. Effects of glucagon-like peptide-1 receptor agonists on histopathological and secondary biomarkers of non-alcoholic steatohepatitis: A systematic review and meta-analysis. Diabetes Obes Metab 2022; 24:337-342. [PMID: 34605124 DOI: 10.1111/dom.14565] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/19/2021] [Accepted: 09/28/2021] [Indexed: 11/29/2022]
Affiliation(s)
- Petr Borodavkin
- Faculty of Life Sciences and Medicine, School of Life Course Sciences, King's College London, London, UK
| | - William Sheridan
- Faculty of Life Sciences and Medicine, School of Life Course Sciences, King's College London, London, UK
| | - Claudia Coelho
- Department of Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Eduard Oštarijaš
- Institute for Translational Medicine, University of Pecs Medical School, Pecs, Hungary
| | - Zoulikha M Zaïr
- Princess Royal University Hospital, Farnborough Common, London, UK
| | - Alexander D Miras
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Barbara McGowan
- Department of Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Carel W le Roux
- Diabetes Complication Research Centre, School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Ireland
| | - Royce P Vincent
- Faculty of Life Sciences and Medicine, School of Life Course Sciences, King's College London, London, UK
- Department of Clinical Biochemistry, King's College Hospital NHS Foundation Trust, London, UK
| | - Georgios K Dimitriadis
- Department of Endocrinology ASO/EASO COM, King's College Hospital NHS Foundation Trust, London, UK
- Obesity, Type 2 Diabetes and Immunometabolism Research Group, Department of Diabetes, Faculty of Life Sciences, School of Life Course Sciences, King's College London, London, UK
- Division of Reproductive Health, Warwick Medical School, University of Warwick, Coventry, UK
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48
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Zhao X, Liu Y, Liu J, Qin J. Therapeutic effects and mechanism of liraglutide on rats with type 2 diabetes and metabolic-associated fatty liver disease. Endocr Metab Immune Disord Drug Targets 2022; 22:963-969. [PMID: 35081898 DOI: 10.2174/1871530322666220126151141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/02/2021] [Accepted: 12/06/2021] [Indexed: 11/22/2022]
Abstract
• Background SREBP-1c/Insig/SCAP acts as a lipid de novo synthesis pathway, and its factors are highly expressed in the endoplasmic reticulum[4]. At present, this pathway has become a research hotspot in the development of metabolic-associated fatty liver disease. However, there are few studies on how various factors in this pathway change after endoplasmic reticulum stress; in particular, the role of the insulin-inducing gene-1 (Insig-1) has not been elucidated in detail. • Objective To investigate whether liraglutide has a therapeutic effect on rats with T2DM and MAFLD and to further study its possible mechanism. • Method rats in the control group and modeling group were fed with normal diet and high-sugar and high-fat diet, respectively . After one month, the mice in the modeling group were injected with 35mg/kg STZ intraperitoneally to establish the model of type 2 diabetes mellitus. T2DM and MAFLD rats were randomly divided into three groups: model group, low dose liraglutide group, and high dose liraglutide group. Fasting blood glucose ,fasting insulin, blood lipid profile, alanine aminotransferase, and aspartate aminotransferase were measured at the end of the 8th week. Paraffin sections were obtained from the same part of the liver of rats in each group and observed by electron microscope after HE staining. Western blot was used to detect the expression of endoplasmic reticulum stress index (GRP78) and negative feedback index of lipid synthesis (Insig-1) in each group. • Results of Liver tissue from the drug intervention groups caused a decrease in lipid droplet vacuoles, and the hepatocytes were arranged neatly again. While the expression of GRP78 rose, Insig-1 declined. There were differences with different doses of liraglutide; the higher the dose was, the more obvious the effect. No such changes were observed in T2DM and MAFLD rats after injection of saline. • Conclusion, we show that liraglutide may have a therapeutic effect on rats with T2DM and MAFLD by reducing endoplasmic reticulum stress in the liver and increasing the expression of Insig-1.
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Affiliation(s)
- Xuanye Zhao
- Department of Endocrinology, Shanxi Provincial People\'s Hospital, No. 29 Shuangtasi Street, Taiyuan 030012, Shanxi Province, China
| | - Yaoji Liu
- Department of Endocrinology, Shanxi Provincial People\\\'s Hospital, No. 29 Shuangtasi Street, Taiyuan 030012, Shanxi Province, China
| | - Jingjin Liu
- Department of Endocrinology, Shanxi Provincial People\'s Hospital, No. 29 Shuangtasi Street, Taiyuan 030012, Shanxi Province, China
| | - Jie Qin
- Department of Endocrinology, Shanxi Provincial People\'s Hospital, No. 29 Shuangtasi Street, Taiyuan 030012, Shanxi Province, China
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Drożdż K, Nabrdalik K, Hajzler W, Kwiendacz H, Gumprecht J, Lip GYH. Metabolic-Associated Fatty Liver Disease (MAFLD), Diabetes, and Cardiovascular Disease: Associations with Fructose Metabolism and Gut Microbiota. Nutrients 2021; 14:103. [PMID: 35010976 PMCID: PMC8746577 DOI: 10.3390/nu14010103] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/23/2021] [Accepted: 12/23/2021] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition associated with type 2 diabetes (T2DM) and cardiovascular disease (CVD). Since systemic metabolic dysfunction underlies NAFLD, the current nomenclature has been revised, and the term metabolic-associated fatty liver disease (MAFLD) has been proposed. The new definition emphasizes the bidirectional relationships and increases awareness in looking for fatty liver disease among patients with T2DM and CVD or its risk factors, as well as looking for these diseases among patients with NAFLD. The most recommended treatment method of NAFLD is lifestyle changes, including dietary fructose limitation, although other treatment methods of NAFLD have recently emerged and are being studied. Given the focus on the liver-gut axis targeting, bacteria may also be a future aim of NAFLD treatment given the microbiome signatures discriminating healthy individuals from those with NAFLD. In this review article, we will provide an overview of the associations of fructose consumption, gut microbiota, diabetes, and CVD in patients with NAFLD.
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Affiliation(s)
- Karolina Drożdż
- Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (K.D.); (H.K.); (J.G.); (G.Y.H.L.)
| | - Katarzyna Nabrdalik
- Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (K.D.); (H.K.); (J.G.); (G.Y.H.L.)
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool L14 3PE, UK
| | - Weronika Hajzler
- Doctoral School, Department of Pediatric Hematology and Oncology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland;
| | - Hanna Kwiendacz
- Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (K.D.); (H.K.); (J.G.); (G.Y.H.L.)
| | - Janusz Gumprecht
- Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (K.D.); (H.K.); (J.G.); (G.Y.H.L.)
| | - Gregory Y. H. Lip
- Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (K.D.); (H.K.); (J.G.); (G.Y.H.L.)
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool L14 3PE, UK
- Department of Clinical Medicine, Aalborg University, 9100 Aalborg, Denmark
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50
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Sun T, Zhang B, Ru QJ, Chen XM, Lv BD. Tocopheryl quinone improves non-alcoholic steatohepatitis (NASH) associated dysmetabolism of glucose and lipids by upregulating the expression of glucagon-like peptide 1 (GLP-1) via restoring the balance of intestinal flora in rats. PHARMACEUTICAL BIOLOGY 2021; 59:723-731. [PMID: 34139927 PMCID: PMC8871605 DOI: 10.1080/13880209.2021.1916542] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
CONTEXT Glucagon-like peptide 1 (GLP-1) and α-tocopheryl quinone can promote the growth of intestinal flora and affect the pathogenesis of non-alcoholic steatohepatitis (NASH). OBJECTIVE This study determines the molecular mechanism of the effect of tocopheryl quinone in the treatment of high cholesterol and cholate diet (HFCC)-induced NASH. MATERIALS AND METHODS Thirty-two male Sprague Dawley (SD) rats grouped as lean control (LC), LC + tocopheryl quinone (1 mL of 3 × 106 dpm tocopheryl quinone via i.p. injection), HFCC (5.1 kcal/g of fat diet), and HFCC + tocopheryl quinone. Profiles of intestinal flora were assessed by 16S ribosomal ribonucleic acid-based analysis. Levels and activity of GLP-1, interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) in intestinal tissues were detected by immunohistochemistry (IHC), Western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS HFCC rats presented higher levels of cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL), while tocopheryl quinone reversed the effects of HFCC. HFCC dysregulated malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), Vitamin E, 12-hydroxyeicosatetraenoic acid (12-HETE), 13-hydroxyoctadecadienoic acid (13-HODE) and nuclear factor kappa B (NF-κB), and the effects of HFCC were reversed by the treatment of tocopheryl quinone. Also, GLP-1 in the HFCC group was down-regulated while the IL-6 and TNF-α activity and endotoxins were all up-regulated. HFCC significantly decreased the number and diversity of bacteria, whereas tocopheryl quinone substantially restored the balance of intestinal flora and promoted the growth of both Bacteroides and Lactobacilli in vitro. DISCUSSION AND CONCLUSIONS α-Tocopheryl quinone relieves HFCC-induced NASH via regulating oxidative stress, GLP-1 expression, intestinal flora imbalance, and the metabolism of glucose and lipids.
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Affiliation(s)
- Tao Sun
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, PR China
- Department of Hepatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Bing Zhang
- Department of Traditional Chinese Medicine, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, PR China
| | - Qing-jing Ru
- Department of Hepatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Xiao-mei Chen
- Department of Hepatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Bo-dong Lv
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, PR China
- CONTACT Bo-dong Lv The Second Clinical Medical College of Zhejiang Chinese Medicine University, No.318 Chaowang Road, Gongshu District, Hangzhou310005, PR China
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