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Yi Y, Qin S, Ding S, Fang J. Polysaccharides in the medicine and food homology to combat obesity via gut-liver axis: A review of possible mechanisms. Int J Biol Macromol 2025; 312:144044. [PMID: 40345304 DOI: 10.1016/j.ijbiomac.2025.144044] [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: 01/15/2025] [Revised: 04/13/2025] [Accepted: 05/06/2025] [Indexed: 05/11/2025]
Abstract
Polysaccharides, as macromolecular carbohydrates present in various medicine and food homology, have gained growing recognition for their potential in combating obesity through multiple mechanisms. Their natural origin and favorable safety profile have made polysaccharides from medicine and food homology (PMFH) an area of significant research interest, particularly in the context of developing effective, safe, and sustainable interventions for obesity management. This review summarized the classification and biological properties of PMFH and then elucidated the pathological characteristics of obesity. We primarily focused on the effects of PMFHs on obesity, with particular attention to the potential mechanisms mediated through the gut-liver axis. These mechanisms encompassed the improvement of fat metabolism imbalances, manager of appetite and energy balance, adjustment of intestinal microbial imbalances, and alleviation of oxidative stress and inflammation. The findings provided critical theoretical insights and data to support the development of anti-obesity dietary and pharmaceutical products. In brief, this review outlined future research directions regarding the potential mechanisms underlying the anti-obesity effects of PMFH, particularly those involving the gut-liver axis.
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Affiliation(s)
- Yuhang Yi
- College of Bioscience and Biotechnology, Hunan Agricultural University, Hunan Engineering Laboratory for Pollution Control and Waste Utilization in Swine Production, Changsha, Hunan 410128, China
| | - Si Qin
- Laboratory of Food Function and Nutrigenomics, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Sujuan Ding
- College of Bioscience and Biotechnology, Hunan Agricultural University, Hunan Engineering Laboratory for Pollution Control and Waste Utilization in Swine Production, Changsha, Hunan 410128, China.
| | - Jun Fang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Hunan Engineering Laboratory for Pollution Control and Waste Utilization in Swine Production, Changsha, Hunan 410128, China.
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Moolla A, Poolman T, Othonos N, Dong J, Smith K, Cornfield T, White S, Ray DW, Mouchti S, Mózes FE, Thomaides-Brears H, Neubauer S, Cobbold JF, Hodson L, Tomlinson JW. Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD. JHEP Rep 2025; 7:101363. [PMID: 40342635 PMCID: PMC12060445 DOI: 10.1016/j.jhepr.2025.101363] [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: 10/25/2024] [Revised: 02/06/2025] [Accepted: 02/11/2025] [Indexed: 05/11/2025] Open
Abstract
Background & Aims Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies deliver histological benefit in people with metabolic dysfunction-associated steatotic liver disease (MASLD). Multiple mechanisms may be important including weight loss, improved glycaemic control and putative direct tissue-specific actions. Following cessation of GLP1-RA therapy, weight regain is common. To dissect the mechanisms underpinning their benefits, we conducted a prospective, randomised, experimental medicine study in people with MASLD, comparing GLP-1RA treatment (liraglutide) to matched lifestyle-induced weight loss and assessed the impact of treatment withdrawal. Methods Twenty-nine participants with MASLD, without type 2 diabetes underwent metabolic phenotyping including measurement de novo lipogenesis (DNL), liver magnetic resonance imaging, body composition, adipose tissue RNA sequencing, circulating proteome, and stool microbiome analysis. Participants were randomised to lifestyle (∼500 kcal energy deficit) or GLP1-RA treatment for 12 weeks, after which investigations were repeated, and treatment stopped; investigations were also repeated 12 weeks after treatment withdrawal. Results Matched weight loss was achieved in both arms. Body composition changes, reductions in alanine aminotransferase, liver steatosis, and disease activity were similar following both treatments. GLP-1RA treatment, but not lifestyle, improved glucose handling, fasting lipids, and significantly deceased DNL. The subcutaneous adipose transcriptome, circulating proteome profile and stool microbiome were not different between groups after treatment. However, 12 weeks after GLP1-RA (but not lifestyle) withdrawal, circulating MMP-10, IL10RB, FGF-23, and Flt3L were elevated, alongside dysregulated adipose gene expression. Conclusions Although matched weight loss through lifestyle or GLP-1RA have comparable effects on hepatic steatosis, GLP-1RA treatment had additional metabolic benefits on glucose homeostasis, lipid profiles, and DNL. However, GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression, and the stool microbiome, predisposing to weight regain. Impact and implications Weight loss, through either lifestyle intervention or pharmacotherapy with GLP-1RA has an equally beneficial impact on the liver, and both strategies should be considered in the management of people with MASLD. GLP-1RA therapy may have additional benefits to improve glucose homeostasis even in the absence of pre-existing type 2 diabetes. Further research is needed to explore the differential impact of treatment withdrawal and the resultant metabolic consequences. Clinical Trials Registration This study is registered at EudraCT (2016-002045-36).
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Affiliation(s)
- Ahmad Moolla
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Toryn Poolman
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
- Structural and Molecular Biology, Faculty of Life Sciences, University College London, London, UK
| | - Nantia Othonos
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Jiawen Dong
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Kieran Smith
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Thomas Cornfield
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Sarah White
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - David W. Ray
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
- NIHR Oxford Health Biomedical Research Centre, University of Oxford, Oxford, UK
- Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
| | | | - Ferenc E. Mózes
- Oxford Centre for Clinical Magnetic Resonance Research (OCMR), John Radcliffe Hospital, University of Oxford, Oxford, UK
| | | | - Stefan Neubauer
- Oxford Centre for Clinical Magnetic Resonance Research (OCMR), John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Jeremy F. Cobbold
- Department of Gastroenterology and Hepatology, Oxford University Hospitals, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Jeremy W. Tomlinson
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
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Rashid Z, Woldesenbet S, Khalil M, Iyer S, Khan MMM, Altaf A, Munir MM, Catalano G, Mumtaz K, Pawlik TM. Impact of GLP-1RA on the Risk of Adverse Liver Outcomes Among Patients With Alcohol-Associated Liver Disease and Type 2 Diabetes. Liver Int 2025; 45:e16132. [PMID: 39403816 PMCID: PMC11892336 DOI: 10.1111/liv.16132] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/18/2024] [Accepted: 10/01/2024] [Indexed: 03/11/2025]
Abstract
BACKGROUND AND AIMS We sought to characterise the impact of GLP-1RA on adverse liver outcomes (ALO) among patients with alcohol-associated liver disease (ALD) and Type 2 diabetes mellitus (T2DM). METHODS Patients with T2DM newly diagnosed with ALD between 2013 and 2020 were identified using IBM MarketScan database and were categorised by GLP-1RA exposure. Overlap propensity score weighting (OPSW) followed by Poisson regression models was used to analyse adjusted risk of ALO, a composite endpoint defined by first occurrence of hepatic decompensation (HD), portal hypertension (PH), hepatocellular carcinoma (HCC) or liver transplantation (LT) relative to GLP-1RA. RESULTS Among 14 730 patients, most individuals were male (n = 9752, 66.2%) with median age of 57 (IQR 52-61) years; 2.2% (n = 317) of patients had GLP-1RA exposure. Overall, 32.0% (n = 4717) of patients experienced HD, 15.9% (n = 2345) had PH, 3.8% (n = 563) developed HCC, while 2.5% (n = 374) underwent transplantation. Non-GLP-1RA patients had higher incidence of HD (32.2% vs. 22.4%) and HCC (3.9% vs. 0.3%) versus patients taking GLP-1RA (both p < 0.001); in contrast, there was no difference in incidence of PH (14.5% vs. 16.0%) and LT (1.3% vs. 2.6%) (both p > 0.05). After OPSW, overall incidence of ALO was lower in GLP-1RA cohort (GLP-1RA: 12.0%, 95%CI 9.0-16.0 vs. non-GLP-1RA: 21.0%, 95%CI 20.0-22.0) with an absolute incidence risk reduction of 9.0% (95%CI 3.0%-15.0%) associated with GLP-1RA. GLP-1RA was most strongly associated with lower likelihood of HD with reduced adjusted incidence rate of 0.56 (95%CI 0.36-0.86) relative to non-GLP-1RA individuals. CONCLUSIONS GLP-1RA may have a hepatoprotective impact among patients with ALD and T2DM.
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Affiliation(s)
- Zayed Rashid
- Department of SurgeryThe Ohio State University Wexner Medical Center and James Comprehensive Cancer CenterColumbusOhioUSA
| | - Selamawit Woldesenbet
- Department of SurgeryThe Ohio State University Wexner Medical Center and James Comprehensive Cancer CenterColumbusOhioUSA
| | - Mujtaba Khalil
- Department of SurgeryThe Ohio State University Wexner Medical Center and James Comprehensive Cancer CenterColumbusOhioUSA
| | - Sidharth Iyer
- Department of SurgeryThe Ohio State University Wexner Medical Center and James Comprehensive Cancer CenterColumbusOhioUSA
| | - Muhammad Muntazir Mehdi Khan
- Department of SurgeryThe Ohio State University Wexner Medical Center and James Comprehensive Cancer CenterColumbusOhioUSA
| | - Abdullah Altaf
- Department of SurgeryThe Ohio State University Wexner Medical Center and James Comprehensive Cancer CenterColumbusOhioUSA
| | - Muhammad Musaab Munir
- Department of SurgeryThe Ohio State University Wexner Medical Center and James Comprehensive Cancer CenterColumbusOhioUSA
| | - Giovanni Catalano
- Department of SurgeryThe Ohio State University Wexner Medical Center and James Comprehensive Cancer CenterColumbusOhioUSA
| | - Khalid Mumtaz
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal MedicineCollege of Medicine, The Ohio State UniversityColumbusOhioUSA
| | - Timothy M. Pawlik
- Department of SurgeryThe Ohio State University Wexner Medical Center and James Comprehensive Cancer CenterColumbusOhioUSA
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Mahapatro A, Bozorgi A, Obulareddy SU, Jain SM, Reddy Korsapati R, Kumar A, Patel K, Soltani Moghadam S, Arya A, Jameel Alotaibi A, Keivanlou MH, Hassanipour S, Hasanpour M, Amini-Salehi E. Glucagon-like peptide-1 agonists in cardiovascular diseases: a bibliometric analysis from inception to 2023. Ann Med Surg (Lond) 2024; 86:6602-6618. [PMID: 39525800 PMCID: PMC11543192 DOI: 10.1097/ms9.0000000000002592] [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: 04/13/2024] [Accepted: 09/15/2024] [Indexed: 11/16/2024] Open
Abstract
Background In recent years, glucagon-like peptide-1 (GLP-1) agonists have garnered increasing attention for their potential cardiovascular benefits beyond glycemic control in patients with diabetes. Understanding the research landscape surrounding GLP-1 agonists and cardiovascular diseases (CVDs) is crucial for informing clinical practice and guiding future research endeavors. This bibliometric analysis aimed to comprehensively assess the scholarly output and trends in this field, shedding light on the evolving landscape of GLP-1 agonists' role in cardiovascular health. Methods The publications concerning GLP-1 agonists in CVDs were gathered from the Web of Science Core Collection, and visualizations were created utilizing Excel 2019, Cite Space, and VOS viewer software. Results and Conclusion Using bibliometric and visual methods, the research hotspots and trends regarding GLP-1 agonists in cardiovascular diseases were pinpointed. Additionally, a thriving interest in GLP-1 agonists research within cardiovascular medicine was observed, with a notable surge in publications from 2016 onwards. The analysis revealed that the United States and China are the leading contributors, accounting for over 50% of the total publications. The University of Copenhagen and the University of Toronto emerged as the most prolific institutions in this field. Co-citation analysis highlighted the influential role of landmark clinical trials, such as the LEADER, ELIXA, and EXSCEL. Keyword trend analysis identified the emergence of newer GLP-1 agonists, such as tirzepatide and semaglutide, as well as a growing focus on topics like 'healthy obesity' and chronic kidney disease. These findings suggest that the research landscape is evolving, with a focus on expanding the therapeutic applications of GLP-1 agonists beyond glycemic control. Overall, this bibliometric analysis provided insights into the current state and future directions of research on GLP-1 agonists and their impact on cardiovascular health, guiding future research endeavors, and informing clinical practice.
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Affiliation(s)
| | - Ali Bozorgi
- Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Shika M. Jain
- MVJ Medical College and Research Hospital, Bengaluru, India
| | | | | | - Kristina Patel
- Shenyang North New Area, Shenyang, Liaoning Province, People’s Republic of China
| | - Saman Soltani Moghadam
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Arash Arya
- Department of Internal Medicine III, Halle University Hospital, Halle (Saale), Germany
| | | | | | - Soheil Hassanipour
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Maryam Hasanpour
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Ehsan Amini-Salehi
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
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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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Abdeldayem FA, Lestingi A, Abol-Ela SS, Alagawany M, Ismail TA, Mostafa NG, El-Shall NA. Application of butyric acid as a feed additive for improving quail performance and health. Poult Sci 2024; 103:104109. [PMID: 39111236 PMCID: PMC11350500 DOI: 10.1016/j.psj.2024.104109] [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] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 07/10/2024] [Accepted: 07/13/2024] [Indexed: 09/22/2024] Open
Abstract
This study evaluated the effects of dietary butyric acid (BA) on the Japanese quail' performance, immunology, lipid profile, cecal microbiota, and antioxidant levels. 250 unsexed, one-week-old quail chicks were divided into 5 groups, each with fifty chicks (5 replicates of 10 chicks). The first group was given the basal diet (BD), while the 2nd to 5th groups were fed BD with 50, 100, 150, and 200 mg BA/kg, respectively. The results indicated that BA improved weight gain and FCR (p < 0.05) and decreased total FI. The 200 mg BA/kg of diet showed the lowest FI (p < 0.05) and the best FCR (p > 0.05). BA boosted immunity through increasing IgA, IgM, IgG, and Complement 3. Significantly lower alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were observed at 150 and 200 mg BA/kg (P < 0.05) than the control group. The BA-supplemented quail showed lower total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) than the control one. This effect was more pronounced for 100 and 200 mg of BA/kg. However, high low-density lipoprotein (HDL) did not differ from the control group (p > 0.05). BA at ≥100 mg/kg diet reduced malondialdehyde (MDA) and induced greater levels of superoxide dismutase (SOD), total antioxidant capacity (TAC), glutathione peroxidase (GPX), globulin, total protein, digestive enzymes than the control group (P < 0.05). BA decreased cecal E. coli, Salmonella, Enterococcus, and Coliforms and increased Lactic acid bacteria (p < 0.05) compared to non-supplemented group. Collectively, the inclusion of 100 mg BA/kg diet is ideal for Japanese quail production and health.
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Affiliation(s)
- Fayza A Abdeldayem
- Poultry Department, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt
| | - Antonia Lestingi
- Department of Veterinary Medicine, University of Bari Aldo Moro, Valenzano, Bari 70010, Italy
| | - Salah S Abol-Ela
- Poultry Department, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt
| | - Mahmoud Alagawany
- Poultry Department, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt.
| | - Tamer Ahmed Ismail
- Department of Clinical Laboratory Sciences, Turabah University College, Taif University, Taif 21944, Saudi Arabia
| | - Nadeen G Mostafa
- Department of Agricultural Microbiology, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt
| | - Nahed A El-Shall
- Department of Poultry and Fish Diseases, Faculty of Veterinary Medicine, Alexandria University, Alexandria, 21944, Egypt
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Abushamat LA, Shah PA, Eckel RH, Harrison SA, Barb D. The Emerging Role of Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis. Clin Gastroenterol Hepatol 2024; 22:1565-1574. [PMID: 38367743 DOI: 10.1016/j.cgh.2024.01.032] [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: 09/25/2023] [Revised: 01/10/2024] [Accepted: 01/16/2024] [Indexed: 02/19/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 1 in 3-4 adult individuals and can progress to metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Insulin resistance plays a central role in MASLD/MASH pathophysiology with higher rates of MASLD (2 in 3) and MASH with fibrosis (1 in 5) in adults with obesity and diabetes. This review summarizes the role of glucagon-like peptide-1 receptor agonists in treating MASLD/MASH. Although not approved by the Food and Drug Administration for the treatment of MASLD, this class of medication is available to treat obesity and type 2 diabetes and has been shown to reverse steatohepatitis, reduce cardiovascular risk, and is safe to use across the spectrum of MASLD with or without fibrosis.
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Affiliation(s)
- Layla A Abushamat
- Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Pir Ahmad Shah
- Gastroenterology and Hepatology, Creighton University, Phoenix, Arizona
| | - Robert H Eckel
- Division of Endocrinology, Metabolism & Diabetes, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | | | - Diana Barb
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida.
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Dave BP, Chorawala MR, Shah IV, Shah NN, Bhagat SU, Prajapati BG, Thakkar PC. From diabetes to diverse domains: the multifaceted roles of GLP-1 receptor agonists. Mol Biol Rep 2024; 51:835. [PMID: 39042283 DOI: 10.1007/s11033-024-09793-y] [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: 04/14/2024] [Accepted: 07/09/2024] [Indexed: 07/24/2024]
Abstract
Glucagon-like Peptide-1 (GLP-1) receptor agonists (GLP-1RAs) emerged as a primary treatment for type-2 diabetes mellitus (T2DM), however, their multifaceted effects on various target organs beyond glycemic control opened a new era of treatment. We conducted a comprehensive literature search using databases including Scopus, Google Scholar, PubMed, and the Cochrane Library to identify clinical, in-vivo, and in-vitro studies focusing on the diverse effects of GLP-1 receptor agonists. Eligible studies were selected based on their relevance to the varied roles of GLP-1RAs in T2DM management and their impact on other physiological functions. Numerous studies have reported the efficacy of GLP-1RAs in improving outcomes in T2DM, with demonstrated benefits including glucose-dependent insulinotropic actions, modulation of insulin signaling pathways, and reductions in glycemic excursions. Additionally, GLP-1 receptors are expressed in various tissues and organs, suggesting their widespread physiological functions beyond glycemic control potentially include neuroprotective, anti-inflammatory, cardioprotective, and metabolic benefits. However, further scientific studies are still underway to maximize the benefits of GLP-1RAs and to discover additional roles in improving health benefits. This article sought to review not only the actions of GLP1RAs in the treatment of T2DM but also explore its effects on potential targets in other disorders.
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Affiliation(s)
- Bhavarth P Dave
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, Gujarat, 380009, India
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, Gujarat, 380009, India
| | - Ishika V Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, Gujarat, 380009, India
| | - Nidhi N Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, Gujarat, 380009, India
| | - Shivam U Bhagat
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, Gujarat, 380009, India
| | - Bhupendra G Prajapati
- Department of Pharmaceutics and Pharmaceutical Technology, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Mehsana, Gujarat, India.
- Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand.
| | - Pratik C Thakkar
- Department of Physiology, Faculty of Medical & Health Sciences, Manaaki Mānawa - The Centre for Heart Research, University of Auckland, 85 Park Road, Auckland, 1142, New Zealand.
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Das S, Ravi H, Babu A, Banerjee M, Kanagavalli R, Dhanasekaran S, Devi Rajeswari V, Venkatraman G, Ramanathan G. Therapeutic potentials of glucose-dependent insulinotropic polypeptide (GIP) in T2DM: Past, present, and future. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 142:293-328. [PMID: 39059989 DOI: 10.1016/bs.apcsb.2023.12.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a worldwide health problem that has raised major concerns to the public health community. This chronic condition typically results from the cell's inability to respond to normal insulin levels. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the primary incretin hormones secreted from the intestinal tract. While clinical research has extensively explored the therapeutic potential of GLP-1R in addressing various T2DM-related abnormalities, the possibility of GIPR playing an important role in T2DM treatment is still under investigation. Evidence suggests that GIP is involved in the pathophysiology of T2DM. This chapter focuses on examining the role of GIP as a therapeutic molecule in combating T2DM, comparing the past, present, and future scenarios. Our goal is to delve into how GIP may impact pancreatic β-cell function, adipose tissue uptake, and lipid metabolism. Furthermore, we will elucidate the mechanistic functions of GIP and its receptors in relation to other clinical conditions like cardiovascular diseases, non-alcoholic fatty liver diseases, neurodegenerative diseases, and renal disorders. Additionally, this chapter will shed light on the latest advancements in pharmacological management for T2DM, highlighting potential structural modifications of GIP and the repurposing of drugs, while also addressing the challenges involved in bringing GIP-based treatments into clinical practice.
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Affiliation(s)
- Soumik Das
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Harini Ravi
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Achsha Babu
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Manosi Banerjee
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - R Kanagavalli
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Sivaraman Dhanasekaran
- School of Energy Technology, Pandit Deendayal Energy University, Knowledge Corridor, Gandhinagar, Gujarat, India
| | - V Devi Rajeswari
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Ganesh Venkatraman
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Gnanasambandan Ramanathan
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
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10
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Saleem M, Mazhar Fareed M, Salman Akbar Saani M, Shityakov S. Network pharmacology and multitarget analysis of Nigella sativa in the management of diabetes and obesity: a computational study. J Biomol Struct Dyn 2024; 42:4800-4816. [PMID: 37350443 DOI: 10.1080/07391102.2023.2222837] [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: 02/02/2023] [Accepted: 06/02/2023] [Indexed: 06/24/2023]
Abstract
Obesity and diabetes are commonly associated with one another and represent a significant global health issue, with a recent surge in disease incidence. Nigella sativa, also known as black cumin, is believed to possess several health benefits, including anti-diabetic, anticancer, antioxidant, antimicrobial, and anti-obesity properties. In this study, we aimed to identify the active compounds derived from N. sativa, which can potentially inhibit key protein targets and signaling pathways associated with diabesity treatment. We employed an exhaustive in silico search, which led to the identification of 22 potential compounds. Out of these, only five hits were found to be non-toxic, including Arabic and ascorbic acids, dihydrocodeine, catechin, and kaempferol. Our analysis revealed that these hits were associated with genes such as AKT1, IL6, SRC, and EGFR. Finally, we conducted molecular docking and molecular dynamics simulations, which identified kaempferol as the best binder for AKT1 in comparison to the reference molecule. Overall, our in silico integrated pipeline provides a useful approach to identify non-toxic phytocompounds as promising drug candidates to treat diabetes and obesity.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Muntaha Saleem
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Muhammad Mazhar Fareed
- Department of Computer Science, School of Science and Engineering, Università degli studi di Verona, Verona, Italy
- Department of Biotechnology, Applied Bioinformatics Group, Università degli studi di Verona, Verona, Italy
| | | | - Sergey Shityakov
- Laboratory of Chemoinformatics, Infochemistry Scientific Center, ITMO University, Saint-Petersburg, Russian Federation
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11
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Krishnan A, Schneider CV, Hadi Y, Mukherjee D, AlShehri B, Alqahtani SA. Cardiovascular and mortality outcomes with GLP-1 receptor agonists vs other glucose-lowering drugs in individuals with NAFLD and type 2 diabetes: a large population-based matched cohort study. Diabetologia 2024; 67:483-493. [PMID: 38117293 PMCID: PMC10844347 DOI: 10.1007/s00125-023-06057-5] [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: 06/26/2023] [Accepted: 10/11/2023] [Indexed: 12/21/2023]
Abstract
AIMS/HYPOTHESIS We aimed to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1RA) in individuals with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus decreases the risk of new-onset adverse cardiovascular events (CVEs) and mortality rate compared with other glucose-lowering drugs in a real setting at a population level. METHODS We conducted a population-based propensity-matched retrospective cohort study using TriNetX. The cohort comprised patients over 20 years old who were newly treated with glucose-lowering drugs between 1 January 2013 and 31 December 2021, and followed until 30 September 2022. New users of GLP-1RAs were matched based on age, demographics, comorbidities and medication use by using 1:1 propensity matching with other glucose-lowering drugs. The primary outcome was the new onset of adverse CVEs, including heart failure, composite incidence of major adverse cardiovascular events (MACE; defined as unstable angina, myocardial infarction, or coronary artery procedures or surgeries) and composite cerebrovascular events (defined as the first occurrence of stroke, transient ischaemic attack, cerebral infarction, carotid intervention or surgery), and the secondary outcome was all-cause mortality. Cox proportional hazards models were used to estimate HRs. RESULTS The study involved 2,835,398 patients with both NAFLD and type 2 diabetes. When compared with the sodium-glucose cotransporter 2 (SGLT2) inhibitors group, the GLP-1RAs group showed no evidence of a difference in terms of new-onset heart failure (HR 0.97; 95% CI 0.93, 1.01), MACE (HR 0.95; 95% CI 0.90, 1.01) and cerebrovascular events (HR 0.99; 95% CI 0.94, 1.03). Furthermore, the two groups had no evidence of a difference in mortality rate (HR 1.06; 95% CI 0.97, 1.15). Similar results were observed across sensitivity analyses. Compared with other second- or third-line glucose-lowering medications, the GLP-1RAs demonstrated a lower rate of adverse CVEs, including heart failure (HR 0.88; 95% CI 0.85, 0.92), MACE (HR 0.89; 95% CI 0.85, 0.94), cerebrovascular events (HR 0.93; 95% CI 0.89, 0.96) and all-cause mortality rate (HR 0.70; 95% CI 0.66, 0.75). CONCLUSIONS/INTERPRETATION In individuals with NAFLD and type 2 diabetes, GLP-1RAs are associated with lower incidences of adverse CVEs and all-cause mortality compared with metformin or other second- and third-line glucose-lowering medications. However, there was no significant difference in adverse CVEs or all-cause mortality when compared with those taking SGLT2 inhibitors.
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Affiliation(s)
- Arunkumar Krishnan
- Department of Supportive Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Medicine, Section of Gastroenterology and Hepatology, West Virginia University School of Medicine, Morgantown, WV, USA.
| | - Carolin V Schneider
- Department of Medicine III, Gastroenterology, Metabolic Diseases, and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Yousaf Hadi
- Department of Medicine, Section of Gastroenterology and Hepatology, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Diptasree Mukherjee
- Department of Medicine, Apex Institute of Medical Science, Kolkata, West Bengal, India
| | - Bandar AlShehri
- Diabetes and Endocrinology, Faculty of Medicine, University of Jeddah, Jeddah, Saudi Arabia
| | - Saleh A Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Liver Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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12
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Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) in the United States is 38%, having increased by 50% within the past 3 decades. The estimated NAFLD prevalence among people with type 2 diabetes is 55-70%. The presence of type 2 diabetes is associated with a higher likelihood of progression of NAFLD to fibrosis development, liver transplant, and death. Cardiovascular disease is the main cause of mortality among people with NAFLD, and the risk of death is significantly higher in people with both NAFLD and type 2 diabetes. NAFLD carries high patient and economic burdens but low awareness among both the general public and health care providers. This article reviews the epidemiology of NAFLD and discusses the need for appropriate risk stratification, referral for specialty care, management of cardiometabolic risk factors, and treatment of the disease. The authors present a call to action to raise awareness of NAFLD and address its increasing burden in a systematic and efficient manner.
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Affiliation(s)
- Zobair M. Younossi
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA; The Global NASH Council, Washington, DC, and the Center for Outcomes Research in Liver Diseases, Washington, DC
| | - Linda Henry
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA; The Global NASH Council, Washington, DC, and the Center for Outcomes Research in Liver Diseases, Washington, DC
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13
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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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14
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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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Wibawa IDN, Mariadi IK, Somayana G, Krisnawardani Kumbara CIY, Sindhughosa DA. Diabetes and fatty liver: Involvement of incretin and its benefit for fatty liver management. World J Diabetes 2023; 14:549-559. [PMID: 37273247 PMCID: PMC10237000 DOI: 10.4239/wjd.v14.i5.549] [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: 12/03/2022] [Revised: 02/02/2023] [Accepted: 04/11/2023] [Indexed: 05/15/2023] Open
Abstract
Fatty liver disease is defined as liver condition characterized by hepatic steatosis, closely related to pathological conditions in type 2 diabetes and obesity. The high prevalence of fatty liver disease in obese patients with type 2 diabetes reached 70%, reflecting the importance of these conditions with fatty liver. Although the exact pathological mechanism of fatty liver disease, specifically non-alcoholic fatty liver disease (NAFLD) remains not completely revealed, insulin resistance is suggested as the major mechanism that bridged the development of NAFLD. Indeed, loss of the incretin effect leads to insulin resistance. Since incretin is closely related to insulin resistance and the resistance of insulin associated with the development of fatty liver disease, this pathway suggested a potential me-chanism that explains the association between type 2 diabetes and NAFLD. Furthermore, recent studies indicated that NAFLD is associated with impaired glucagon-like peptide-1, resulting in decreased incretin effect. Nevertheless, improving the incretin effect becomes a reasonable approach to manage fatty liver disease. This review elucidates the involvement of incretin in fatty liver disease and recent studies of incretin as the management for fatty liver disease.
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Affiliation(s)
- I Dewa Nyoman Wibawa
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | - I Ketut Mariadi
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | - Gde Somayana
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | | | - Dwijo Anargha Sindhughosa
- Internal Medicine Resident, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
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16
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Cazac GD, Lăcătușu CM, Ștefănescu G, Mihai C, Grigorescu ED, Onofriescu A, Mihai BM. Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease-Current Background, Hopes, and Perspectives. Metabolites 2023; 13:metabo13050581. [PMID: 37233622 DOI: 10.3390/metabo13050581] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/27/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease worldwide, reaching one of the highest prevalences in patients with type 2 diabetes mellitus (T2DM). For now, no specific pharmacologic therapies are approved to prevent or treat NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are currently evaluated as potential candidates for NAFLD treatment in patients with T2DM. Some representatives of this class of antihyperglycemic agents emerged as potentially beneficial in patients with NAFLD after several research studies suggested they reduce hepatic steatosis, ameliorate lesions of nonalcoholic steatohepatitis (NASH), or delay the progression of fibrosis in this population. The aim of this review is to summarize the body of evidence supporting the effectiveness of GLP-1RA therapy in the management of T2DM complicated with NAFLD, describing the studies that evaluated the effects of these glucose-lowering agents in fatty liver disease and fibrosis, their possible mechanistic justification, current evidence-based recommendations, and the next steps to be developed in the field of pharmacological innovation.
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Affiliation(s)
- Georgiana-Diana Cazac
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Cristina-Mihaela Lăcătușu
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Gabriela Ștefănescu
- Unit of Medical Semiology and Gastroenterology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Cătălina Mihai
- Unit of Medical Semiology and Gastroenterology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Elena-Daniela Grigorescu
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Alina Onofriescu
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Bogdan-Mircea Mihai
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
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17
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Tsamos G, Vasdeki D, Koufakis T, Michou V, Makedou K, Tzimagiorgis G. Therapeutic Potentials of Reducing Liver Fat in Non-Alcoholic Fatty Liver Disease: Close Association with Type 2 Diabetes. Metabolites 2023; 13:metabo13040517. [PMID: 37110175 PMCID: PMC10141666 DOI: 10.3390/metabo13040517] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/21/2023] [Accepted: 03/29/2023] [Indexed: 04/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most widespread chronic liver disease worldwide, confers a significant burden on health systems and leads to increased mortality and morbidity through several extrahepatic complications. NAFLD comprises a broad spectrum of liver-related disorders, including steatosis, cirrhosis, and hepatocellular carcinoma. It affects almost 30% of adults in the general population and up to 70% of people with type 2 diabetes (T2DM), sharing common pathogenetic pathways with the latter. In addition, NAFLD is closely related to obesity, which acts in synergy with other predisposing conditions, including alcohol consumption, provoking progressive and insidious liver damage. Among the most potent risk factors for accelerating the progression of NAFLD to fibrosis or cirrhosis, diabetes stands out. Despite the rapid rise in NAFLD rates, identifying the optimal treatment remains a challenge. Interestingly, NAFLD amelioration or remission appears to be associated with a lower risk of T2DM, indicating that liver-centric therapies could reduce the risk of developing T2DM and vice versa. Consequently, assessing NAFLD requires a multidisciplinary approach to identify and manage this multisystemic clinical entity early. With the continuously emerging new evidence, innovative therapeutic strategies are being developed for the treatment of NAFLD, prioritizing a combination of lifestyle changes and glucose-lowering medications. Based on recent evidence, this review scrutinizes all practical and sustainable interventions to achieve a resolution of NAFLD through a multimodal approach.
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Affiliation(s)
- Georgios Tsamos
- Division of Gastroenterology, Norfolk and Norwich University Hospital, Norwich NR4 7UY, UK
| | - Dimitra Vasdeki
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Vassiliki Michou
- Sports Medicine Laboratory, School of Physical Education & Sport Science, Aristotle University of Thessaloniki, 57001 Thessaloniki, Greece
| | - Kali Makedou
- Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Georgios Tzimagiorgis
- Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
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Ji J, Wu L, Wei J, Wu J, Guo C. The Gut Microbiome and Ferroptosis in MAFLD. J Clin Transl Hepatol 2023; 11:174-187. [PMID: 36406312 PMCID: PMC9647110 DOI: 10.14218/jcth.2022.00136] [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: 03/21/2022] [Revised: 05/22/2022] [Accepted: 06/12/2022] [Indexed: 12/04/2022] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and is proposed to replace the previous name, nonalcoholic fatty liver disease (NAFLD). Globally, MAFLD/NAFLD is the most common liver disease, with an incidence rate ranging from 6% to 35% in adult populations. The pathogenesis of MAFLD/NAFLD is closely related to insulin resistance (IR), and the genetic susceptibility to acquired metabolic stress-associated liver injury. Similarly, the gut microbiota in MAFLD/NAFLD is being revaluated by scientists, as the gut and liver influence each other via the gut-liver axis. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis has a key role in the pathological progression of MAFLD/NAFLD, and inhibition of ferroptosis may become a novel therapeutic strategy for the treatment of NAFLD. This review focuses on the main mechanisms behind the promotion of MAFLD/NAFLD occurrence and development by the intestinal microbiota and ferroptosis. It outlines new strategies to target the intestinal microbiota and ferroptosis to facilitate future MAFLD/NAFLD therapies.
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Affiliation(s)
- Jie Ji
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liwei Wu
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jue Wei
- Department of Gastroenterology Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Correspondence to: Chuanyong Guo, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, NO. 301, Middle Yanchang Road, Jing’an District, Shanghai 200072, China. ORCID: https://orcid.org/0000-0002-6527-4673. E-mail: ; Jianye Wu: Department of Gastroenterology, Putuo People’s Hospital, NO. 1291, Jiangning road, Putuo, Shanghai 200060, China. ORCID: https://orcid.org/0000-0003-2675-4241. E-mail:
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Correspondence to: Chuanyong Guo, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, NO. 301, Middle Yanchang Road, Jing’an District, Shanghai 200072, China. ORCID: https://orcid.org/0000-0002-6527-4673. E-mail: ; Jianye Wu: Department of Gastroenterology, Putuo People’s Hospital, NO. 1291, Jiangning road, Putuo, Shanghai 200060, China. ORCID: https://orcid.org/0000-0003-2675-4241. E-mail:
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19
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Zhao Y, Zhao W, Bu H, Toshiyoshi M, Zhao Y. Liraglutide on type 2 diabetes mellitus with nonalcoholic fatty liver disease: A systematic review and meta-analysis of 16 RCTs. Medicine (Baltimore) 2023; 102:e32892. [PMID: 36820578 PMCID: PMC9907937 DOI: 10.1097/md.0000000000032892] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity of type 2 diabetes mellitus (T2DM). Our aim is to investigate the effects of liraglutide on T2DM with NAFLD. METHODS Relevant articles published from the earliest publication to March 2022 were selected from several databases. The Cochrane Collaboration's RevMan software was used for the analysis. RESULTS Sixteen studies are selected for this meta-analysis, which includes totally 634 patients in the treatment group and 630 patients in the control group. As a result, 14 studies show that fasting plasma glucose levels of the experimental group are lower than that of the control group; 15 studies show that glycosylated hemoglobin A1c levels of the experimental group are lower than that of the control group; 13 studies show that triglyceride levels of the experimental group are lower than that of the control group; twelve studies show that total cholesterol levels of the experimental group are lower than that of the control group; 10 studies show that alanine aminotransferase levels of the experimental group is lower than that of the control group; 10 studies show that no significant difference in changes in aspartate transaminase between 2 groups; 13 studies show that low density lipoprotein cholesterol levels of the experimental group is lower than that of the control group; 9 studies show that no significant difference in changes in high density lipoprotein cholesterol between 2 groups; 7 studies mentioned adverse effects and the difference is significant. CONCLUSION Liraglutide is potentially curative for T2DM with NAFLD.
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Affiliation(s)
- Yan Zhao
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenli Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
- Liver Center, Saga University Hospital, Saga University, Saga, Japan
| | - Huaien Bu
- School of Health Science and Engineering, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Maeda Toshiyoshi
- International Education College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ye Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
- * Correspondence: Ye Zhao, Department of Public Health, International College, Krirk University, Bangkok 10220, Thailand (e-mail: )
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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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Wernicke C, Pohrt A, Pletsch-Borba L, Apostolopoulou K, Hornemann S, Meyer N, Machann J, Gerbracht C, Tacke F, Pfeiffer AF, Spranger J, Mai K. Effect of unsaturated fat and protein intake on liver fat in people at risk of unhealthy aging: 1-year results of a randomized controlled trial. Am J Clin Nutr 2023; 117:785-793. [PMID: 36804020 DOI: 10.1016/j.ajcnut.2023.01.010] [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: 07/25/2022] [Revised: 01/08/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Short-term trials indicate improvement of intrahepatic lipids (IHLs) and metabolism by dietary protein or unsaturated fatty acids (UFAs) beyond weight loss. OBJECTIVES We aimed to assess the effect of a dietary intervention high in protein and UFAs on IHLs and metabolic outcome after 12 mo, as long-term effects of such a combined intervention are unknown. METHODS Within a 36-mo randomized controlled trial, eligible subjects (aged 50 to 80 y, ≥1 risk factor for unhealthy aging) were randomly assigned to either intervention group (IG) with high intake of mono-/poly-UFAs [15-20 percent of total energy (%E)/10%-15%E, respectively], plant protein (15%-25%E), and fiber (≥30 g/d), or control group [CG, usual care, dietary recommendations of the German Nutrition Society (fat 30%E/carbohydrates 55%E/protein 15%E)]. Stratification criteria were sex, known cardiovascular disease, heart failure, arterial hypertension, type 2 diabetes, and cognitive or physical impairment. Nutritional counseling and supplementation of foods mirroring the intended dietary pattern were performed in the IG. Diet-induced effects on IHLs, analyzed by magnetic resonance spectroscopy, as well as on lipid and glucose metabolism were predefined secondary endpoints. RESULTS IHL content was analyzed in 346 subjects without significant alcohol consumption at baseline and in 258 subjects after 12 mo. Adjusted for weight loss, sex, and age, we observed a comparable decline of IHLs in IG and CG (-33.3%; 95% CI: -49.3, -12.3%; n = 128 compared with -21.8%; 95% CI: -39.7, 1.5%; n = 130; P = 0.179), an effect that became significant by comparing adherent IG subjects to adherent CG subjects (-42.1%; 95% CI: -58.1, -20.1%; n = 88 compared with -22.2%; 95% CI: -40.7, 2.0%; n = 121; P = 0.013). Compared with the CG, decline of LDL cholesterol (LDL-C) and total cholesterol (TC) was stronger in the IG (for LDL-C P = 0.019, for TC P = 0.010). Both groups decreased in triglycerides and insulin resistance (P for difference between groups P = 0.799 and P = 0.124, respectively). CONCLUSIONS Diets enriched with protein and UFAs have beneficial long-term effects on liver fat and lipid metabolism in adherent older subjects. This study was registered at the German Clinical Trials Register, https://www.drks.de/drks_web/setLocale_EN.do, DRKS00010049. Am J Clin Nutr 20XX;xx:xx-xx.
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Affiliation(s)
- Charlotte Wernicke
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany
| | - Anne Pohrt
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Germany
| | - Laura Pletsch-Borba
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany
| | - Konstantina Apostolopoulou
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany
| | - Silke Hornemann
- NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, München-Neuherberg, Germany
| | - Nina Meyer
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany
| | - Jürgen Machann
- German Center for Diabetes Research, München-Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Germany
| | - Christiana Gerbracht
- NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hepatology and Gastroenterology, 10117 Berlin, Germany
| | - Andreas Fh Pfeiffer
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, München-Neuherberg, Germany
| | - Joachim Spranger
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
| | - Knut Mai
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
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Yazıcı D, Yapıcı Eser H, Kıyıcı S, Sancak S, Sezer H, Uygur M, Yumuk V. Clinical Impact of Glucagon-Like Peptide-1 Receptor Analogs on the Complications of Obesity. Obes Facts 2023; 16:149-163. [PMID: 36349778 PMCID: PMC10028372 DOI: 10.1159/000526808] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 08/04/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Obesity is a chronic disease associated with increased morbidity and mortality due to its complications. The aims of obesity treatment are primarily to accomplish weight loss, and prevention or treatment of its complications. Lifestyle changes along with behavioral therapy constitute the first-line treatment of obesity followed by pharmacotherapy. Glucagon-like peptide receptor analogs (GLP-1 RAs) are among the approved pharmacotherapy options. Their central effect on suppressing appetite results in considerable weight loss. However, their effect on the complications of obesity has not been very well recognized. This review aims to analyze the effects of GLP-1 RAs on the complications of obesity, as diabetes mellitus, hypertension, nonalcoholic steatohepatitis (NASH), cardiovascular diseases, polycystic ovary syndrome, infertility, obstructive sleep apnea (OSA), osteoarthritis, cancer and central nervous system problems. SUMMARY Data from preclinical studies and clinical trials have been thoroughly evaluated. Effects regarding the complications as far as the scope of this review have covered can be summarized as blood glucose lowering, blood pressure lowering, resolution of NASH, improving major cardiovascular events, improving fertility and sex hormone levels, and improvement in OSA symptoms and in cognitive scores. Although the mechanisms are not fully elucidated, it is clear that the effects are not solely due to weight loss, but some pleiotropic effects like decreased inflammation, oxidative stress, and fibrosis also play a role in some of the complications. KEY MESSAGES Treating obesity is not only enabling weight loss but ameliorating complications related to obesity. Thus, any antiobesity medication has to have some favorable effects on the complications. As far as the GLP-RA's analogs are concerned, there seems to be an improvement in many of the complications regardless of the weight loss effect of these medications.
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Affiliation(s)
- Dilek Yazıcı
- Koç University Medical School Section of Endocrinology and Metabolism, Istanbul, Turkey
- *Dilek Yazıcı,
| | - Hale Yapıcı Eser
- Koç University Medical School Department of Psychiatry, Istanbul, Turkey
| | - Sinem Kıyıcı
- Health Sciences University Bursa Yİ Education and Research Hospital, Bursa, Turkey
| | - Seda Sancak
- Health Sciences University Fatih Sultan Mehmet Education and Research Hospital, Istanbul, Turkey
| | - Havva Sezer
- Koç University Medical School Section of Endocrinology and Metabolism, Istanbul, Turkey
| | - Melin Uygur
- Marmara University Medical School, Section of Endocrinology and Metabolism, Istanbul, Turkey
| | - Volkan Yumuk
- Cerrahpaşa U. Medical School Section of Endocrinology and Metabolism, Istanbul, Turkey
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Nguyen IT, Joles JA, Verhaar MC, Lamb HJ, Dekkers IA. Obesity in relation to cardiorenal function. VISCERAL AND ECTOPIC FAT 2023:243-264. [DOI: 10.1016/b978-0-12-822186-0.00006-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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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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Chen X, Chen C, Fu X. Hypoglycemic activity in vitro and vivo of a water-soluble polysaccharide from Astragalus membranaceus. Food Funct 2022; 13:11210-11222. [PMID: 36222262 DOI: 10.1039/d2fo02298b] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The polysaccharide AMP as one main bioactive component of Astragalus membranaceus (Fisch.) Bunge was separated and characterized. The results showed that AMP was a typical acidic heteropolysaccharide dominated by glucose, galacturonic acid and arabinose with typical shear-thinning and fluid-like behavior. Scanning electron microscopy images showed that AMP existed in the state of lamellar aggregates with a smooth compact surface. In addition, AMP exhibited strong antioxidant activity with an oxygen radical absorption capacity value of 278.68 ± 9.31 μM TE per g, and excellent α-glucosidase inhibitory activity and cholate binding ability. Furthermore, in vivo, AMP treatment significantly decreased blood glucose and serum insulin levels, improved glucose intolerance and insulin resistance, regulated the blood lipid profile, alleviated oxidative stress, and relieved liver damage in type 2 diabetes mellitus (T2DM) mice. Pearson correlation analysis suggested that the mitigation of oxidative stress contributed to the hypoglycemic effect of AMP, indicating that it is a beneficial functional food ingredient for T2DM.
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Affiliation(s)
- Xiaoxia Chen
- Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, 381 Wushan Road, Guangzhou 510640, China.
| | - Chun Chen
- Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, 381 Wushan Road, Guangzhou 510640, China. .,SCUT-Zhuhai Institute of Modern Industrial Innovation, Zhuhai, 510641, China.,Guangzhou Institute of Modern Industrial Technology, Nansha, 511458, China.,Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, Guangzhou 510640, China
| | - Xiong Fu
- Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, 381 Wushan Road, Guangzhou 510640, China. .,SCUT-Zhuhai Institute of Modern Industrial Innovation, Zhuhai, 510641, China.,Guangzhou Institute of Modern Industrial Technology, Nansha, 511458, China.,Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, Guangzhou 510640, China.,Overseas Expertise Introduction Center for Discipline Innovation of Food Nutrition and Human Health (111 Center), Guangzhou 510640, China
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26
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Xiao R, Wang R, Li S, Kang X, Ren Y, Sun E, Wang C, He J, Zhan J. Preliminary Evaluation of Potential Properties of Three Probiotics and Their Combination with Prebiotics on GLP-1 Secretion and Type 2 Diabetes Alleviation. J FOOD QUALITY 2022; 2022:1-9. [DOI: 10.1155/2022/8586843] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2024] Open
Abstract
Type 2 diabetes (T2D) is a disease of global concern characterized by hyperglycemia and insulin resistance. Many studies found that glucagonlike peptide-1 (GLP-1) is an incretin hormone that can alleviate hyperglycemia and T2D. Recently, probiotics and their combination with prebiotics have been found to show great potentials of blood glucose regulation and T2D alleviation. Given the important role of GLP-1 in T2D, screening probiotics with the capacity of promoting GLP-1 secretion is of great help for providing a novel application of T2D treatment. In the current study, we evaluated the effects of three probiotics, namely, Lactobacillus paracasei LC-37 (LC-37), Bifidobacterium animals MN-Gup (MN-Gup), and Bifidobacterium longum BBMN68 (BBMN68), and their combination with prebiotics on promoting GLP-1 secretion using NCI-H716 cells. The results showed that LC-37 and MN-Gup could stimulate more GLP-1 secretion in NCI-H716 cells, but BBMN68 had no significant effect. Further evaluation suggested that the two combinations of LC-37 with isomaltooligosaccharide (IMO) and MN-Gup with galactooligosaccharide (GOS) had the best performance on promoting GLP-1 secretion in vitro. Subsequently, the effects of the two combinations on promoting GLP-1 secretion and alleviating T2D were investigated in vivo using high fat diet (HFD) and streptozotocin (STZ) treated rats. The results showed that the two combinations could significantly reduce fasting blood glucose levels, improve insulin resistance, and modulate serum lipid profiles in HFD/STZ-treated rats. These results will help understand the potential of promoting GLP-1 secretion of LC-37 and MN-Gup and provide theoretical basis for their applications in fermented milk or other foods.
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Affiliation(s)
- Ran Xiao
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
- Mengniu Hi-Tech Dairy Product Beijing Co. Ltd., Beijing 101100, China
| | - Ran Wang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
| | - Shusen Li
- Mengniu Hi-Tech Dairy Product Beijing Co. Ltd., Beijing 101100, China
| | - Xiaohong Kang
- Mengniu Hi-Tech Dairy Product Beijing Co. Ltd., Beijing 101100, China
| | - Yimei Ren
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
| | - Erna Sun
- Mengniu Hi-Tech Dairy Product Beijing Co. Ltd., Beijing 101100, China
| | - Chenyuan Wang
- Mengniu Hi-Tech Dairy Product Beijing Co. Ltd., Beijing 101100, China
| | - Jingjing He
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
| | - Jing Zhan
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
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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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Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol 2022; 10:393-406. [PMID: 35468325 DOI: 10.1016/s2213-8587(22)00070-5] [Citation(s) in RCA: 267] [Impact Index Per Article: 89.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/28/2022] [Accepted: 02/10/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 receptor agonist under development for the treatment of type 2 diabetes. The aim of this substudy was to characterise the changes in liver fat content (LFC), volume of visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT) in response to tirzepatide or insulin degludec in a subpopulation of the SURPASS-3 study. METHODS This substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial was done at 45 medical research centres and hospitals across eight countries (Argentina, Austria, Greece, Hungary, Italy, Romania, Spain, and the USA). Eligible participants were adults with type 2 diabetes, a baseline HbA1c 7·0-10·5% (53-91 mmol/mol), a BMI of at least 25 kg/m2, stable weight, were insulin-naive, and on treatment with metformin alone or in combination with a SGLT2 inhibitor for at least 3 months before screening. In addition to the main study inclusion criteria, substudy participants had a fatty liver index of at least 60. Participants had an MRI scan and were randomised (1:1:1:1) in the main study to subcutaneous injection once per week of tirzepatide 5 mg, 10 mg, or 15 mg, or subcutaneous injection once per day of titrated insulin degludec, using an interactive web-response system, and were stratified by country, HbA1c, and concomitant oral anti-hyperglycaemic medication. The primary efficacy endpoint was the change from baseline in LFC (as measured by MRI-proton density fat fraction [MRI-PDFF]) at week 52 using pooled data from the tirzepatide 10 mg and 15 mg groups versus insulin degludec. Analyses were assessed in the enrolled MRI population, which consisted of participants in the modified intention-to-treat population of the main study who also had a valid MRI at either baseline or after baseline. This is a substudy of the trial registered with ClinicalTrials.gov, number NCT03882970, and is complete. FINDINGS From April 1, 2019, to Nov 15, 2019, 502 participants were assessed for eligibility to participate in this substudy, 296 (59%) of whom were included in the enrolled MRI population and randomly assigned to treatment (tirzepatide 5 mg, n=71; tirzepatide 10 mg, n=79; tirzepatide 15 mg, n=72; and insulin degludec, n=74). Baseline demographics and clinical characteristics were similar across all treatment groups. From an overall mean baseline LFC of 15·71% (SD 8·93), the absolute reduction in LFC at week 52 was significantly greater for the pooled tirzepatide 10 mg and 15 mg groups (-8·09%, SE 0·57) versus the insulin degludec group (-3·38%, 0·83). The estimated treatment difference versus insulin degludec was -4·71% (95% CI -6·72 to -2·70; p<0·0001). The reduction in LFC was significantly correlated (p≤0·0006) with baseline LFC (ρ=-0·71), reductions in VAT (ρ=0·29), reductions in ASAT (ρ=0·33), and reductions in body weight (ρ=0·34) in the tirzepatide groups. INTERPRETATION Tirzepatide showed a significant reduction in LFC and VAT and ASAT volumes compared with insulin degludec in this subpopulation of patients with type 2 diabetes in the SURPASS-3 study. These data provide additional evidence on the metabolic effects of this novel dual GIP and GLP-1 receptor agonist. FUNDING Eli Lilly and Company.
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Affiliation(s)
- Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes, and Metabolism, The University of Florida, Gainesville, FL, USA
| | | | - Ross Bray
- Eli Lilly and Company, Indianapolis, IN, USA
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29
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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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The Coexistence of Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus. J Clin Med 2022; 11:jcm11051375. [PMID: 35268466 PMCID: PMC8910939 DOI: 10.3390/jcm11051375] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/28/2022] [Accepted: 03/01/2022] [Indexed: 12/12/2022] Open
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) is growing worldwide. Epidemiological data suggest a strong relationship between NAFLD and T2DM. This is associated with common risk factors and pathogenesis, where obesity, insulin resistance and dyslipidemia play pivotal roles. Expanding knowledge on the coexistence of NAFLD and T2DM could not only protect against liver damage and glucotoxicity, but may also theoretically prevent the subsequent occurrence of other diseases, such as cancer and cardiovascular disorders, as well as influence morbidity and mortality rates. In everyday clinical practice, underestimation of this problem is still observed. NAFLD is not looked for in T2DM patients; on the contrary, diagnosis for glucose metabolism disturbances is usually not performed in patients with NAFLD. However, simple and cost-effective methods of detection of fatty liver in T2DM patients are still needed, especially in outpatient settings. The treatment of NAFLD, especially where it coexists with T2DM, consists mainly of lifestyle modification. It is also suggested that some drugs, including hypoglycemic agents, may be used to treat NAFLD. Therefore, the aim of this review is to detail current knowledge of NAFLD and T2DM comorbidity, its prevalence, common pathogenesis, diagnostic procedures, complications and treatment, with special attention to outpatient clinics.
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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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Syzygium samarangense leaf extract exhibits distinct antidiabetic activities: Evidences from in silico and in vivo studies. ARAB J CHEM 2022. [DOI: 10.1016/j.arabjc.2022.103822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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Yen FS, Hsu CC, Wei JCC, Hou MC, Hwu CM. Selection and Warning of Evidence-Based Antidiabetic Medications for Patients With Chronic Liver Disease. Front Med (Lausanne) 2022; 9:839456. [PMID: 35252271 PMCID: PMC8888965 DOI: 10.3389/fmed.2022.839456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/26/2022] [Indexed: 11/13/2022] Open
Abstract
The global prevalence of chronic liver disease and diabetes mellitus (DM) has gradually increased potentially due to changes in diet and lifestyle. The choice of antidiabetic medications for patients with coexisting DM and chronic liver disease is complicated. Severe liver injury may decrease the metabolism of antidiabetic medications, resulting in elevated drug concentrations and adverse effects. The choice of antidiabetic medications in patients with chronic liver disease has not been well studied. The long-term outcomes of antidiabetic medications in patients with chronic liver disease have gained attention recently. Herein, we reviewed relevant articles to extend our understanding on the selection and warning of antidiabetic medications for patients with chronic liver disease.
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Affiliation(s)
| | - Chih-Cheng Hsu
- Institute of Population Health Sciences, National Health Research Institute, Miaoli, Taiwan
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
- Department of Family Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan
| | - James Cheng-Chung Wei
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Ming-Chih Hou
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chii-Min Hwu
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
- Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther 2022; 7:48. [PMID: 35165272 PMCID: PMC8844085 DOI: 10.1038/s41392-022-00904-4] [Citation(s) in RCA: 797] [Impact Index Per Article: 265.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 02/08/2023] Open
Abstract
Peptide drug development has made great progress in the last decade thanks to new production, modification, and analytic technologies. Peptides have been produced and modified using both chemical and biological methods, together with novel design and delivery strategies, which have helped to overcome the inherent drawbacks of peptides and have allowed the continued advancement of this field. A wide variety of natural and modified peptides have been obtained and studied, covering multiple therapeutic areas. This review summarizes the efforts and achievements in peptide drug discovery, production, and modification, and their current applications. We also discuss the value and challenges associated with future developments in therapeutic peptides.
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Kalra S, Mithal A, Zargar AH, Sethi B, Dharmalingam M, Ghosh S, Sen R. Indian Phenotype Characteristics Among Patients with Type 2 Diabetes Mellitus: Insights from a Non-interventional Nationwide Registry in India. Endocrinology 2022; 18:63-70. [PMID: 35949363 PMCID: PMC9354966 DOI: 10.17925/ee.2022.18.1.63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 04/04/2022] [Indexed: 11/24/2022]
Abstract
Background: Indian patients with type 2 diabetes mellitus (T2D)
constitute one-sixth of affected adults globally. Here, we evaluate the
association of body mass index (BMI) with body fat percentage (BF%) and glycated
haemoglobin (HbA1c) levels among patients with T2D in India.
Method: This was a cross-sectional Indian registry study across 845
geographically diverse zones between December 2017 and August 2019.
Results: Of 37,927 patients, 55.6% were men, with a mean
± standard deviation age of 54.2 ± 11.5 years and HbA1c of 8.3
± 1.71%. Mean ± standard deviation BMI and BF% were 27.0 ±
4.6 kg/m2 and 32.0 ± 8.0%, respectively. Overall, 15.4% of patients were
overweight, and 25.0% were obese. Despite fewer males (20.7%) having BMI-based
obesity than females (31.2%), around three-quarters of both sexes had
BF%-defined obesity (males 77.2%; females 71.2%). One-third of males (34.6%) and
41.9% of females had BF%-defined obesity despite normal BMI. The association was
substantiated by a moderately significant correlation (r=0.51) between BMI and
BF% in the overall population (p<0.0001). Conclusion: This
pan-India registry presents a real-world reflection of the Asian Indian
phenotype: high BF% despite lower BMI in people with T2D. This highlights the
importance of primordial and primary prevention, and may guide decisions on the
choice of agents for glycaemic control, with a preference for drugs that promote
weight loss or are weight neutral.
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Affiliation(s)
- Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal, India
| | - Ambrish Mithal
- Department of Endocrinology, Max Healthcare, Saket, India
| | | | - Bipin Sethi
- Department of Endocrinology, CARE Super Specialty Hospital &
Transplant Centre, Hyderabad, India
| | - Mala Dharmalingam
- Department of Endocrinology, Ramaiah Medical College, Bengaluru,
India
| | - Sujoy Ghosh
- Department of Endocrinology, Institute of Post-Graduate Medical Education
and Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata,
India
| | - Ranjini Sen
- AstraZeneca Pharma India Ltd, Bengaluru, India
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Chen X, Chen C, Fu X. Hypoglycemic effect of polysaccharide from Astragalus membranaceus on type 2 diabetic mice based on “gut microbiota-mucosal barrier”. Food Funct 2022; 13:10121-10133. [DOI: 10.1039/d2fo02300h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Astragalus membranaceus polysaccharide (APP), the main active constituent possesses numerous bioactivities. In this research, the T2DM model mice was combined with streptozotocin to study the hypoglycemic effect and mechanism of...
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Yaribeygi H, Maleki M, Butler AE, Jamialahmadi T, Sahebkar A. The Impact of Incretin-Based Medications on Lipid Metabolism. J Diabetes Res 2021; 2021:1815178. [PMID: 35005028 PMCID: PMC8731296 DOI: 10.1155/2021/1815178] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
Pathophysiological pathways that are induced by chronic hyperglycemia negatively impact lipid metabolism. Thus, diabetes is commonly accompanied by varying degrees of dyslipidemia which is itself a major risk factor for further macro- and microvascular diabetes complications such as atherosclerosis and nephropathy. Therefore, normalizing lipid metabolism is an attractive goal for therapy in patients with diabetes. Incretin-based medications are a novel group of antidiabetic agents with potent hypoglycemic effects. While the impact of incretins on glucose metabolism is clear, recent evidence indicates their positive modulatory roles on various aspects of lipid metabolism. Therefore, incretins may offer additional beneficial effects beyond that of glucose normalization. In the current review, how these antidiabetic medications can regulate lipid homeostasis and the possible cellular pathways involved are discussed, incorporating related clinical evidence about incretin effects on lipid homeostasis.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alexandra E. Butler
- Research Department, Royal College of Surgeons in Ireland, PO Box 15503, Adliya, Bahrain
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Hurtado-Carneiro V, Dongil P, Pérez-García A, Álvarez E, Sanz C. Preventing Oxidative Stress in the Liver: An Opportunity for GLP-1 and/or PASK. Antioxidants (Basel) 2021; 10:antiox10122028. [PMID: 34943132 PMCID: PMC8698360 DOI: 10.3390/antiox10122028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 02/07/2023] Open
Abstract
The liver’s high metabolic activity and detoxification functions generate reactive oxygen species, mainly through oxidative phosphorylation in the mitochondria of hepatocytes. In contrast, it also has a potent antioxidant mechanism for counterbalancing the oxidant’s effect and relieving oxidative stress. PAS kinase (PASK) is a serine/threonine kinase containing an N-terminal Per-Arnt-Sim (PAS) domain, able to detect redox state. During fasting/feeding changes, PASK regulates the expression and activation of critical liver proteins involved in carbohydrate and lipid metabolism and mitochondrial biogenesis. Interestingly, the functional inactivation of PASK prevents the development of a high-fat diet (HFD)-induced obesity and diabetes. In addition, PASK deficiency alters the activity of other nutrient sensors, such as the AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). In addition to the expression and subcellular localization of nicotinamide-dependent histone deacetylases (SIRTs). This review focuses on the relationship between oxidative stress, PASK, and other nutrient sensors, updating the limited knowledge on the role of PASK in the antioxidant response. We also comment on glucagon-like peptide 1 (GLP-1) and its collaboration with PASK in preventing the damage associated with hepatic oxidative stress. The current knowledge would suggest that PASK inhibition and/or exendin-4 treatment, especially under fasting conditions, could ameliorate disorders associated with excess oxidative stress.
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Affiliation(s)
- Verónica Hurtado-Carneiro
- Department of Physiology, Faculty of Medicine, Institute of Medical Research at the San Carlos Clinic Hospital (IdISSC), Complutense University of Madrid, Ciudad Universitaria, 28040 Madrid, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Institute of Medical Research at the San Carlos Clinic Hospital (IdISSC), Complutense University of Madrid, Ciudad Universitaria, 28040 Madrid, Spain; (P.D.); (A.P.-G.); (E.Á.)
- Correspondence:
| | - Pilar Dongil
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Institute of Medical Research at the San Carlos Clinic Hospital (IdISSC), Complutense University of Madrid, Ciudad Universitaria, 28040 Madrid, Spain; (P.D.); (A.P.-G.); (E.Á.)
- Department of Cell Biology, Faculty of Medicine, Institute of Medical Research at the San Carlos Clinic Hospital (IdISSC), Complutense University of Madrid, Ciudad Universitaria, 28040 Madrid, Spain;
| | - Ana Pérez-García
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Institute of Medical Research at the San Carlos Clinic Hospital (IdISSC), Complutense University of Madrid, Ciudad Universitaria, 28040 Madrid, Spain; (P.D.); (A.P.-G.); (E.Á.)
- Department of Cell Biology, Faculty of Medicine, Institute of Medical Research at the San Carlos Clinic Hospital (IdISSC), Complutense University of Madrid, Ciudad Universitaria, 28040 Madrid, Spain;
| | - Elvira Álvarez
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Institute of Medical Research at the San Carlos Clinic Hospital (IdISSC), Complutense University of Madrid, Ciudad Universitaria, 28040 Madrid, Spain; (P.D.); (A.P.-G.); (E.Á.)
| | - Carmen Sanz
- Department of Cell Biology, Faculty of Medicine, Institute of Medical Research at the San Carlos Clinic Hospital (IdISSC), Complutense University of Madrid, Ciudad Universitaria, 28040 Madrid, Spain;
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Dobbie LJ, Kassab M, Davison AS, Grace P, Cuthbertson DJ, Hydes TJ. Low Screening Rates Despite a High Prevalence of Significant Liver Fibrosis in People with Diabetes from Primary and Secondary Care. J Clin Med 2021; 10:jcm10245755. [PMID: 34945051 PMCID: PMC8706667 DOI: 10.3390/jcm10245755] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 12/14/2022] Open
Abstract
Diabetes is a driver of non-alcoholic fatty liver disease (NAFLD) and fibrosis. We determine current practices in examining liver fibrosis in people with diabetes and record prevalence levels in primary and secondary care. We extracted HbA1c results ≥48 mmol/mol to identify people with diabetes, then examined the proportion who had AST, ALT, and platelets results, facilitating calculation of non-invasive fibrosis tests (NIT), or an enhanced liver fibrosis score. Fibrosis markers were requested in only 1.49% (390/26,090), of which 29.7% (n = 106) had evidence of significant fibrosis via NIT. All patients at risk of fibrosis had undergone transient elastography (TE), biopsy or imaging. TE and biopsy data showed that 80.6% of people with raised fibrosis markers had confirmed significant fibrosis. We also show that fibrosis levels as detected by NIT are marginally lower in patients treated with newer glucose lowering agents (sodium-glucose transporter protein 2 inhibitors, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists). In conclusion by utilising a large consecutively recruited dataset we demonstrate that liver fibrosis is infrequently screened for in patients with diabetes despite high prevalence rates of advanced fibrosis. This highlights the need for cost-effectiveness analyses to support the incorporation of widespread screening into national guidelines and the requirement for healthcare practitioners to incorporate NAFLD screening into routine diabetes care.
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Affiliation(s)
- Laurence J. Dobbie
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L9 7AL, UK; (L.J.D.); (D.J.C.)
| | - Mohamed Kassab
- Department of Gastroenterology and Hepatology, Liverpool University Hospitals Foundation Trust, Liverpool L7 8XP, UK;
| | - Andrew S. Davison
- Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Liverpool University Hospitals Foundation Trust, Liverpool L7 8XP, UK;
- Liverpool Clinical Laboratories, Liverpool University Hospitals Foundation Trust, Liverpool L7 8XP, UK;
| | - Pete Grace
- Liverpool Clinical Laboratories, Liverpool University Hospitals Foundation Trust, Liverpool L7 8XP, UK;
| | - Daniel J. Cuthbertson
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L9 7AL, UK; (L.J.D.); (D.J.C.)
| | - Theresa J. Hydes
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L9 7AL, UK; (L.J.D.); (D.J.C.)
- Department of Gastroenterology and Hepatology, Liverpool University Hospitals Foundation Trust, Liverpool L7 8XP, UK;
- Correspondence:
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Ala M, Eftekhar SP. Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8790369. [PMID: 34765085 PMCID: PMC8577929 DOI: 10.1155/2021/8790369] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 10/18/2021] [Indexed: 12/14/2022]
Abstract
Sestrin2 is a stress-inducible metabolic regulator and a conserved antioxidant protein which has been implicated in the pathogenesis of several diseases. Sestrin2 can protect against atherosclerosis, heart failure, hypertension, myocardial infarction, stroke, spinal cord injury neurodegeneration, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, acute kidney injury (AKI), chronic kidney disease (CKD), and pulmonary inflammation. Oxidative stress and cellular damage signals can alter the expression of Sestrin2 to compensate for organ damage. Different stress signals such as those mediated by P53, Nrf2/ARE, HIF-1α, NF-κB, JNK/c-Jun, and TGF-β/Smad signaling pathways can induce Sestrin2 expression. Subsequently, Sestrin2 activates Nrf2 and AMPK. Furthermore, Sestrin2 is a major negative regulator of mTORC1. Sestrin2 indirectly regulates the expression of several genes and reprograms intracellular signaling pathways to attenuate oxidative stress and modulate a large number of cellular events such as protein synthesis, cell energy homeostasis, mitochondrial biogenesis, autophagy, mitophagy, endoplasmic reticulum (ER) stress, apoptosis, fibrogenesis, and lipogenesis. Sestrin2 vigorously enhances M2 macrophage polarization, attenuates inflammation, and prevents cell death. These alterations in molecular and cellular levels improve the clinical presentation of several diseases. This review will shed light on the beneficial effects of Sestrin2 on several diseases with an emphasis on underlying pathophysiological effects.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Seyed Parsa Eftekhar
- Student Research Committee, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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Brown E, Hydes T, Hamid A, Cuthbertson DJ. Emerging and Established Therapeutic Approaches for Nonalcoholic Fatty Liver Disease. Clin Ther 2021; 43:1476-1504. [PMID: 34446271 DOI: 10.1016/j.clinthera.2021.07.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE Nonalcoholic fatty liver disease (NAFLD), more recently referred to as metabolic-associated fatty liver disease, refers to a disease spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, associated with hepatic complications (including liver fibrosis, cirrhosis, and hepatocellular carcinoma) and extrahepatic complications (particularly cardiometabolic complications, including type 2 diabetes and cardiovascular disease). Treatment options include lifestyle interventions (dietary modification and physical activity programs) and pharmacologic interventions. Treatment aims should be broad, with a hepatic focus (to improve/reverse hepatic inflammation, fibrosis, and steatohepatitis), ideally with additional extrahepatic effects affecting metabolic co-morbidities (eg, insulin resistance, glucose dysregulation, dyslipidemia), causing weight loss and affording cardiovascular protection. NASH and fibrosis represent the main histopathological features that warrant treatment to prevent disease progression. Despite a paucity of established treatments, the array of potential molecular targets, pathways, and potential treatments is continually evolving. The goal of this article was to provide a narrative review summarizing the emerging and more established therapeutic options considering the complex pathophysiology of NAFLD and the important long-term sequelae of this condition. METHODS The literature was reviewed by using PubMed, conference abstracts, and press releases from early-phase clinical studies to provide an overview of the evidence. FINDINGS As understanding of the pathophysiology of NASH/NAFLD evolves, drugs with different mechanisms of action, targeting different molecular targets and aberrant pathways that mediate hepatic steatosis, inflammation, and fibrosis, have been developed and are being tested in clinical trials. Pharmacologic therapies fall into 4 main categories according to the molecular targets/pathways they disrupt: (1) meta-bolic targets, targeting insulin resistance, hepatic de novo lipogenesis, or substrate utilization; (2) inflam-matory pathways, inhibiting inflammatory cell recruitment/signaling, reduce oxidative/endoplasmic reticulum stress or are antiapoptotic; (3) the liver-gut axis, which modulates bile acid enterohepatic circulation/signaling or alters gut microbiota; and (4) antifibrotic targets, targeting hepatic stellate cells, decrease collagen deposition or increase fibrinolysis. IMPLICATIONS Lifestyle modification must remain the cornerstone of treatment. Pharmacologic treatment is reserved for NASH or fibrosis, the presence of which requires histopathological confirmation. The disease complexity provides a strong rationale for combination therapies targeting multiple pathways simultaneously.
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Affiliation(s)
- Emily Brown
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom.
| | - T Hydes
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - A Hamid
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - D J Cuthbertson
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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Guerra JVS, Dias MMG, Brilhante AJVC, Terra MF, García-Arévalo M, Figueira ACM. Multifactorial Basis and Therapeutic Strategies in Metabolism-Related Diseases. Nutrients 2021; 13:nu13082830. [PMID: 34444990 PMCID: PMC8398524 DOI: 10.3390/nu13082830] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 12/11/2022] Open
Abstract
Throughout the 20th and 21st centuries, the incidence of non-communicable diseases (NCDs), also known as chronic diseases, has been increasing worldwide. Changes in dietary and physical activity patterns, along with genetic conditions, are the main factors that modulate the metabolism of individuals, leading to the development of NCDs. Obesity, diabetes, metabolic associated fatty liver disease (MAFLD), and cardiovascular diseases (CVDs) are classified in this group of chronic diseases. Therefore, understanding the underlying molecular mechanisms of these diseases leads us to develop more accurate and effective treatments to reduce or mitigate their prevalence in the population. Given the global relevance of NCDs and ongoing research progress, this article reviews the current understanding about NCDs and their related risk factors, with a focus on obesity, diabetes, MAFLD, and CVDs, summarizing the knowledge about their pathophysiology and highlighting the currently available and emerging therapeutic strategies, especially pharmacological interventions. All of these diseases play an important role in the contamination by the SARS-CoV-2 virus, as well as in the progression and severity of the symptoms of the coronavirus disease 2019 (COVID-19). Therefore, we briefly explore the relationship between NCDs and COVID-19.
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Affiliation(s)
- João V. S. Guerra
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Pharmaceutical Sciences, Faculty Pharmaceutical Sciences, University of Campinas, Campinas 13083-970, Brazil
| | - Marieli M. G. Dias
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
| | - Anna J. V. C. Brilhante
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biorenewables National Laboratory (LNBR), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil
| | - Maiara F. Terra
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
| | - Marta García-Arévalo
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Correspondence: or (M.G.-A.); (A.C.M.F.)
| | - Ana Carolina M. Figueira
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Correspondence: or (M.G.-A.); (A.C.M.F.)
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Fan S, Shi X, Yao J, Zhong M, Feng P. The efficacy of glucagon-like peptide 1 receptor agonists in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 112:627-635. [PMID: 32496108 DOI: 10.17235/reed.2020.6392/2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND non-alcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome and is highly prevalent all over the world. New drugs are urgently needed for the treatment of NAFLD. The aim of this meta-analysis was to assess the efficacy of glucagon-like peptide 1 receptor agonists (GLP-1RAs) in patients with NAFLD. METHOD English language publications in the PubMed, Cochrane Library, Embase and Web of Science databases were searched from inception to October 2019. All randomized controlled trials (RCTs) of GLP-1RAs treatment for NAFLD were considered. Standardized mean difference (SMD) with 95 % confidence intervals (CIs) were pooled using the fixed-effects or random-effects model. RESULTS six RCTs, involving 406 patients, were included in the analysis. A significant improvement was found in liver fat fraction (LFF) (SMD = -0.33, 95 % CI, -0.64 to -0.03, p = 0.034), body mass index (BMI) (SMD: -0.89, 95 % CI: -1.60 to -0.19, p = 0.012) and adiponectin (SMD: 0.66, 95 % CI: 0.37 to 0.95, p = 0.000) with GLP-1RAs treatment. There were no significant differences in serum alanine aminotransferase (ALT) (SMD: -0.52, 95 % CI: -1.04 to 0.01, p = 0.054) and aspartate transaminase (AST) (SMD: -0.20, 95 % CI: -0.54 to 0.15, p = 0.134) reduction between the GLP-1RAs and control groups. In the subgroup analysis, exenatide was associated with an improvement in serum ALT (SMD = -1.25, 95 % CI: -1.68 to -0.82, p = 0.000) and AST (SMD = -0.62, 95 % CI: -1.16 to -0.08, p = 0.024). Liraglutide was associated with a reduction in BMI (SMD = -0.44, 95 % CI: -0.77 to -0.11, p = 0.010) and an increase in adiponectin (SMD = -0.33, 95 % CI, -0.64 to -0.03, p = 0.034). CONCLUSION our study suggested that GLP-1RAs may improve LFF, BMI and adiponectin in patients with NAFLD. Furthermore, the potential efficacy to treat NAFLD was also shown. More high-quality RCTs are needed to validate our findings.
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Affiliation(s)
- Simin Fan
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Xiaoyan Shi
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Jia Yao
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Min Zhong
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Peimin Feng
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
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Bowden Davies KA, Norman JA, Thompson A, Mitchell KL, Harrold JA, Halford JCG, Wilding JPH, Kemp GJ, Cuthbertson DJ, Sprung VS. Short-Term Physical Inactivity Induces Endothelial Dysfunction. Front Physiol 2021; 12:659834. [PMID: 33897466 PMCID: PMC8064120 DOI: 10.3389/fphys.2021.659834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/08/2021] [Indexed: 11/13/2022] Open
Abstract
Objective This study examined the effects of a short-term reduction in physical activity, and subsequent resumption, on metabolic profiles, body composition and cardiovascular (endothelial) function. Design Twenty-eight habitually active (≥10,000 steps/day) participants (18 female, 10 male; age 32 ± 11 years; BMI 24.3 ± 2.5 kg/m2) were assessed at baseline, following 14 days of step-reduction and 14 days after resuming habitual activity. Methods Physical activity was monitored throughout (SenseWear Armband). Endothelial function (flow mediated dilation; FMD), cardiorespiratory fitness ( V . O 2 peak) and body composition including liver fat (dual-energy x-ray absorptiometry and magnetic resonance spectroscopy) were determined at each assessment. Statistical analysis was performed using one-way within subject's ANOVA; data presented as mean (95% CI). Results Participants decreased their step count from baseline by 10,111 steps/day (8949, 11,274; P < 0.001), increasing sedentary time by 103 min/day (29, 177; P < 0.001). Following 14 days of step-reduction, endothelial function was reduced by a 1.8% (0.4, 3.3; P = 0.01) decrease in FMD. Following resumption of habitual activity, FMD increased by 1.4%, comparable to the baseline level 0.4% (-1.8, 2.6; P = 1.00). Total body fat, waist circumference, liver fat, whole body insulin sensitivity and cardiorespiratory fitness were all adversely affected by 14 days step-reduction (P < 0.05) but returned to baseline levels following resumption of activity. Conclusion This data shows for the first time that whilst a decline in endothelial function is observed following short-term physical inactivity, this is reversed on resumption of habitual activity. The findings highlight the need for public health interventions that focus on minimizing time spent in sedentary behavior.
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Affiliation(s)
- Kelly A Bowden Davies
- Department of Sport and Exercise Sciences, Manchester Metropolitan University, Manchester, United Kingdom.,Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.,Obesity and Endocrinology Research Group, Clinical Sciences Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Juliette A Norman
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.,Obesity and Endocrinology Research Group, Clinical Sciences Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Andrew Thompson
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Katie L Mitchell
- Institute of Public Health, University of Liverpool, Liverpool, United Kingdom
| | - Joanne A Harrold
- Institute of Public Health, University of Liverpool, Liverpool, United Kingdom
| | | | - John P H Wilding
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.,Obesity and Endocrinology Research Group, Clinical Sciences Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Graham J Kemp
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.,Liverpool Magnetic Resonance Imaging Centre, University of Liverpool, Liverpool, United Kingdom
| | - Daniel J Cuthbertson
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.,Obesity and Endocrinology Research Group, Clinical Sciences Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Victoria S Sprung
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.,Obesity and Endocrinology Research Group, Clinical Sciences Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom.,Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
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Pinyopornpanish K, Leerapun A, Pinyopornpanish K, Chattipakorn N. Effects of Metformin on Hepatic Steatosis in Adults with Nonalcoholic Fatty Liver Disease and Diabetes: Insights from the Cellular to Patient Levels. Gut Liver 2021; 15:827-840. [PMID: 33820884 PMCID: PMC8593497 DOI: 10.5009/gnl20367] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 12/05/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) patients with diabetes constitute a subgroup of patients with a high rate of liver-related complications. Currently, there are no specific drug recommendations for these patients. Metformin, a conventional insulin sensitizer agent, has been widely prescribed in patients with diabetes. Metformin treatment has been shown to be effective at alleviating hepatic lipogenesis in animal models of NAFLD, with a variety of mechanisms being deemed responsible. To date, most studies have enrolled diabetic patients who are treated with metformin, with the drug being taken continuously throughout the study. Although evidence exists regarding the benefits of metformin for NAFLD in preclinical studies, reports on the efficacy of metformin in adult NAFLD patients have had some discrepancies regarding changes in liver biochemistry and hepatic fat content. Evidence has also suggested possible effects of metformin as regards the prevention of hepatocellular carcinoma tumorigenesis. This review was performed to comprehensively summarize the available in vitro, in vivo and clinical studies regarding the effects of metformin on liver steatosis for the treatment of adult NAFLD patients with diabetes. Consistent reports as well as controversial findings are included in this review, and the mechanistic insights are also provided. In addition, this review focuses on the efficacy of metformin as a monotherapy and as a combined therapy with other antidiabetic medications.
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Affiliation(s)
| | - Apinya Leerapun
- Division of Gastroenterology, Department of Internal Medicine, Chiang Mai, Thailand
| | | | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Chiang Mai, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
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Zhou R, Lin C, Cheng Y, Zhuo X, Li Q, Xu W, Zhao L, Yang L. Liraglutide Alleviates Hepatic Steatosis and Liver Injury in T2MD Rats via a GLP-1R Dependent AMPK Pathway. Front Pharmacol 2021; 11:600175. [PMID: 33746742 PMCID: PMC7970416 DOI: 10.3389/fphar.2020.600175] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), ranging from non-alcoholic fatty liver to non-alcoholic steatohepatitis, can be prevalent in patients with type 2 diabetes mellitus (T2DM). However, no antidiabetic drug has been approved for the treatment of NAFLD in T2DM patients. Multiple daily injections of basal-bolus insulin are often the final therapeutic option for T2DM. We found that insulin treatment aggravated hepatic steatosis and oxidative stress in Zucker diabetic fatty (ZDF) rats. In addition to glycaemic control, we demonstrated the stimulatory role of liraglutide in relieving hepatic steatosis and liver injury in ZDF rats. Interestingly, liraglutide could also alleviate insulin-aggravated hepatic fatty accumulation. The glucagon-like peptide-1 (GLP-1) agonists liraglutide and Ex-4 activated the expression of peroxisome proliferator-activated receptor alpha (PPARα) via a GLP-1 receptor-dependent 5′ AMP-activated protein kinase pathway. As a nuclear transcription factor, PPARα could mediate the effect of GLP-1 in alleviating hepatic steatosis by differentially regulating the expression of its target genes, including acetyl CoA carboxylase and carnitine palmitoyl transferase la both in vitro and in vivo. Moreover, GLP-1 could relieve liver injury by decreasing oxidative stress stimulated by hepatic steatosis. Insulin might aggravate hepatic steatosis and liver injury by inhibiting GLP-1R expression. The findings indicate the feasibility of liraglutide treatment combined with basal insulin in attenuating hepatic steatosis and liver injury in ZDF rats. This knowledge, and the evidence for the underlying mechanism, provide a theoretical basis for the combination treatment recommended by the latest clinical practice guidelines for T2DM.
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Affiliation(s)
- Rui Zhou
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Chuman Lin
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yanzhen Cheng
- Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyun Zhuo
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Qinghua Li
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Wen Xu
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Li Yang
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Koutoukidis DA, Koshiaris C, Henry JA, Noreik M, Morris E, Manoharan I, Tudor K, Bodenham E, Dunnigan A, Jebb SA, Aveyard P. The effect of the magnitude of weight loss on non-alcoholic fatty liver disease: A systematic review and meta-analysis. Metabolism 2021; 115:154455. [PMID: 33259835 DOI: 10.1016/j.metabol.2020.154455] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/27/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Trials show that weight loss interventions improve biomarkers of non-alcoholic fatty liver disease (NAFLD), but it is unclear if a dose-response relationship exists. OBJECTIVE We aimed to quantify the dose-response relationship between the magnitude of weight loss and improvements in NAFLD. METHODS Nine databases and trial registries were searched until October 2020. Single-arm, non-randomized comparative, or randomized trials of weight loss interventions (behavioral weight loss programs [BWLPs], pharmacotherapy, or bariatric surgery) in people with NAFLD were eligible for inclusion if they reported an association between changes in weight and changes in blood, radiological, or histological biomarkers of liver disease. The review followed Cochrane methods and the risk of bias was assessed using the Newcastle-Ottawa scale. Pooled unstandardized b coefficients were calculated using random-effect meta-analyses. RESULTS Forty-three studies (BWMPs: 26, pharmacotherapy: 9, surgery: 8) with 2809 participants were included. The median follow-up was 6 (interquartile range: 6) months. The direction of effect was generally consistent but the estimates imprecise. Every 1 kg of weight lost was associated with a 0.83-unit (95% CI: 0.53 to 1.14, p < 0.0001, I2 = 92%, n = 18) reduction in alanine aminotransferase (U/L), a 0.56-unit (95% CI: 0.32 to 0.79, p < 0.0001, I2 = 68%, n = 11) reduction in aspartate transaminase (U/L), and a 0.77 percentage point (95% CI: 0.51 to 1.03, p < 0.0001, I2 = 72%, n = 11) reduction in steatosis assessed by radiology or histology. There was evidence of a dose-response relationship with liver inflammation, ballooning, and resolution of NAFLD or NASH, but limited evidence of a dose-response relationship with fibrosis or NAFLD activity score. On average, the risk of bias for selection and outcome was medium and low, respectively. CONCLUSION Clinically significant improvements in NAFLD are achieved even with modest weight loss, but greater weight loss is associated with greater improvements. Embedding support for formal weight loss programs as part of the care pathway for the treatment of NAFLD could reduce the burden of disease. PROSPERO CRD42018093676.
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Affiliation(s)
- Dimitrios A Koutoukidis
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; NIHR Oxford Biomedical Research Centre, Oxford OX2 6GG, UK.
| | - Constantinos Koshiaris
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK.
| | - John A Henry
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK.
| | - Michaela Noreik
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; NIHR Oxford Biomedical Research Centre, Oxford OX2 6GG, UK.
| | - Elizabeth Morris
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK.
| | - Indrani Manoharan
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK.
| | - Kate Tudor
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; NIHR Oxford Biomedical Research Centre, Oxford OX2 6GG, UK.
| | - Emma Bodenham
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK
| | - Anna Dunnigan
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK
| | - Susan A Jebb
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; NIHR Oxford Biomedical Research Centre, Oxford OX2 6GG, UK.
| | - Paul Aveyard
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; NIHR Oxford Biomedical Research Centre, Oxford OX2 6GG, UK.
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Coppola S, Avagliano C, Calignano A, Berni Canani R. The Protective Role of Butyrate against Obesity and Obesity-Related Diseases. Molecules 2021; 26:molecules26030682. [PMID: 33525625 PMCID: PMC7865491 DOI: 10.3390/molecules26030682] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 01/21/2021] [Accepted: 01/25/2021] [Indexed: 12/14/2022] Open
Abstract
Worldwide obesity is a public health concern that has reached pandemic levels. Obesity is the major predisposing factor to comorbidities, including type 2 diabetes, cardiovascular diseases, dyslipidemia, and non-alcoholic fatty liver disease. The common forms of obesity are multifactorial and derive from a complex interplay of environmental changes and the individual genetic predisposition. Increasing evidence suggest a pivotal role played by alterations of gut microbiota (GM) that could represent the causative link between environmental factors and onset of obesity. The beneficial effects of GM are mainly mediated by the secretion of various metabolites. Short-chain fatty acids (SCFAs) acetate, propionate and butyrate are small organic metabolites produced by fermentation of dietary fibers and resistant starch with vast beneficial effects in energy metabolism, intestinal homeostasis and immune responses regulation. An aberrant production of SCFAs has emerged in obesity and metabolic diseases. Among SCFAs, butyrate emerged because it might have a potential in alleviating obesity and related comorbidities. Here we reviewed the preclinical and clinical data that contribute to explain the role of butyrate in this context, highlighting its crucial contribute in the diet-GM-host health axis.
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Affiliation(s)
- Serena Coppola
- Department of Translational Medical Science, University of Naples Federico II, 80131 Naples, Italy;
- ImmunoNutriton Lab at CEINGE Advanced Biotechnologies, University of Naples Federico II, 80131 Naples, Italy
| | - Carmen Avagliano
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (C.A.); (A.C.)
| | - Antonio Calignano
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (C.A.); (A.C.)
| | - Roberto Berni Canani
- Department of Translational Medical Science, University of Naples Federico II, 80131 Naples, Italy;
- ImmunoNutriton Lab at CEINGE Advanced Biotechnologies, University of Naples Federico II, 80131 Naples, Italy
- European Laboratory for the Investigation of Food Induced Diseases (ELFID), University of Naples Federico II, 80131 Naples, Italy
- Task Force on Microbiome Studies, University of Naples Federico II, 80131 Naples, Italy
- Correspondence: ; Tel.: +39-081-7462680
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He Y, Ao N, Yang J, Wang X, Jin S, Du J. The preventive effect of liraglutide on the lipotoxic liver injury via increasing autophagy. Ann Hepatol 2021; 19:44-52. [PMID: 31787541 DOI: 10.1016/j.aohep.2019.06.023] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 06/25/2019] [Accepted: 06/25/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing. Previous studies indicated that Liraglutide, glucagon-like peptide-1 analogue, could regulate glucose homeostasis as a valuable treatment for Type 2 Diabetes. However, the precise effect of Liraglutide on NAFLD model in rats and the mechanism remains unknown. In this study, we investigated the molecular mechanism by which Liraglutide ameliorates hepatic steatosis in a high-fat diet (HFD)-induced rat model of NAFLD in vivo and in vitro. MATERIALS AND METHODS NALFD rat models and hepatocyte steatosis in HepG2 cells were induced by HFD and palmitate fatty acid treatment, respectively. AMPK inhibitor, Compound C was added in HepG2 cells. Autophagy-related proteins LC3, Beclin1 and Atg7, and AMPK pathway-associated proteins were evaluated by Western blot and RT-PCR. RESULTS Liraglutide enhanced autophagy as showed by the increased expression of the autophagy markers LC3, Beclin1 and Atg7 in HFD rats and HepG2 cells treated with palmitate fatty acid. In vitro, The AMPK inhibitor exhibited an inhibitory effect on Liraglutide-induced autophagy enhancement with the deceased expression of LC3, Beclin1 and Atg7. Additionally, Liraglutide treatment elevated AMPK levels and TSC1, decreased p-mTOR expression. CONCLUSIONS Liraglutide could upregulate autophagy to decrease lipid over-accumulation via the AMPK/mTOR pathway.
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Affiliation(s)
- Yini He
- Department of General Practice, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Na Ao
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jing Yang
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaochen Wang
- Department of Endocrinology, The People's Hospital of Liaoning Province, Shenyang, Liaoning, China
| | - Shi Jin
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jian Du
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet. Transl Res 2021; 227:75-88. [PMID: 32711187 DOI: 10.1016/j.trsl.2020.07.008] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 07/14/2020] [Accepted: 07/16/2020] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder related to type 2 diabetes (T2D). The disease can evolve toward nonalcoholic steatohepatitis (NASH), a state of hepatic inflammation and fibrosis. There is presently no drug that effectively improves and/or prevents NAFLD/NASH/fibrosis. GLP-1 receptor agonists (GLP-1Ra) are effective in treating T2D. As with the endogenous gut incretins, GLP-1Ra potentiate glucose-induced insulin secretion. In addition, GLP-1Ra limit food intake and weight gain, additional beneficial properties in the context of obesity/insulin-resistance. Nevertheless, these pleiotropic effects of GLP-1Ra complicate the elucidation of their direct action on the liver. In the present study, we used the classical methionine-choline deficient (MCD) dietary model to investigate the potential direct hepatic actions of the GLP-1Ra liraglutide. A 4-week infusion of liraglutide (570 µg/kg/day) did not impact body weight, fat accretion or glycemic control in MCD-diet fed mice, confirming the suitability of this model for avoiding confounding factors. Liraglutide treatment did not prevent lipid deposition in the liver of MCD-fed mice but limited the accumulation of C16 and C24-ceramide/sphingomyelin species. In addition, liraglutide treatment alleviated hepatic inflammation (in particular accumulation of M1 pro-inflammatory macrophages) and initiation of fibrosis. Liraglutide also influenced the composition of gut microbiota induced by the MCD-diet. This included recovery of a normal Bacteroides proportion and, among the Erysipelotrichaceae family, a shift between Allobaculum and Turicibacter genera. In conclusion, liraglutide prevents accumulation of C16 and C24-ceramides/sphingomyelins species, inflammation and initiation of fibrosis in MCD-diet-fed mice liver, suggesting beneficial hepatic actions independent of weight loss and global hepatic steatosis.
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