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Qi L, Groeger M, Sharma A, Goswami I, Chen E, Zhong F, Ram A, Healy K, Hsiao EC, Willenbring H, Stahl A. Adipocyte inflammation is the primary driver of hepatic insulin resistance in a human iPSC-based microphysiological system. Nat Commun 2024; 15:7991. [PMID: 39266553 PMCID: PMC11393072 DOI: 10.1038/s41467-024-52258-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 08/28/2024] [Indexed: 09/14/2024] Open
Abstract
Interactions between adipose tissue, liver and immune system are at the center of metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. To address the need for an accurate in vitro model, we establish an interconnected microphysiological system (MPS) containing white adipocytes, hepatocytes and proinflammatory macrophages derived from isogenic human induced pluripotent stem cells. Using this MPS, we find that increasing the adipocyte-to-hepatocyte ratio moderately affects hepatocyte function, whereas macrophage-induced adipocyte inflammation causes lipid accumulation in hepatocytes and MPS-wide insulin resistance, corresponding to initiation of metabolic dysfunction-associated steatotic liver disease. We also use our MPS to identify and characterize pharmacological intervention strategies for hepatic steatosis and systemic insulin resistance and find that the glucagon-like peptide-1 receptor agonist semaglutide improves hepatocyte function by acting specifically on adipocytes. These results establish our MPS modeling the adipose tissue-liver axis as an alternative to animal models for mechanistic studies or drug discovery in metabolic diseases.
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Affiliation(s)
- Lin Qi
- Department of Nutritional Science and Toxicology, College of Natural Resources, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Marko Groeger
- Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
- Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Aditi Sharma
- Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Ishan Goswami
- Department of Bioengineering, College of Engineering, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Erzhen Chen
- Department of Nutritional Science and Toxicology, College of Natural Resources, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Fenmiao Zhong
- Department of Nutritional Science and Toxicology, College of Natural Resources, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Apsara Ram
- Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Kevin Healy
- Department of Bioengineering, College of Engineering, University of California Berkeley, Berkeley, CA, 94720, USA
- Department of Materials Science and Engineering, College of Engineering, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Edward C Hsiao
- Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Holger Willenbring
- Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA, 94143, USA.
- Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
- Liver Center, University of California San Francisco, San Francisco, CA, 94143, USA.
| | - Andreas Stahl
- Department of Nutritional Science and Toxicology, College of Natural Resources, University of California Berkeley, Berkeley, CA, 94720, USA.
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Schwartz SS, Corkey BE, R Gavin J, DeFronzo RA, Herman ME. Advances and counterpoints in type 2 diabetes. What is ready for translation into real-world practice, ahead of the guidelines. BMC Med 2024; 22:356. [PMID: 39227924 PMCID: PMC11373437 DOI: 10.1186/s12916-024-03518-5] [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: 03/02/2024] [Accepted: 07/08/2024] [Indexed: 09/05/2024] Open
Abstract
This review seeks to address major gaps and delays between our rapidly evolving body of knowledge on type 2 diabetes and its translation into real-world practice. Through updated and improved best practices informed by recent evidence and described herein, we stand to better attain A1c targets, help preserve beta cell integrity and moderate glycemic variability, minimize treatment-emergent hypoglycemia, circumvent prescribing to "treatment failure," and prevent long-term complications. The first topic addressed in this review concerns updates in the 2023 and 2024 diabetes treatment guidelines for which further elaboration can help facilitate integration into routine care. The second concerns advances in diabetes research that have not yet found their way into guidelines, though they are endorsed by strong evidence and are ready for real-world use in appropriate patients. The final theme addresses lingering misconceptions about the underpinnings of type 2 diabetes-fundamental fallacies that continue to be asserted in the textbooks and continuing medical education upon which physicians build their approaches. A corrected and up-to-date understanding of the disease state is essential for practitioners to both conceptually and translationally manage initial onset through late-stage type 2 diabetes.
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Affiliation(s)
- Stanley S Schwartz
- Main Line Health, Wynnewood, PA, USA
- University of Pennsylvania, Philadelphia, PA, USA
| | - Barbara E Corkey
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - James R Gavin
- Emory University School of Medicine, Atlanta, GA, USA
| | - Ralph A DeFronzo
- Department of Medicine, Diabetes Division, University of Texas Health Science Center, South Texas. Veterans Health Care System and Texas Diabetes Institute, 701 S. Zarzamoro, San Antonio, TX, 78207, USA
| | - Mary E Herman
- Social Alchemy: Building Physician Competency Across the Globe, 5 Ave Sur #36, Antigua, Sacatepéquez, Guatemala.
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3
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Scheen AJ. Underuse of GLP-1 receptor agonists in the management of type 2 diabetes despite a favorable benefit-safety profile. Expert Opin Drug Saf 2024; 23:797-810. [PMID: 38738549 DOI: 10.1080/14740338.2024.2354885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 05/09/2024] [Indexed: 05/14/2024]
Abstract
INTRODUCTION Patients with type 2 diabetes (T2DM) are at high risk of atherosclerotic cardiovascular disease (ASCVD) and cardiovascular death. Cardiovascular protection is a key objective in T2DM. AREAS COVERED Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM in placebo-controlled trials, a finding confirmed in observational studies compared with other glucose-lowering agents. Overall, GLP-1RAs have a good safety profile associated with a favorable benefit/risk ratio for the management of T2DM, even if their cost-effectiveness might be questionable. International guidelines recommend GLP-1RAs as preferred glucose-lowering agents in patients with ASCVD and as a valuable alternative in overweight/obese patients with T2DM. However, real-life studies worldwide revealed that only a minority of patients receive a GLP-1RA, despite a positive trend for increased prescriptions in recent years. Surprisingly, however, fewer patients with established ASCVD are treated with these cardioprotective antihyperglycemic agents versus patients without ASCVD. EXPERT OPINION The reasons for GLP-1RA underuse in clinical practice are multiple. Multifaceted and coordinated interventions targeting all actors of the health-care system must be implemented to stimulate the adoption of GLP-1RAs as part of routine cardiovascular care among patients with T2DM, especially in those with ASCVD.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, Liège, Belgium
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium
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4
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Lee J, Li Y, Cheng JT, Liu IM, Cheng KC. Development of Syringaldehyde as an Agonist of the GLP-1 Receptor to Alleviate Diabetic Disorders in Animal Models. Pharmaceuticals (Basel) 2024; 17:538. [PMID: 38675498 PMCID: PMC11054907 DOI: 10.3390/ph17040538] [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: 03/15/2024] [Revised: 04/10/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
The phenolic aldehyde syringaldehyde (SA) has been shown to have an antihyperglycemic effect in diabetic rats due to increased glucose utilization and insulin sensitivity. To understand the direct effect of SA on the GLP-1 receptor, STZ-induced diabetic rats were used. The levels of pro-inflammatory cytokines, liver enzymes, and renal function were measured using specific ELISA kits. The mechanisms of SA effects were investigated using CHO-K1 cells, pancreatic Min-6 cells, and cardiomyocyte H9c2 cells. The results indicated that the antihyperglycemic effect of SA in diabetic rats was abolished by blocking the GLP-1 receptor with an antagonist. SA has a direct effect on the GLP-1 receptor when using CHO-K1 cells transfected with the exogenous GLP-1 receptor gene. In addition, SA stimulated insulin production in Min-6 cells by activating GLP-1 receptors. SA caused a dose-dependent rise in GLP-1 receptor mRNA levels in cardiac H9c2 cells. These in vitro results support the notion that SA has a direct effect on the GLP-1 receptor. Otherwise, SA inhibited the increase of pro-inflammatory cytokines, including interleukins and tumor TNF-α, in type 1 diabetic rats in a dose-dependent manner. Moreover, as with liraglutide, SA reduced plasma lipid profiles, including total cholesterol and triglyceride, in mixed diet-induced type 2 diabetic rats. Intriguingly, chronic treatment with SA (as with liraglutide) reversed the functions of both the liver and the kidney in these diabetic rats. SA displayed less efficiency in reducing body weight and food consumption compared to liraglutide. In conclusion, SA effectively activates GLP-1 receptors, resulting in a reduction in diabetic-related complications in rats. Therefore, it is beneficial to develop SA as a chemical agonist for clinical applications in the future.
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Affiliation(s)
- Jenpei Lee
- Department of Neurosurgery, Da Chien General Hospital, Miaoli City 36052, Taiwan;
| | - Yingxiao Li
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien City 970302, Taiwan;
| | - Juei-Tang Cheng
- Graduate Institute of Medical Science, Chang Jung Christian University, Tainan City 71101, Taiwan
| | - I-Min Liu
- Department of Pharmacy, College of Pharmacy and Health Care, Tajen University, Pingtung 90741, Taiwan;
| | - Kai-Chun Cheng
- Department of Pharmacy, College of Pharmacy and Health Care, Tajen University, Pingtung 90741, Taiwan;
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Chrysavgis LG, Kazanas S, Bafa K, Rozani S, Koloutsou ME, Cholongitas E. Glucagon-like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide, and Glucagon Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Medication in New Liver Disease Nomenclature. Int J Mol Sci 2024; 25:3832. [PMID: 38612640 PMCID: PMC11012092 DOI: 10.3390/ijms25073832] [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: 02/11/2024] [Revised: 03/15/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that regulate postprandial glucose regulation, stimulating insulin secretion from pancreatic β-cells in response to food ingestion. Modified GLP-1 receptor agonists (GLP-1RAs) are being administered for the treatment of obesity and type 2 diabetes mellitus (T2DM). Strongly related to those disorders, metabolic dysfunction-associated steatotic liver disease (MASLD), especially its aggressive form, defined as metabolic dysfunction-associated steatohepatitis (MASH), is a major healthcare burden associated with high morbidity and extrahepatic complications. GLP-1RAs have been explored in MASH patients with evident improvement in liver dysfunction enzymes, glycemic control, and weight loss. Importantly, the combination of GLP-1RAs with GIP and/or glucagon RAs may be even more effective via synergistic mechanisms in amelioration of metabolic, biochemical, and histological parameters of MASLD but also has a beneficial impact on MASLD-related complications. In this current review, we aim to provide an overview of incretins' physiology, action, and signaling. Furthermore, we provide insight into the key pathophysiological mechanisms through which they impact MASLD aspects, as well as we analyze clinical data from human interventional studies. Finally, we discuss the current challenges and future perspectives pertinent to this growing area of research and clinical medicine.
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Affiliation(s)
- Lampros G. Chrysavgis
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Spyridon Kazanas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Konstantina Bafa
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Sophia Rozani
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Maria-Evangelia Koloutsou
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece;
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
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Zuo Q, Park NH, Lee JK, Santaliz-Casiano A, Madak-Erdogan Z. Navigating nonalcoholic fatty liver disease (NAFLD): Exploring the roles of estrogens, pharmacological and medical interventions, and life style. Steroids 2024; 203:109330. [PMID: 37923152 DOI: 10.1016/j.steroids.2023.109330] [Citation(s) in RCA: 3] [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: 09/07/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
The pursuit of studying this subject is driven by the urgency to address the increasing global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) and its profound health implications. NAFLD represents a significant public health concern due to its association with metabolic disorders, cardiovascular complications, and the potential progression to more severe conditions like non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Liver estrogen signaling is important for maintaining liver function, and loss of estrogens increases the likelihood of NAFLD in postmenopausal women. Understanding the multifaceted mechanisms underlying NAFLD pathogenesis, its varied treatment strategies, and their effectiveness is crucial for devising comprehensive and targeted interventions. By unraveling the intricate interplay between genetics, lifestyle, hormonal regulation, and gut microbiota, we can unlock insights into risk stratification, early detection, and personalized therapeutic approaches. Furthermore, investigating the emerging pharmaceutical interventions and dietary modifications offers the potential to revolutionize disease management. This review reinforces the role of collaboration in refining NAFLD comprehension, unveiling novel therapeutic pathways, and ultimately improving patient outcomes for this intricate hepatic condition.
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Affiliation(s)
- Qianying Zuo
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
| | - Nicole Hwajin Park
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
| | - Jenna Kathryn Lee
- Department of Neuroscience, Northwestern University, Evanston, IL 60208, USA
| | - Ashlie Santaliz-Casiano
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
| | - Zeynep Madak-Erdogan
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute of Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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Maldonado-Rojas ADC, Zuarth-Vázquez JM, Uribe M, Barbero-Becerra VJ. Insulin resistance and Metabolic dysfunction-associated steatotic liver disease (MASLD): Pathways of action of hypoglycemic agents. Ann Hepatol 2024; 29:101182. [PMID: 38042482 DOI: 10.1016/j.aohep.2023.101182] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 11/02/2023] [Accepted: 11/15/2023] [Indexed: 12/04/2023]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by overweight/obesity, and the presence of type 2 diabetes mellitus is the most important criterion. We propose an independent disease perspective without exclusion criteria and with less heterogeneity and greater impact because, according to the National Health and Nutrition Survey (ENSANUT), in Mexico, 25 % of adults over 60 years of age suffer from diabetes, and 96 % of those over 50 years of age have abdominal obesity. Due to the impact of insulin resistance in the pathophysiology of MASLD, which results in damage to hepatocytes, this work aims to provide an overview of the action pathways of hypoglycemic agents such as glucagon-like-1 receptor agonist and peroxisome proliferator-activated receptor-gamma agonists, whose importance lies in the fact that they are currently undergoing phase 2 studies, as well as dipeptidyl peptidase 4 inhibitors and sodium-glucose co-transporter type 2 inhibitors, which are undergoing phase 1 study trials.
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Affiliation(s)
- Andrea Del Carmen Maldonado-Rojas
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico; Universidad Popular Autónoma del Estado de Puebla (UPAEP), Mexico City, Puebla, Mexico
| | - Julia María Zuarth-Vázquez
- Internal Medicine Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico; Endocrinology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Misael Uribe
- Gastroenterology and Obesity Unit. Medica Sur Clinic & Foundation, Mexico City, Mexico
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Millán-Rodríguez C, Castelló CP, Caballero-Valderrama MDR, Esquivias GB. Clinical Management of Non-alcoholic Steatohepatitis and the Role of the Cardiologist. Eur Cardiol 2023; 18:e64. [PMID: 38213666 PMCID: PMC10782421 DOI: 10.15420/ecr.2023.22] [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: 05/02/2023] [Accepted: 06/05/2023] [Indexed: 01/13/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of fat-associated liver conditions that increase risk of cardiovascular disease and mortality. The diagnosis and clinical management of NAFLD remain a challenge for cardiologists. Our group performed a systematic review in PubMed of the relationship between NAFLD and cardiovascular disease, identifying 35 relevant articles. NAFLD is likely to be the liver's expression of metabolic syndrome and increases the risk of several cardiovascular diseases, including coronary artery disease, stroke, heart failure and electrical disorders, and chronic kidney disease. Echocardiography is a useful tool to check early subclinical abnormalities in heart structure and function linked to NAFLD progression, such as cardiac diastolic impairment or epicardial fat thickness. Currently, NAFLD is predominantly managed by lifestyle changes with the aim of weight loss, based on the Mediterranean diet and intense exercise training. Despite the lack of approved drugs for NAFLD, new potential treatments, mainly glucagon-like peptide-1 agonists or sodium-glucose cotransporter 2 inhibitors, could change cardiologists' approach to this pathology.
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Affiliation(s)
| | | | | | - Gonzalo Barón Esquivias
- Cardiology Unit, University Hospital Virgen del RocíoSeville, Spain
- Cardiovascular Pathophysiology Group, Institute of Biomedicine of Seville – IBiS, University of Seville/ University Hospital Virgen del Rocío/ Spanish National Research CouncilSeville, Spain
- Centro de Investigación en Biomedicina en Red Cardiovascular (CIBER-CV)Madrid, Spain
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Domingues I, Leclercq IA, Beloqui A. Nonalcoholic fatty liver disease: Current therapies and future perspectives in drug delivery. J Control Release 2023; 363:415-434. [PMID: 37769817 DOI: 10.1016/j.jconrel.2023.09.040] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 08/27/2023] [Accepted: 09/20/2023] [Indexed: 10/03/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects approximately 25% of the adult population worldwide. This pathology can progress into end-stage liver disease with life-threatening complications, and yet no pharmacologic therapy has been approved. NAFLD is commonly characterized by excessive fat accumulation in the liver and is in closely associated with insulin resistance and metabolic disorders, which suggests that NAFLD is the hepatic manifestation of metabolic syndrome. Regarding treatment options, the current validated strategy relies on lifestyle modifications (exercise and diet restrictions). Although there are no approved drug-based treatments, several clinical trials are ongoing. Novel targets are being discovered, and the repurposing of drugs that show promising effects in NAFLD is starting to gain more interest. The field of nanotechnology has been growing at an increasing rate, with new and more efficient drug delivery strategies being developed for NAFLD treatment. Nanocarriers can easily encapsulate drugs that need to be better protected from the organism to exert their effect or that need help at reaching their target, thereby helping achieve a better bioavailability. Drug delivery systems can also be designed to target the site of the disease, in this case, the liver. In this review, we focus on the current knowledge of NAFLD pathology, the targets being considered for clinical trials, and the current guidelines and ongoing clinical trials, with a specific focus on potential oral treatments for NAFLD using promising drug delivery strategies.
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Affiliation(s)
- Inês Domingues
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200 Brussels, Belgium
| | - Isabelle A Leclercq
- UCLouvain, Université catholique de Louvain, Institute of Experimental and Clinical Research, Laboratory of Hepato-Gastroenterology, Avenue Emmanuel Mounier 53, 1200 Brussels, Belgium.
| | - Ana Beloqui
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200 Brussels, Belgium; WEL Research Institute, Avenue Pasteur, 6, 1300 Wavre, Belgium.
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10
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Folli F, Finzi G, Manfrini R, Galli A, Casiraghi F, Centofanti L, Berra C, Fiorina P, Davalli A, La Rosa S, Perego C, Higgins PB. Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets. Am J Physiol Endocrinol Metab 2023; 325:E595-E609. [PMID: 37729025 PMCID: PMC10874655 DOI: 10.1152/ajpendo.00236.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/15/2023] [Accepted: 09/16/2023] [Indexed: 09/22/2023]
Abstract
Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments.
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Affiliation(s)
- Franco Folli
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
- Unit of Diabetes, Endocrinology and Metabolism, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - Giovanna Finzi
- Unit of Pathology, Department of Oncology, ASST Sette Laghi, Varese, Italy
| | - Roberto Manfrini
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
- Unit of Diabetes, Endocrinology and Metabolism, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - Alessandra Galli
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Francesca Casiraghi
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
| | - Lucia Centofanti
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
| | - Cesare Berra
- IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Alberto Davalli
- Diabetes and Endocrinology Unit, Department of Internal Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano La Rosa
- Unit of Pathology, Department of Medicine and Technological Innovation, University of Insubria, Varese, Italy
| | - Carla Perego
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Paul B Higgins
- Department of Life & Physical Sciences, Atlantic Technological University, Letterkenny, Ireland
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Bandyopadhyay S, Das S, Samajdar SS, Joshi SR. Role of semaglutide in the treatment of nonalcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis. Diabetes Metab Syndr 2023; 17:102849. [PMID: 37717295 DOI: 10.1016/j.dsx.2023.102849] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 08/18/2023] [Accepted: 08/25/2023] [Indexed: 09/19/2023]
Abstract
AIM This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of 24 weeks of semaglutide treatment in patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). METHODS PubMed, Embase, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov databases were searched for relevant studies. The primary outcome was the change in the serum alanine transaminase level. The secondary outcomes were changes in liver stiffness, liver function test parameters, metabolic parameters, and safety. Pooled mean differences and relative risks were calculated using random-effects models. RESULTS Six hundred studies were screened and eight were included (n = 2413). Semaglutide treatment showed a reduction in serum alanine transaminase [mean difference: 14.07 U/L (95% CI: 19.39 to -8.75); p < 0.001] and aspartate transaminase [mean difference: 6.89 U/L (95% CI: 9.14 to -4.63); p < 0.001] levels. There was a significant improvement in liver fat content [mean difference: 4.97% (95% CI: 6.65 to -3.29); p < 0.001] and liver stiffness [mean difference: 0.96 kPa (95% CI: 1.87 to -0.04); p = 0.04]. There were significant improvements in the glycated hemoglobin level and the lipid profile. However, the risk of serious adverse events [relative risk: 1.54 (95% CI: 1.02 to 2.34); p = 0.04] was high following semaglutide treatment as compared to placebo; the most common ones were gastrointestinal (nausea and vomiting, dyspepsia, decreased appetite, constipation, and diarrhea) and gallbladder-related diseases. CONCLUSION Treatment with 24 weeks of semaglutide could significantly improve liver enzymes, reduce liver stiffness, and improve metabolic parameters in patients with NAFLD/NASH. However, the gastrointestinal adverse effects could be a major concern.
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Affiliation(s)
| | - Saibal Das
- Indian Council of Medical Research - Centre for Ageing and Mental Health, Kolkata, India; Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden
| | - Shambo Samrat Samajdar
- Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, India
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12
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Arvanitakis K, Koufakis T, Popovic D, Maltese G, Mustafa O, Doumas M, Giouleme O, Kotsa K, Germanidis G. GLP-1 Receptor Agonists in Obese Patients with Inflammatory Bowel Disease: from Molecular Mechanisms to Clinical Considerations and Practical Recommendations for Safe and Effective Use. Curr Obes Rep 2023; 12:61-74. [PMID: 37081371 DOI: 10.1007/s13679-023-00506-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/09/2023] [Indexed: 04/22/2023]
Abstract
PURPOSE OF REVIEW To discuss current literature and provide practical recommendations for the safe and effective use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in people with inflammatory bowel disease (IBD) and type 2 diabetes (T2D) and/or obesity. The molecular mechanisms that justify the potential benefits of GLP-1 RA in IBD and the links between IBD, obesity, and cardiovascular disease are also discussed. RECENT FINDINGS Preliminary data suggest that GLP-1 RA can modulate crucial pathways in the pathogenesis of IBD, such as chronic inflammation circuits, intestinal tight junctions, and gut microbiome dysbiosis, setting the stage for human trials to investigate the role of these agents in the treatment of IBD among people with or without diabetes and obesity. However, gastrointestinal side effects related to GLP-1 RA need appropriate clinical management to mitigate risks and maximize the benefits of therapy in people with IBD. GLP-1 RA originally emerged as drugs for the treatment of hyperglycemia and are currently licensed for the management of T2D and/or overweight/obesity. However, their wealth of pleiotropic actions soon raised expectations that they might confer benefits on non-metabolic disorders. Future studies are expected to clarify whether GLP-1 RA deserve an adjunct place in the arsenal of drugs against IBD.
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Affiliation(s)
- Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Djordje Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Giuseppe Maltese
- Department of Diabetes and Endocrinology, Epsom & St Helier University Hospitals, Surrey, SM5 1AA, UK
- Unit for Metabolic Medicine, Cardiovascular Division, Faculty of Life Sciences & Medicine, King's College, London, UK
| | - Omar Mustafa
- Department of Diabetes, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK
- King's College London, London, UK
| | - Michael Doumas
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Olga Giouleme
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece.
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece.
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13
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Wang YD, Wu LL, Qi XY, Wang YY, Liao ZZ, Liu JH, Xiao XH. New insight of obesity-associated NAFLD: Dysregulated "crosstalk" between multi-organ and the liver? Genes Dis 2023; 10:799-812. [PMID: 37396503 PMCID: PMC10308072 DOI: 10.1016/j.gendis.2021.12.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 10/28/2021] [Accepted: 12/01/2021] [Indexed: 11/18/2022] Open
Abstract
Obesity plays a crucial role in the development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism for the pathogenesis of obesity-associated NAFLD remains largely obscure. Although the "multiple hit" theory provides a more accurate explanation of NAFLD pathogenesis, it still cannot fully explain precisely how obesity causes NAFLD. The liver is the key integrator of the body's energy needs, receiving input from multiple metabolically active organs. Thus, recent studies have advocated the "multiple crosstalk" hypothesis, highlighting that obesity-related hepatic steatosis may be the result of dysregulated "crosstalk" among multiple extra-hepatic organs and the liver in obesity. A wide variety of circulating endocrine hormones work together to orchestrate this "crosstalk". Of note, with deepening understanding of the endocrine system, the perception of hormones has gradually risen from the narrow sense (i.e. traditional hormones) to the broad sense of hormones as organokines and exosomes. In this review, we focus on the perspective of organic endocrine hormones (organokines) and molecular endocrine hormones (exosomes), summarizing systematically how the two types of new hormones mediate the dialogue between extra-hepatic organs and liver in the pathogenesis of obesity-related NAFLD.
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Affiliation(s)
- Ya-Di Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Liang-Liang Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xiao-Yan Qi
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Yuan-Yuan Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Zhe-Zhen Liao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Jiang-Hua Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xin-Hua Xiao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
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14
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Nouri-Vaskeh M, Khalili N, Khalaji A, Behnam P, Alizadeh L, Ebrahimi S, Gilani N, Mohammadi M, Madinehzadeh SA, Zarei M. Circulating glucagon-like peptide-1 level in patients with liver cirrhosis. Arch Physiol Biochem 2023; 129:373-378. [PMID: 33043692 DOI: 10.1080/13813455.2020.1828479] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1), a gut-derived incretin hormone, plays a pivotal role in glucose-induced insulin secretion. Currently, the role of incretin hormones in the pathogenesis of cirrhosis is not clearly defined. This study aimed to investigate circulating levels of GLP-1 in liver cirrhosis and its association with the severity of liver disease. METHODS A total of 80 participants including 39 patients with a definite diagnosis of liver cirrhosis and 41 healthy controls recruited in this cross-sectional study. Circulating levels of GLP-1 were determined using the ELISA method. The severity of liver cirrhosis was assessed according to the Child-Pugh, MELD (i), MELD-Na, MELD New, and UK end-stage liver disease score (UKELD) criteria. RESULTS The mean age of patients and healthy subjects was 42.51 ± 12.80 and 42.07 ± 10.92 years, respectively (p value = .869). The mean MELD (i), MELD-Na, MELD New, UKELD, and Child-Pugh scores were 14.36 ± 4.26, 15.26 ± 4.81, 14.74 ± 4.66, 52.33 ± 3.82, and 7.28 ± 1.50, respectively. In this study, circulating levels of GLP-1 were statistically lower in cirrhotic patients compared with healthy controls (95.26 ± 17.15 vs 111.84 ± 38.14 pg/mL; p value = .017). CONCLUSION Larger prospective studies are needed to explore the incretin effect in cirrhosis patients compared with healthy individuals.
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Affiliation(s)
- Masoud Nouri-Vaskeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Neda Khalili
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirreza Khalaji
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pouya Behnam
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Alizadeh
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sara Ebrahimi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Gilani
- Department of Statistics and Epidemiology, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Mohammadi
- Department of Biological Science, University of Calgary, Calgary, Canada
- Center for Bioengineering Research and Education, University of Calgary, Calgary, Canada
| | | | - Mohammad Zarei
- Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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15
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Shamardl HAMA, Ibrahim NA, Merzeban DH, Elamir AM, Golam RM, Elsayed AM. Resveratrol and Dulaglutide ameliorate adiposity and liver dysfunction in rats with diet-induced metabolic syndrome: Role of SIRT-1 / adipokines / PPARγ and IGF-1. Daru 2023:10.1007/s40199-023-00458-y. [PMID: 36991247 DOI: 10.1007/s40199-023-00458-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 03/05/2023] [Indexed: 03/31/2023] Open
Abstract
BACKGROUND Adiposity and non-alcoholic fatty liver disease (NAFLD) are common characteristics of metabolic syndrome (MS). Understanding the underlying pathogenesis is crucial for the development of new remedies. Resveratrol controls obesity and glycemic disorders in patients with MS. OBJECTIVES This study aimed to evaluate the effect of resveratrol and dulaglutide on adipose tissues and liver in rats with MS, declaring their possible mechanisms. METHODS Rats allocated as Control, MS (induced by a high fat/ high sucrose diet for eight weeks), MS + Resveratrol (30 mg/kg/day orally), and MS + Dulaglutide (0.6 mg/kg twice weekly SC); drugs administration was in the last four weeks. Serum biochemical measurements were done. Liver and visceral fat were processed for biochemistry, histopathology, and immunohistochemistry. RESULTS MS results demonstrated significantly increased systolic and diastolic blood pressure, anthropometric measurements, serum levels of alanine aminotransferase (ALT), glycemic indices, and lipids with decreased HDL-C. Tissue levels of leptin, malondialdehyde (MDA), and TNF-α reactivity significantly increased. Expression of adiponectin, PPARγ, and insulin growth factor-1 (IGF-1) decreased. Also, Western blotting mRNA gene expression of liver SIRT-1 was down-regulated. Resveratrol and dulaglutide significantly and effectively reversed MS complexity, ameliorating all findings, particularly NAFLD and adiposity-induced inflammation. Resveratrol significantly appears superior to dulaglutide regarding the effects on hemodynamics, lipids, adipokines, IGF-1 levels, and adipocyte size. Parallel, dulaglutide has more influence on glycemic control. CONCLUSION Protective effects of the drugs may be through correlations between SIRT-1/adipokines/IGF-1 and PPARγ, improving the cross-talk between insulin resistance, obesity markers, liver dysfunction, and TNF-α. Promising multi-beneficial therapies of resveratrol or dulaglutide in MS are recommended clinically for this purpose. Showing the Experimental Design.
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Affiliation(s)
| | - Noha A Ibrahim
- Histology and Cell Biology Department, Faculty of Medicine, Fayoum University, Fayoum, 19052, Egypt
| | - Dina H Merzeban
- Medical Physiology DepartmentFaculty of Medicine, Fayoum University, Fayoum, 19052, Egypt
| | - Azza M Elamir
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Fayoum University, Fayoum, 19052, Egypt
| | - Rehab M Golam
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Fayoum University, Fayoum, 19052, Egypt
| | - Asmaa M Elsayed
- Histology and Cell Biology Department, Faculty of Medicine, Fayoum University, Fayoum, 19052, Egypt
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16
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Menekşe B, Batman A. Effect of Exenatide on Nonalcoholic Steatohepatitis and Inflammation-Related Indices in Diabetic Patients with Non-Alcoholic Fatty Liver Disease. Metab Syndr Relat Disord 2023; 21:205-213. [PMID: 36944132 DOI: 10.1089/met.2022.0088] [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] [Indexed: 03/23/2023] Open
Abstract
Purpose: Diabetes mellitus is a chronic disease often associated with nonalcoholic steatohepatitis (NASH) and obesity. Both obesity and NASH are closely related to inflammation. In this study, we examined how exenatide, a glucagon-like peptide 1 analog, affects inflammatory and NASH-related markers in patients with diabetes. Methods: This retrospective study was conducted on 100 patients who visited our hospital with a diagnosis of type 2 diabetes mellitus. NASH-related indices and inflammatory indices were calculated from data obtained at baseline and at the third month of exenatide treatment. All data were analyzed first in all patients, and then the patients were grouped according to glycosylated hemoglobin A1c (HbA1c) levels of <8% or ≥8% and body mass index (BMI) of <40 or ≥40 kg/m2 and their data were reanalyzed. Results: A highly significant improvement was found in the conventional lipid profile. Among NASH-related indices, the nonalcoholic fatty liver disease (NAFLD) fibrosis score and aspartate aminotransferase-platelet ratio index (APRI) showed statistically significant decreases (P < 0.001 and P = 0.016, respectively). In particular, these significant decreases were independent of BMI and glycemic parameters. No statistically significant change was found in inflammatory indices. The decreases in NAFLD fibrosis score and APRI were statistically more significant in the group with HbA1c ≥8% (P = 0.021 and P = 0.002, respectively) and the group with BMI ≥40 kg/m2 (P = 0.002 and P = 0.029, respectively). Conclusions: Besides its established effects, such as lowering fasting plasma glucose levels and weight loss, exenatide exerts positive effects on the conventional lipid profile and NASH-associated indexes.
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Affiliation(s)
- Burak Menekşe
- Department of Internal Medicine, Aksaray Training and Research Hospital, Aksaray, Turkey
| | - Adnan Batman
- Department of Endocrinology and Metabolism, School of Medicine, Koc University, Istanbul, Turkey
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17
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Abenavoli L, Maurizi V, Rinninella E, Tack J, Di Berardino A, Santori P, Rasetti C, Procopio AC, Boccuto L, Scarpellini E. Fecal Microbiota Transplantation in NAFLD Treatment. Medicina (B Aires) 2022; 58:medicina58111559. [PMID: 36363516 PMCID: PMC9695159 DOI: 10.3390/medicina58111559] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022] Open
Abstract
Introduction: Gut microbiota is not only a taxonomic biologic ecosystem but is also involved in human intestinal and extra-intestinal functions such as immune system modulation, nutrient absorption and digestion, as well as metabolism regulation. The latter is strictly linked to non-alcoholic fatty liver disease (NAFLD) pathophysiology. Materials and methods: We reviewed the literature on the definition of gut microbiota, the concepts of “dysbiosis” and “eubiosis”, their role in NAFLD pathogenesis, and the data on fecal microbiota transplantation (FMT) in these patients. We consulted the main medical databases using the following keywords, acronyms, and their associations: gut microbiota, eubiosis, dysbiosis, bile acids, NAFLD, and FMT. Results: Gut microbiota qualitative and quantitative composition is different in healthy subjects vs. NALFD patients. This dysbiosis is associated with and involved in NAFLD pathogenesis and evolution to non-acoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma (HCC). In detail, microbial-driven metabolism of bile acids (BAs) and interaction with hepatic and intestinal farnesoid nuclear X receptor (FXR) have shown a determinant role in liver fat deposition and the development of fibrosis. Over the use of pre- or probiotics, FMT has shown preclinical and initial clinical promising results in NAFLD treatment through re-modulation of microbial dysbiosis. Conclusions: Promising clinical data support a larger investigation of gut microbiota dysbiosis reversion through FMT in NAFLD using randomized clinical trials to design precision-medicine treatments for these patients at different disease stages.
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy
| | - Valentina Maurizi
- Internal Medicine Residency Program, Università Politecnica delle Marche, 60121 Ancona, Italy
| | - Emanuele Rinninella
- Clinical Nutrition Unit, Fondazione Policlinico A. Gemelli IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Jan Tack
- T.A.R.G.I.D., Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Arianna Di Berardino
- Clinical Nutrition and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy
| | - Pierangelo Santori
- Hepatology and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy
| | - Carlo Rasetti
- Clinical Nutrition and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy
- Hepatology and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy
| | | | - Luigi Boccuto
- Healthcare Genetics and Genomics Doctoral Program, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, 105 Sikes Hall, Clemson, SC 29631, USA
| | - Emidio Scarpellini
- T.A.R.G.I.D., Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
- Clinical Nutrition and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy
- Correspondence: ; Tel.: +3907-3579-3301; Fax: +3907-3579-3306
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Polyzos SA, Goulis DG, Giouleme O, Germanidis GS, Goulas A. Anti-obesity Medications for the Management of Nonalcoholic Fatty Liver Disease. Curr Obes Rep 2022; 11:166-179. [PMID: 35501557 DOI: 10.1007/s13679-022-00474-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/11/2022] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW Obesity is closely associated with nonalcoholic fatty liver disease (NAFLD), a highly prevalent disease without any approved medication. The aim of this review was to summarize the evidence on the effect of anti-obesity medications on NAFLD, especially focusing on hepatic histology. RECENT FINDINGS Orlistat and some glucagon-like peptide-1 receptor analogs, including liraglutide and semaglutide, have beneficial effects on hepatic steatosis and inflammation, but not fibrosis. Other anti-obesity medications, including lorcaserin, setmelanotide, phentermine hydrochloric, phentermine/topiramate, and naltrexone/bupropion, have been minimally investigated in NAFLD. Furthermore, medications like sodium-glucose cotransporter-2 inhibitors and farnesoid X receptor have shown beneficial effects in both NAFLD and obesity, but they have not been licensed for either disease. Liraglutide, semaglutide, and orlistat may be currently used in selected patients with obesity and NAFLD. Further research is warranted, since targeting obesity may provide additional benefits on its comorbidities, including NAFLD.
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Affiliation(s)
- Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
| | - Dimitrios G Goulis
- Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Olga Giouleme
- 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgios S Germanidis
- 1st Department of Internal Medicine, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
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Zhang Q, Chen Q, Yan C, Niu C, Zhou J, Liu J, Song Y, Zhou F, Fan Y, Ren J, Xu H, Zhang B. The Absence of STING Ameliorates Non-Alcoholic Fatty Liver Disease and Reforms Gut Bacterial Community. Front Immunol 2022; 13:931176. [PMID: 35844603 PMCID: PMC9279660 DOI: 10.3389/fimmu.2022.931176] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 05/30/2022] [Indexed: 01/18/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the primary causes of cirrhosis and a major risk factor for hepatocellular carcinoma and liver-related death. It has been correlated with changes in the gut microbiota, which promote its development by regulating insulin resistance, bile acid and choline metabolism, and inflammation. Recent studies suggested a controversial role of the stimulator of interferon genes (STING) in the development of NAFLD. Here, we showed that as an immune regulator, STING aggravates the progression of NAFLD in diet-induced mice and correlated it with the changes in hepatic lipid metabolism and gut microbiota diversity. After feeding wild-type (WT) and STING deletion mice with a normal control diet (NCD) or a high-fat diet (HFD), the STING deletion mice showed decreased lipid accumulation and liver inflammation compared with WT mice fed the same diet. In addition, STING specifically produced this hepatoprotective effect by inhibiting the activation of CD8+ T cells. The gut microbiota analysis revealed significant differences in intestinal bacteria between STING deletion mice and WT mice under the same diet and environmental conditions; moreover, differential bacterial genera were associated with altered metabolic phenotypes and involved in related metabolic pathways. Overall, our findings reveal the important regulatory role that STING plays in the progression of NAFLD. In addition, the change in intestinal microbiota diversity may be the contributing factor.
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Affiliation(s)
- Qiang Zhang
- Department of Gastroenterology, Yancheng Third People’s Hospital (The Yancheng School of Clinical Medicine of Nanjing Medical University), Yancheng, China
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
- Department of Digestive Disease, School of Medicine, Xiamen University, Xiamen, China
| | - Qiongyun Chen
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
- Department of Digestive Disease, School of Medicine, Xiamen University, Xiamen, China
| | - Changsheng Yan
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
- Department of Digestive Disease, School of Medicine, Xiamen University, Xiamen, China
| | - Chunyan Niu
- Department of Gastroenterology, Nanjing Lishui People’s Hospital (Zhongda Hospital Lishui Branch, Southeast University), Nanjing, China
| | - Jingping Zhou
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
| | - Jingjing Liu
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
| | - Yang Song
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
| | - Fei Zhou
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
| | - Yanyun Fan
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
| | - Jianlin Ren
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
- Department of Digestive Disease, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Key Laboratory of Intestinal Microbiome and Human Health, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, China
| | - Hongzhi Xu
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
- Department of Digestive Disease, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Key Laboratory of Intestinal Microbiome and Human Health, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, China
| | - Bangzhou Zhang
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
- Department of Digestive Disease, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Key Laboratory of Intestinal Microbiome and Human Health, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China
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20
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Gravina AG, Romeo M, Pellegrino R, Tuccillo C, Federico A, Loguercio C. Just Drink a Glass of Water? Effects of Bicarbonate-Sulfate-Calcium-Magnesium Water on the Gut-Liver Axis. Front Pharmacol 2022; 13:869446. [PMID: 35837275 PMCID: PMC9274271 DOI: 10.3389/fphar.2022.869446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/16/2022] [Indexed: 12/18/2022] Open
Abstract
Background and Aim: Fonte Essenziale® water is a bicarbonate-sulfate-calcium-magnesium water, low in sodium, recognized by the Italian health care system in hydropinotherapy and hepatobiliary dyspepsia therapy. We wanted to explore its effects on the gut-liver axis and microbiota in non-alcoholic fatty liver disease patients. Patients and Methods: We considered enrollment for 70 patients, of which four were excluded. We finally enrolled 55 patients with ultrasound-documented steatosis (SPs+) and 11 patients without it (SPs-). They then drank 400 ml of water for 6 months in the morning on an empty stomach. Routine hematochemical and metabolic parameters, oxidative stress parameters, gastrointestinal hormone levels, and fecal parameters of the gut microbiota were evaluated at three different assessment times, at baseline (T0), after 6 months (T6), and after a further 6 months of water washout (T12). We lost, in follow-up, 4 (T6) and 22 (T12) patients. Results: Between T0-T6, we observed a significant Futuin A and Selenoprotein A decrease and a GLP-1 and PYY increase in SPs+ and the same for Futuin A and GLP-1 in SPs-. Effects were lost at T12. In SPs+, between T0-T12 and T6-12, a significant reduction in Blautia was observed; between T0-T12, a reduction of Collinsella unc. was observed; and between T0-T12 and T6-12, an increase in Subdoligranulum and Dorea was observed. None of the bacterial strains we analyzed varied significantly in the SPs- population. Conclusion: These results indicate beneficial effects of water on gastrointestinal hormones and hence on the gut-liver axis in the period in which subjects drank water both in SPs- and in SPs+.
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21
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Li YX, Cheng KC, Liu IM, Niu HS. Myricetin Increases Circulating Adropin Level after Activation of Glucagon-like Peptide 1 (GLP-1) Receptor in Type-1 Diabetic Rats. Pharmaceuticals (Basel) 2022; 15:ph15020173. [PMID: 35215286 PMCID: PMC8877079 DOI: 10.3390/ph15020173] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/16/2022] [Accepted: 01/22/2022] [Indexed: 02/05/2023] Open
Abstract
Myricetin is a common plant-derived flavonoid, considered an agonist of glucagon-like peptide 1 (GLP-1) receptor. It improves glycemic control and helps reduce body weight in diabetic subjects. The potential mechanisms of action of myricetin in this context might be enhancing the secretion of β-endorphin (BER) to activate peripheral μ-opioid receptors. Moreover, adropin is a nutritionally regulated peptide hormone, which regulates energy metabolism, and plays a role in ameliorating diabetes. Because their mechanisms of insulin sensitivity are closely related, we hypothesized that myricetin may interact with adropin and plasma BER. The present study investigated the glucose-lowering effect of acute and chronic treatments of myricetin in type-1 diabetic rats. Plasma BER and adropin levels were determined by enzyme-linked immunosorbent assay (ELISA). The secretion of BER was measured in rats who received adrenalectomy. The changes in adropin gene (Enho) or mRNA level of GLP-1 receptor were measured using qPCR analysis. The results showed that myricetin dose-dependently increased plasma BER and adropin levels like the reduction of hyperglycemia after bolus injection as acute treatment. In addition, these effects of myricetin were inhibited by the antagonist of GLP-1 receptor. Moreover, in HepG2 cell line, myricetin induced GLP-1 receptor activation, which modulated the expression of adropin. In diabetic rats, the plasma adropin increased by myricetin is mainly through endogenous β-endorphin after activation of GLP-1 receptor via bolus injection as acute treatment. Additionally, chronic treatment with myricetin increased adropin secretion in diabetic rats. In conclusion, our results provide a new finding that activation of opioid μ-receptor in the liver may enhance circulating adropin in animals.
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Affiliation(s)
- Ying-Xiao Li
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien 970302, Taiwan;
| | - Kai-Chun Cheng
- Department of Pharmacy, College of Pharmacy and Health Care, Tajen University, Pingtung County 90741, Taiwan; (K.-C.C.); (I.-M.L.)
| | - I-Min Liu
- Department of Pharmacy, College of Pharmacy and Health Care, Tajen University, Pingtung County 90741, Taiwan; (K.-C.C.); (I.-M.L.)
| | - Ho-Shan Niu
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien 970302, Taiwan;
- Correspondence:
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22
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Laurindo LF, Barbalho SM, Guiguer EL, da Silva Soares de Souza M, de Souza GA, Fidalgo TM, Araújo AC, de Souza Gonzaga HF, de Bortoli Teixeira D, de Oliveira Silva Ullmann T, Sloan KP, Sloan LA. GLP-1a: Going beyond Traditional Use. Int J Mol Sci 2022; 23:739. [PMID: 35054924 PMCID: PMC8775408 DOI: 10.3390/ijms23020739] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 02/07/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a human incretin hormone derived from the proglucagon molecule. GLP-1 receptor agonists are frequently used to treat type 2 diabetes mellitus and obesity. However, the hormone affects the liver, pancreas, brain, fat cells, heart, and gastrointestinal tract. The objective of this study was to perform a systematic review on the use of GLP-1 other than in treating diabetes. PubMed, Cochrane, and Embase were searched, and the PRISMA guidelines were followed. Nineteen clinical studies were selected. The results showed that GLP-1 agonists can benefit defined off-medication motor scores in Parkinson's Disease and improve emotional well-being. In Alzheimer's disease, GLP-1 analogs can improve the brain's glucose metabolism by improving glucose transport across the blood-brain barrier. In depression, the analogs can improve quality of life and depression scales. GLP-1 analogs can also have a role in treating chemical dependency, inhibiting dopaminergic release in the brain's reward centers, decreasing withdrawal effects and relapses. These medications can also improve lipotoxicity by reducing visceral adiposity and decreasing liver fat deposition, reducing insulin resistance and the development of non-alcoholic fatty liver diseases. The adverse effects are primarily gastrointestinal. Therefore, GLP-1 analogs can benefit other conditions besides traditional diabetes and obesity uses.
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Affiliation(s)
- Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marília 17500-000, SP, Brazil
| | - Elen Landgraf Guiguer
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marília 17500-000, SP, Brazil
| | - Maricelma da Silva Soares de Souza
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Gabriela Achete de Souza
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Thiago Marques Fidalgo
- Department of Psychiatry, Federal University of São Paulo, R. Sena Madureira 04021-001, SP, Brazil;
| | - Adriano Cressoni Araújo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
| | - Heron F. de Souza Gonzaga
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
| | - Daniel de Bortoli Teixeira
- Postgraduate Program in Animal Health, Production and Environment, University of Marilia, Marília 17525-902, SP, Brazil;
| | - Thais de Oliveira Silva Ullmann
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Katia Portero Sloan
- Texas Institute for Kidney and Endocrine Disorders, Lufkin, TX 75904, USA; (K.P.S.); (L.A.S.)
| | - Lance Alan Sloan
- Texas Institute for Kidney and Endocrine Disorders, Lufkin, TX 75904, USA; (K.P.S.); (L.A.S.)
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
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Unsal İO, Calapkulu M, Sencar ME, Cakal B, Ozbek M. Evaluation of NAFLD fibrosis, FIB-4 and APRI score in diabetic patients receiving exenatide treatment for non-alcoholic fatty liver disease. Sci Rep 2022; 12:283. [PMID: 34997159 PMCID: PMC8741957 DOI: 10.1038/s41598-021-04361-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023] Open
Abstract
There is a closely relationship between the development and progression of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD) and obesity and diabetes. NAFLD fibrosis scores should be routinely used to rule out patients with advanced fibrosis. High scores may help identify patients at higher risk of all causes andliverrelated morbidity and mortality. The aim of this study was to investigate the association between exenatide and fibrosis scores. The effect of exenatide treatment on fibrosis scores was evaluated in type 2 diabetes mellitus (DM) patients with MAFLD. Evaluation was made of 50 patients with type 2 DM and MAFLD. The NFS, FIB4 and APRI scores were calculated before and after 6 months of treatment. After 6 months of exenatide treatment, the NFS and APRI scores were determined to have decreased significantly. Exenatide was observed to control blood glucose, reduce body weight and improve fibrosis scores in MAFLD patients with type 2 diabetes.
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Affiliation(s)
- İlknur Ozturk Unsal
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Sehit Omer Halisdemir Avenue, 06110, Ankara, Turkey.
| | - Murat Calapkulu
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Sehit Omer Halisdemir Avenue, 06110, Ankara, Turkey
| | - Muhammed Erkam Sencar
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Sehit Omer Halisdemir Avenue, 06110, Ankara, Turkey
| | - Basak Cakal
- Department of Gastroenterology, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey
| | - Mustafa Ozbek
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Sehit Omer Halisdemir Avenue, 06110, Ankara, Turkey
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24
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Lv Y, Zhang J, Yang T, Sun J, Hou J, Chen Z, Yu X, Yuan X, Lu X, Xie T, Yu T, Su X, Liu G, Zhang C, Li L. Non-Alcoholic Fatty Liver Disease (NAFLD) Is an Independent Risk Factor for Developing New-Onset Diabetes After Acute Pancreatitis: A Multicenter Retrospective Cohort Study in Chinese Population. Front Endocrinol (Lausanne) 2022; 13:903731. [PMID: 35692404 PMCID: PMC9174455 DOI: 10.3389/fendo.2022.903731] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/20/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Numerous studies validated frequent glucose dysfunction in patients with acute pancreatitis (AP). However, the prevalence of new-onset diabetes in individuals after a first episode of AP varies widely among previous studies. This study aims to determine the incidence of post-acute pancreatitis diabetes mellitus (PPDM-A) in Chinese people and further identify potential risk factors that influence diabetes development in patients with AP. METHODS This was a multi-center retrospective cohort study including 6009 inpatients with a first attack of AP. A total of 1804 patients with AP without known endocrine pancreatic disorders or other pancreatic exocrine diseases were eligible for analysis. Data was collected from medical records by hospital information system and telephone follow-ups after discharge. The multiple logistic regression analysis was established to evaluate the potential influencing factors of PPDM-A. RESULTS The prevalence of newly diagnosed diabetes after a first episode of AP in China was 6.2%. Data showed that patients who developed PPDM-A were more likely to be younger (X2 = 6.329, P = 0.012), experienced longer hospital stays (X2 = 6.949, P = 0.008) and had a higher frequency of overweight or obesity (X2 = 11.559, P = 0.003) compared to those with normal glycemia. The frequency of stress hyperglycemia on admission (X2 = 53.815, P < 0.001), hyperlipidemia (X2 = 33.594, P < 0.001) and non-alcoholic fatty liver disease (NAFLD) (X2 = 36.335, P < 0.001) were significantly higher among individuals with PPDM-A compared with control group. Also, patients with PPDM-A were more likely to be hyperlipidemic AP (X2 = 16.304, P = 0.001) and show a higher degree of severity (X2 = 7.834, P = 0.020) and recurrence rate (X2 = 26.908, P < 0.001) of AP compared to those without diabetes. In addition, multiple logistic regression analysis indicated that stress hyperglycemia, hyperlipidemia, NAFLD and repeated attacks of AP were the independent influence factors for developing PPDM-A. CONCLUSION Our study first demonstrated the prevalence of secondary diabetes in Chinese patients after AP. The disorder of glucose metabolism in individuals with AP should be regularly evaluated in clinical practice. Further studies are needed to verify the relationship between liver and pancreas in keeping glucose homeostasis under AP condition.
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Affiliation(s)
- Yingqi Lv
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jun Zhang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Ting Yang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jinfang Sun
- Key Laboratory of Environmental, Medicine Engineering, Ministry of Education, school of Public Health, Southeast University, Nanjing, China
| | - Jiaying Hou
- Department of Endocrinology, Changji Branch, First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Zhiwei Chen
- Department of Endocrinology, Hunan Provincial People’s Hospital (First Affiliated Hospital of Hunan Normal University), Changsha, China
| | - Xuehua Yu
- Department of Gastroenterology, Hebei General Hospital, Shijiazhuang, China
| | - Xuelu Yuan
- Department of Endocrinology, Yixing Second People’s Hospital, Wuxi, China
| | - Xuejia Lu
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Ting Xie
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Ting Yu
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Xianghui Su
- Department of Endocrinology, Changji Branch, First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Gaifang Liu
- Department of Gastroenterology, Hebei General Hospital, Shijiazhuang, China
- *Correspondence: Ling Li, ; Chi Zhang, ; Gaifang Liu,
| | - Chi Zhang
- Department of Endocrinology, Hunan Provincial People’s Hospital (First Affiliated Hospital of Hunan Normal University), Changsha, China
- *Correspondence: Ling Li, ; Chi Zhang, ; Gaifang Liu,
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
- *Correspondence: Ling Li, ; Chi Zhang, ; Gaifang Liu,
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25
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Niu S, Chen S, Chen X, Ren Q, Yue L, Pan X, Zhao H, Li Z, Chen X. Semaglutide ameliorates metabolism and hepatic outcomes in an NAFLD mouse model. Front Endocrinol (Lausanne) 2022; 13:1046130. [PMID: 36568109 PMCID: PMC9780435 DOI: 10.3389/fendo.2022.1046130] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/14/2022] [Indexed: 12/14/2022] Open
Abstract
PURPOSE The aim of this study was to evaluate changes in body weight, liver weight, blood glucose, liver injury markers, pro-inflammatory factors and oxidative stress marker levels in obese mice with HFD induced NAFLD after semaglutide use. PATIENTS AND METHODS The 24 C57BL6J mice were randomly divided into three groups (NCD, HFD and Sema) for the assessment of metabolic status, inflammatory factor and oxidative stress marker levels, liver histopathology in mice. Liver metabolomics was determined by liquid chromatography/mass spectrometry (LC-MS) method. RESULTS The mice body weight, liver weight, blood glucose, TG, TCHO, LDL and pro-inflammatory factors were significantly reduced after semaglutide. Meanwhile, semaglutide increased the SOD level. Semaglutide treatment significantly improved the pathological changes such as hepatocyte steatosis, balloon degeneration and lymphoid foci by HE. It also significantly reduced lipid droplet by Oil Red O. The mitochondria were swollen, the volume increased, the cristae were partially broken and reduced, the intramembrane matrix was partially dissolved, and the mitophagy structure was visible in the visual field. There were 6 metabolites down-regulated and 2 metabolites significantly up-regulated after semaglutide treatment. CONCLUSIONS Semaglutide can reduce blood glucose level and liver fat accumulation and play an anti-inflammatory role in advanced NAFLD that due to the effects of HFD.
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Affiliation(s)
- Shu Niu
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Endocrine, Shijiazhuang People's Hospital, Shijiazhuang, Hebei, China
| | - Shuchun Chen
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Internal Medical, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xing Chen
- Department of Internal Medical, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Qingjuan Ren
- Department of Endocrine, Shijiazhuang People's Hospital, Shijiazhuang, Hebei, China
| | - Lin Yue
- Department of Endocrine, The Third Hospital of Shijiazhuang, Shijiazhuang, Hebei, China
| | - Xiaoyu Pan
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Huiying Zhao
- Department of Endocrine, Shijiazhuang People's Hospital, Shijiazhuang, Hebei, China
| | - Zelin Li
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaoyi Chen
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
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Santos-Laso A, Gutiérrez-Larrañaga M, Alonso-Peña M, Medina JM, Iruzubieta P, Arias-Loste MT, López-Hoyos M, Crespo J. Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets. Biomedicines 2021; 10:biomedicines10010046. [PMID: 35052726 PMCID: PMC8773141 DOI: 10.3390/biomedicines10010046] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/23/2021] [Accepted: 12/23/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with results expected in the near future. Here, we summarize the key aspects of NAFLD pathogenesis and therapeutic targets in this frequent disorder, highlighting the most recent advances in the field and future research directions.
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Affiliation(s)
- Alvaro Santos-Laso
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- Correspondence: (A.S.-L.); (J.C.)
| | - María Gutiérrez-Larrañaga
- Department of Immunology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.G.-L.); (M.L.-H.)
| | - Marta Alonso-Peña
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
| | - Juan M. Medina
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
| | - Paula Iruzubieta
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), 28029 Madrid, Spain
| | - María Teresa Arias-Loste
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), 28029 Madrid, Spain
| | - Marcos López-Hoyos
- Department of Immunology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.G.-L.); (M.L.-H.)
| | - Javier Crespo
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), 28029 Madrid, Spain
- Correspondence: (A.S.-L.); (J.C.)
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27
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Zheng W, Li L, Li H. Phytochemicals modulate pancreatic islet β cell function through glucagon-like peptide-1-related mechanisms. Biochem Pharmacol 2021; 197:114817. [PMID: 34717897 DOI: 10.1016/j.bcp.2021.114817] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/22/2021] [Accepted: 10/25/2021] [Indexed: 11/19/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor-based therapies have been developed and extensively applied in clinical practice. GLP-1 plays an important role in improving glycemic homeostasis by stimulating insulin biosynthesis and secretion, suppressing glucagon activity, delaying gastric emptying, and reducing appetite and food ingestion. Furthermore, GLP-1 has positive effects on β-cell function by promoting β-cell proliferation and neogenesis while simultaneously reducing apoptosis. Here, we summarize possible mechanisms of action of GLP-1 upon pancreatic islets as well as describe phytochemicals that modulate pancreatic islet β cell function through glucagon-like peptide-1-related mechanisms. Together, this information provides potential lead compound candidates against diabetes that function as GLP-1 receptor-based pharmacotherapy.
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Affiliation(s)
- Wanfang Zheng
- Institute of Pharmacology, Zhejiang University of Technology, Hangzhou 310014, People's Republic of China
| | - Linghuan Li
- Institute of Pharmacology, Zhejiang University of Technology, Hangzhou 310014, People's Republic of China
| | - Hanbing Li
- Institute of Pharmacology, Zhejiang University of Technology, Hangzhou 310014, People's Republic of China; Section of Endocrinology, School of Medicine, Yale University, New Haven 06520, USA.
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Effects of Roux-en-Y Gastric Bypass and Sleeve Gastrectomy on Non-Alcoholic Fatty Liver Disease: A 12-Month Follow-Up Study with Paired Liver Biopsies. J Clin Med 2021; 10:jcm10173783. [PMID: 34501231 PMCID: PMC8432029 DOI: 10.3390/jcm10173783] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/20/2021] [Accepted: 08/22/2021] [Indexed: 12/25/2022] Open
Abstract
Roux-en-Y gastric bypass (RYGB) improves, and can sometimes resolve, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) but data based on histological assessment for the efficacy of sleeve gastrectomy (SG) in resolving NAFLD are sparse. Consequently, we aimed to compare the efficacy of RYGB vs. SG on NAFLD 12 months after surgery. In a prospective cohort study, 40 patients with obesity underwent bariatric surgery (16 RYGB and 24 SG). During surgery, a liver biopsy was taken and repeated 12 months later. NAFLD severity was evaluated using the NAFLD Activity Score (NAS) and Kleiner Fibrosis score. RYGB and SG patients were comparable at baseline. Mean (standard deviation, SD) NAS was 3.3 (0.9) in RYGB and 3.1 (1.4) in SG (p = 0.560) with similar degrees of steatosis, inflammation, and ballooning. Two RYGB patients, and six SG patients, had NASH (p = 0.439). Twelve months after surgery, NAS was significantly and comparably (p = 0.241) reduced in both RYGB (−3.00 (95% CI −3.79–−2.21), p < 0.001) and SG (−2.25 (95% CI −2.92–−1.59), p < 0.001) patients. RYGB patients had significantly more reduced (p = 0.007) liver steatosis (−0.91 (95% CI −1.47–−1.2) than SG patients (−0.33 (95% CI −0.54–−0.13) and greater improvement in the plasma lipid profile. Fibrosis declined non-significantly. NASH was resolved in seven of eight patients without a worsening of their fibrosis. RYGB and SG have similar beneficial effects on NAS and NASH without the worsening of fibrosis. RYGB is associated with a more pronounced reduction in liver steatosis.
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Han H, Jiang Y, Wang M, Melaku M, Liu L, Zhao Y, Everaert N, Yi B, Zhang H. Intestinal dysbiosis in nonalcoholic fatty liver disease (NAFLD): focusing on the gut-liver axis. Crit Rev Food Sci Nutr 2021; 63:1689-1706. [PMID: 34404276 DOI: 10.1080/10408398.2021.1966738] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders in humans, partly because it is closely related to metabolic disorders of the liver with increasing prevalence. NAFLD begins with hepatic lipid accumulation, which may cause inflammation and eventually lead to fibrosis in the liver. Numerous studies have demonstrated the close relationship between gut dysfunction (especially the gut microbiota and its metabolites) and the occurrence and progression of NAFLD. The bidirectional communication between the gut and liver, named the gut-liver axis, is mainly mediated by the metabolites derived from both the liver and gut through the biliary tract, portal vein, and systemic circulation. Herein, we review the effects of the gut-liver axis on the pathogenesis of NAFLD. We also comprehensively describe the potential molecular mechanisms from the perspective of the role of liver-derived metabolites and gut-related components in hepatic metabolism and inflammation and gut health, respectively. The study provides insights into the mechanisms underlying current summarizations that support the intricate interactions between a disordered gut and NAFLD and can provide novel strategies to lessen the prevalence and consequence of NAFLD.
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Affiliation(s)
- Hui Han
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China.,Precision Livestock and Nutrition Unit, Gembloux Agro-Bio Tech, University of Liège, Gembloux, Belgium
| | - Yi Jiang
- Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Hubei, China
| | - Mengyu Wang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Mebratu Melaku
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China.,Department of Animal Production and Technology, College of Agriculture, Woldia University, Woldia, Ethiopia
| | - Lei Liu
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Yong Zhao
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Nadia Everaert
- Precision Livestock and Nutrition Unit, Gembloux Agro-Bio Tech, University of Liège, Gembloux, Belgium
| | - Bao Yi
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
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Bignotto M, Dei Cas M, Paroni R, Bianco E, Zermiani P, Gangale MG, Zadro V, Maregatti M, Piagnani A, Russo A, Baldassarre D, Folli F, Battezzati PM, Zuin M. CA.ME.LI.A. An epidemiological study on the prevalence of CArdiovascular, MEtabolic, LIver and Autoimmune diseases in Northern Italy. Nutr Metab Cardiovasc Dis 2021; 31:1416-1426. [PMID: 33814235 DOI: 10.1016/j.numecd.2021.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS CA.ME.LI.A (CArdiovascular risks, MEtabolic syndrome, LIver and Autoimmune disease) is a cross-sectional, epidemiological study performed between 2009-2011 in Abbiategrasso (Milan, Italy) to estimate the prevalence of cardiovascular risk factors, metabolic syndrome, liver and autoimmune diseases in the general adult population. This report focuses on the description and presentation of baseline characteristics of the population. METHODS AND RESULTS Citizens were randomly selected from the city electoral registers (n = 30903), yielding a sample of 2554 subjects (M = 1257, F = 1297; age, 47 ± 15 yrs; range 18-77 yrs). Men had higher prevalence of overweight or obesity (60.8% vs 41.6%; p < 0.0001) and greater thickness of visceral adipose tissue (40 ± 19 vs 27 ± 17 mm; p < 0.0001); no gender difference was found in subcutaneous adipose tissue thickness. Men also showed higher levels of serum triglycerides, γ-GT, fasting blood glucose, insulin and Homa-IR Index, while HDL, CRP, and prevalence of elevated (>5.0 mg/L) CRP were lower. Compared to normal weight men, risk-ratio (RR) of CRP elevation was 1.32 (ns) in overweight and 2.68 (p < 0.0001) in obese subjects. The corresponding figures in females were 2.68 (p < 0.0001) and 5.18 (p < 0.0001). Metabolic syndrome was more frequent in men (32.7% vs 14.5%; RR: 2.24, p < 0.0001). Interadventitia common carotid artery diameter was higher in men and increased with age and BMI. CONCLUSIONS The present study reports on the overall characteristics of a large population from Northern Italy. It aims to identify the associations among cardiovascular risk factors to prevent their development and progression, improve healthy lifestyle and identify subjects liable to pharmacological interventions.
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Affiliation(s)
- Monica Bignotto
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Michele Dei Cas
- Clinical Biochemistry and Mass Spectrometry, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Rita Paroni
- Clinical Biochemistry and Mass Spectrometry, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Elena Bianco
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Paola Zermiani
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Maria G Gangale
- ASST Ovest Milanese, via Papa Giovanni Paolo II, Legnano, Milan, Italy
| | - Valentina Zadro
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Margherita Maregatti
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Alessandra Piagnani
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Antonio Russo
- Epidemiology Unit, Agency for Health Protection of Milan, Corso Italia 19, 20122, Milan, Italy
| | - Damiano Baldassarre
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy; Centro Cardiologico Monzino, IRCCS, Milan, Italy
| | - Franco Folli
- Endocrinology and Metabolism, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy; ASST Santi Paolo e Carlo, University Hospital San Paolo, via A. Di Rudini', Milan, Italy.
| | - Pier Maria Battezzati
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy; ASST Santi Paolo e Carlo, University Hospital San Paolo, via A. Di Rudini', Milan, Italy
| | - Massimo Zuin
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy; ASST Santi Paolo e Carlo, University Hospital San Paolo, via A. Di Rudini', Milan, Italy.
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Xia M, Rong S, Zhu X, Yan H, Chang X, Sun X, Zeng H, Li X, Zhang L, Chen L, Wu L, Ma H, Hu Y, He W, Gao J, Pan B, Hu X, Lin H, Bian H, Gao X. Osteocalcin and Non-Alcoholic Fatty Liver Disease: Lessons From Two Population-Based Cohorts and Animal Models. J Bone Miner Res 2021; 36:712-728. [PMID: 33270924 DOI: 10.1002/jbmr.4227] [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: 05/19/2020] [Revised: 11/22/2020] [Accepted: 11/27/2020] [Indexed: 12/17/2022]
Abstract
Osteocalcin regulates energy metabolism in an active undercarboxylated/uncarboxylated form. However, its role on the development of non-alcoholic fatty liver disease (NAFLD) is still controversial. In the current study, we investigated the causal relationship of circulating osteocalcin with NAFLD in two human cohorts and studied the effect of uncarboxylated osteocalcin on liver lipid metabolism through animal models. We analyzed the correlations of serum total/uncarboxylated osteocalcin with liver steatosis/fibrosis in a liver biopsy cohort of 196 participants, and the causal relationship between serum osteocalcin and the incidence/remission of NAFLD in a prospective community cohort of 2055 subjects from Shanghai Changfeng Study. Serum total osteocalcin was positively correlated with uncarboxylated osteocalcin (r = 0.528, p < .001). Total and uncarboxylated osteocalcin quartiles were inversely associated with liver steatosis, inflammation, ballooning, and fibrosis grades in both male and female participants (all p for trend <.05). After adjustment for confounding glucose, lipid, and bone metabolism parameters, the male and female participants with lowest quartile of osteocalcin still had more severe liver steatosis, with multivariate-adjusted odds ratios (ORs) of 7.25 (1.07-49.30) and 4.44 (1.01-19.41), respectively. In the prospective community cohort, after a median of 4.2-year follow-up, the female but not male participants with lowest quartile of osteocalcin at baseline had higher risk to develop NAFLD (hazard ratio [HR] = 1.90; 95% confidence interval [CI] 1.14-3.16) and lower chance to achieve NAFLD remission (HR = 0.56; 95% CI 0.31-1.00). In wild-type mice fed a Western diet, osteocalcin treatment alleviated hepatic steatosis and reduced hepatic SREBP-1 and its downstream proteins expression. In mice treated with osteocalcin for a short term, hepatic SREBP-1 expression was decreased without changes of glucose level or insulin sensitivity. When SREBP-1c was stably expressed in a human SREBP-1c transgenic rat model, the reduction of lipogenesis induced by osteocalcin treatment was abolished. In conclusion, circulating osteocalcin was inversely associated with NAFLD. Osteocalcin reduces liver lipogenesis via decreasing SREBP-1c expression. © 2020 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Mingfeng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Shunxing Rong
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xiaopeng Zhu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Hongmei Yan
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Xinxia Chang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Xiaoyang Sun
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Hailuan Zeng
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Xiaoming Li
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Linshan Zhang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Lingyan Chen
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li Wu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Hui Ma
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yu Hu
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wanyuan He
- Department of Ultrasonography, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Gao
- Center of Clinical Epidemiology and EBM of Fudan University, Shanghai, China
- Department of Nutrition, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Baishen Pan
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiqi Hu
- Department of Pathology, Medical College, Fudan University, Shanghai, China
| | - Huandong Lin
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Hua Bian
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
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Hupa-Breier KL, Dywicki J, Hartleben B, Wellhöner F, Heidrich B, Taubert R, Mederacke YSE, Lieber M, Iordanidis K, Manns MP, Wedemeyer H, Hardtke-Wolenski M, Jaeckel E. Dulaglutide Alone and in Combination with Empagliflozin Attenuate Inflammatory Pathways and Microbiome Dysbiosis in a Non-Diabetic Mouse Model of NASH. Biomedicines 2021; 9:biomedicines9040353. [PMID: 33808404 PMCID: PMC8066839 DOI: 10.3390/biomedicines9040353] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/22/2021] [Accepted: 03/25/2021] [Indexed: 12/15/2022] Open
Abstract
Dysregulation of glucose homeostasis plays a major role in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it activates proinflammatory and profibrotic processes. Beneficial effects of antiglycemic treatments such as GLP-1 agonist or SGLT-2 inhibitor on NASH in patients with diabetes have already been investigated. However, their effect on NASH in a non-diabetic setting remains unclear. With this aim, we investigated the effect of long-acting GLP1-agonist dulaglutide and SGLT-2 inhibitor empagliflozin and their combination in a non-diabetic mouse model of NASH. C57BL/6 mice received a high-fat-high-fructose (HFHC) diet with a surplus of cholesterol for 16 weeks. After 12 weeks of diet, mice were treated with either dulaglutide, empagliflozin or their combination. Dulaglutide alone and in combination with empagliflozin led to significant weight loss, improved glucose homeostasis and diminished anti-inflammatory and anti-fibrotic pathways. Combination of dulaglutide and empagliflozin further decreased MoMFLy6CHigh and CD4+Foxp3+ T cells. No beneficial effects for treatment with empagliflozin alone could be shown. While no effect of dulaglutide or its combination with empaglifozin on hepatic steatosis was evident, these data demonstrate distinct anti-inflammatory effects of dulaglutide and their combination with empagliflozin in a non-diabetic background, which could have important implications for further treatment of NASH.
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Affiliation(s)
- Katharina Luise Hupa-Breier
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
- Correspondence: ; Tel.: +49-(0)-511-532-6992
| | - Janine Dywicki
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Björn Hartleben
- Department of Pathology, Hannover Medical School, 30625 Hannover, Germany;
| | - Freya Wellhöner
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Young-Seon Elisabeth Mederacke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Maren Lieber
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Konstantinos Iordanidis
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
- Department of Gastroenterology and Hepatology, Essen University Hospital, University Duisburg-Essen, 45147 Essen, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
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Dai Y, He H, Li S, Yang L, Wang X, Liu Z, An Z. Comparison of the Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Metabolic Associated Fatty Liver Disease: Updated Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2021; 11:622589. [PMID: 33664710 PMCID: PMC7924308 DOI: 10.3389/fendo.2020.622589] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/28/2020] [Indexed: 02/05/2023] Open
Abstract
AIMS Metabolic associated fatty liver disease (MAFLD) is the most common cause of chronic liver disease and is a major health and economic burden in society. New drugs are urgently needed to treat MAFLD. This systematic review and meta-analysis was conducted to evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with MAFLD. METHOD We searched PubMed, Embase, Cochrane Library database, and Web of Science since 1977. We selected all randomized controlled trials which met the inclusion and exclusion criteria and evaluated the quality of evidence. A random-effects meta-analysis was performed to assess all the primary and second outcomes. RESULTS Eight randomized controlled trials, including 396 patients, of which 265 patients had type 2 diabetes mellitus, met the inclusion criteria. Compared with the placebo or active agents group, the GLP-RA group showed a significant reduction in the liver fat content [weight mean difference (WMD) -3.17%, 95%CI -5.30 to -1.03, P < 0.0001], body weight (WMD -4.58 kg, 95%CI -8.07 to -1.10, P = 0.010), waist circumference (WMD -3.74 cm, 95%CI -6.73 to -0.74, P = 0.010), alanine aminotransferase (WMD -10.73 U/L, 95%CI -20.94 to -0.52, P = 0.04), γ- glutamyl transferase (WMD -12.25 U/L,95% -18.85 to -5.66, P = 0.0003, with I²=23%), fasting blood glucose (MD, -0.36 mmol/L; 95%CI, -0.69 to -0.03, P = 0.030), and hemoglobin A1c (WMD -0.36%, 95%CI -0.52 to -0.19, P < 0.0001). The reported adverse events were gastrointestinal complications with no serious adverse events, and most symptoms were relieved within 1-2 weeks after dose titration. CONCLUSION GLP-RAs may improve liver injury and metabolic disorder in patients with MAFLD, regardless of the presence of type 2 diabetes mellitus. The benefits of GLP-RAs treatment outweigh the adverse effects of drugs in patients with MAFLD.
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Affiliation(s)
- Yuzhao Dai
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - He He
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Lidan Yang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xia Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zhi Liu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenmei An
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
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Wang Y, Alkhalidy H, Liu D. The Emerging Role of Polyphenols in the Management of Type 2 Diabetes. Molecules 2021; 26:molecules26030703. [PMID: 33572808 PMCID: PMC7866283 DOI: 10.3390/molecules26030703] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Type 2 diabetes (T2D) is a fast-increasing health problem globally, and it results from insulin resistance and pancreatic β-cell dysfunction. The gastrointestinal (GI) tract is recognized as one of the major regulatory organs of glucose homeostasis that involves multiple gut hormones and microbiota. Notably, the incretin hormone glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells plays a pivotal role in maintaining glucose homeostasis via eliciting pleiotropic effects, which are largely mediated via its receptor. Thus, targeting the GLP-1 signaling system is a highly attractive therapeutic strategy to treatment T2D. Polyphenols, the secondary metabolites from plants, have drawn considerable attention because of their numerous health benefits, including potential anti-diabetic effects. Although the major targets and locations for the polyphenolic compounds to exert the anti-diabetic action are still unclear, the first organ that is exposed to these compounds is the GI tract in which polyphenols could modulate enzymes and hormones. Indeed, emerging evidence has shown that polyphenols can stimulate GLP-1 secretion, indicating that these natural compounds might exert metabolic action at least partially mediated by GLP-1. This review provides an overview of nutritional regulation of GLP-1 secretion and summarizes recent studies on the roles of polyphenols in GLP-1 secretion and degradation as it relates to metabolic homeostasis. In addition, the effects of polyphenols on microbiota and microbial metabolites that could indirectly modulate GLP-1 secretion are also discussed.
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Affiliation(s)
- Yao Wang
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA;
| | - Hana Alkhalidy
- Department of Nutrition and Food Technology, Jordan University of Science and Technology, Irbid 22110, Jordan;
| | - Dongmin Liu
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA;
- Correspondence: ; Tel.: +1-540-231-3402; Fax: +1-540-231-3916
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Ramanan SP, Mohamed MWF, Aung SS, Sange I, Hamid P. Treatment of Fatty Liver Disease: The Present and the Future. Cureus 2021; 13:e12713. [PMID: 33614318 PMCID: PMC7883529 DOI: 10.7759/cureus.12713] [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] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) progressing to non-alcoholic steatohepatitis (NASH), cirrhosis, end-stage liver disease (ESRD), and hepatocellular carcinoma (HCC) is emerging as a global epidemic. Obesity, diabetes, and metabolic syndrome are some of the leading risk factors for NAFLD. The most prevalent treatment to stop the progression is aimed at dietary modification and lifestyle changes. Bariatric surgery is indicated for patients with morbid obesity with NAFLD. The progression of NAFLD to NASH and HCC can be arrested at various stages of pathogenesis by the already prevalent drugs and the emerging newer molecular and genetic targets. This review article analyzed various preclinical animal trials and clinical trials and has summarized various groups of drugs that can be life-altering in patients diagnosed with NAFLD. This study also discusses the obstacles in taking these clinical trials to bedside treatment.
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Affiliation(s)
- Sruthi Priyavadhana Ramanan
- Medicine/Surgery, Saveetha Medical College, Chennai, IND.,Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mohamed Wael F Mohamed
- Neurological Surgery, Royal London Hospital, London, GBR.,Neurosciences, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Su Sandi Aung
- Medicine and Surgery, University of Medicine 1, Yangon, MMR.,Neurosciences, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ibrahim Sange
- Medicine, KJ Somaiya Medical College, Mumbai, IND.,Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Pousette Hamid
- Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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36
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Barbero-Becerra V, Juárez-Hernández E, Chávez-Tapia NC, Uribe M. Inulin as a Clinical Therapeutic Intervention in Metabolic Associated Fatty Liver Disease. FOOD REVIEWS INTERNATIONAL 2021. [DOI: 10.1080/87559129.2020.1867997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
| | - Eva Juárez-Hernández
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
| | | | - Misael Uribe
- Gastroenterology and Obesity Unit., Medica Sur Clinic & Foundation, Mexico City, Mexico
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Lee SP, Qi J, Xu G, Rankin MM, Littrell J, Xu JZ, Bakaj I, Pocai A. GRK Inhibition Potentiates Glucagon-Like Peptide-1 Action. Front Endocrinol (Lausanne) 2021; 12:652628. [PMID: 34054727 PMCID: PMC8160450 DOI: 10.3389/fendo.2021.652628] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/09/2021] [Indexed: 12/11/2022] Open
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and β-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated β-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function in vitro and in vivo. GRK inhibition is a potential therapeutic approach to enhance endogenous and pharmacologically stimulated GLP-1R signaling.
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Affiliation(s)
- Seunghun P. Lee
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
| | - Jenson Qi
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
| | - Guozhang Xu
- Discovery Sciences, Janssen Research & Development, Spring House, PA, United States
| | - Matthew M. Rankin
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
| | - James Littrell
- Discovery Sciences, Janssen Research & Development, Spring House, PA, United States
| | - June Zhi Xu
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
| | - Ivona Bakaj
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
| | - Alessandro Pocai
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
- *Correspondence: Alessandro Pocai,
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38
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Kořínková L, Pražienková V, Černá L, Karnošová A, Železná B, Kuneš J, Maletínská L. Pathophysiology of NAFLD and NASH in Experimental Models: The Role of Food Intake Regulating Peptides. Front Endocrinol (Lausanne) 2020; 11:597583. [PMID: 33324348 PMCID: PMC7726422 DOI: 10.3389/fendo.2020.597583] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity, diabetes, insulin resistance, sedentary lifestyle, and Western diet are the key factors underlying non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases in developed countries. In many cases, NAFLD further progresses to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and to hepatocellular carcinoma. The hepatic lipotoxicity and non-liver factors, such as adipose tissue inflammation and gastrointestinal imbalances were linked to evolution of NAFLD. Nowadays, the degree of adipose tissue inflammation was shown to directly correlate with the severity of NAFLD. Consumption of higher caloric intake is increasingly emerging as a fuel of metabolic inflammation not only in obesity-related disorders but also NAFLD. However, multiple causes of NAFLD are the reason why the mechanisms of NAFLD progression to NASH are still not well understood. In this review, we explore the role of food intake regulating peptides in NAFLD and NASH mouse models. Leptin, an anorexigenic peptide, is involved in hepatic metabolism, and has an effect on NAFLD experimental models. Glucagon-like peptide-1 (GLP-1), another anorexigenic peptide, and GLP-1 receptor agonists (GLP-1R), represent potential therapeutic agents to prevent NAFLD progression to NASH. On the other hand, the deletion of ghrelin, an orexigenic peptide, prevents age-associated hepatic steatosis in mice. Because of the increasing incidence of NAFLD and NASH worldwide, the selection of appropriate animal models is important to clarify aspects of pathogenesis and progression in this field.
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Affiliation(s)
- L. Kořínková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
| | - V. Pražienková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
| | - L. Černá
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
| | - A. Karnošová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
| | - B. Železná
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
| | - J. Kuneš
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
- Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
| | - Lenka Maletínská
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia
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Yang T, Yang H, Heng C, Wang H, Chen S, Hu Y, Jiang Z, Yu Q, Wang Z, Qian S, Wang J, Wang T, Du L, Lu Q, Yin X. Amelioration of non-alcoholic fatty liver disease by sodium butyrate is linked to the modulation of intestinal tight junctions in db/db mice. Food Funct 2020; 11:10675-10689. [PMID: 33216087 DOI: 10.1039/d0fo01954b] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The intestinal microenvironment, a potential factor that contributes to the development of non-alcoholic fatty liver disease (NALFD) and type 2 diabetes (T2DM), has a close relationship with intestinal tight junctions (TJs). Here, we show that the disruption of intestinal TJs in the intestines of 16-week-old db/db mice and in high glucose (HG)-cultured Caco-2 cells can both be improved by sodium butyrate (NaB) in a dose-dependent manner in vitro and in vivo. Accompanying the improved intestinal TJs, NaB not only relieved intestine inflammation of db/db mice and HG and LPS co-cultured Caco-2 cells but also restored intestinal Takeda G-protein-coupled (TGR5) expression, resulting in up-regulated serum GLP-1 levels. Subsequently, the GLP-1 analogue Exendin-4 was used to examine the improvement of lipid accumulation in HG and free fatty acid (FFA) co-cultured HepG2 cells. Finally, we used 16-week-old db/db mice to examine the hepatoprotective effects of NaB and its producing strain Clostridium butyricum. Our data showed that NaB and Clostridium butyricum treatment significantly reduced the levels of blood glucose and serum transaminase and markedly reduced T2DM-induced histological alterations of the liver, together with improved liver inflammation and lipid accumulation. These findings suggest that NaB and Clostridium butyricum are a potential adjuvant treatment strategy for T2DM-induced NAFLD; their hepatoprotective effect was linked to the modulation of intestinal TJs, causing the restoration of glucose and lipid metabolism and the improvement of inflammation in hepatocytes.
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Affiliation(s)
- Tingting Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
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Gao Z, Song GY, Ren LP, Ma HJ, Ma BQ, Chen SC. β-catenin mediates the effect of GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose diet. Eur J Histochem 2020; 64. [PMID: 32930541 PMCID: PMC7507137 DOI: 10.4081/ejh.2020.3160] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 09/05/2020] [Indexed: 12/13/2022] Open
Abstract
The hypoglycemic drug GLP-1 receptor agonist can ameliorate hepatic steatosis but the mechanism is not clear. Intake of high fructose leads to non-alcoholic fatty liver disease by stimulating lipid synthesis, and β-catenin is the key molecule for realizing GLP-1 function in extrahepatic tissues; with the discovery of GLP-1 receptor in liver, we speculate that β-catenin might mediate GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose. Wistar rats were fed with high fructose diet for 8 weeks and then treated with GLP-1 receptor agonist exenatide for 4 weeks; the changes of lipid synthesis pathway factors, the expression and nuclear translocation of β-catenin, and the hepatic steatosis of the rats were observed. After the intervention of exenatide, the hepatic steatosis induced by high fructose was improved, the nuclear translocation and expression of β-catenin were facilitated, and the mRNA and protein expression of the upstream regulator SREBP-1 and the downstream key enzymes ACC, FAS and SCD-1 of de novo lipogenesis were down-regulated. GLP-1 receptor agonist may ameliorate hepatic steatosis induced by high fructose by β-catenin regulating de novo lipogenesis pathway. GLP-1 receptor agonist may be a potential new drug for the treatment of non-alcoholic fatty liver disease, and the β-catenin may be an important target for the drug therapy.
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Affiliation(s)
- Zhe Gao
- Department of Internal Medicine, Hebei Medical University; Department of Endocrinology, Hebei General Hospital, Shijiazhuang.
| | - Guang-Yao Song
- Department of Internal Medicine, Hebei Medical University; Department of Endocrinology, Hebei General Hospital, Shijiazhuang.
| | - Lu-Ping Ren
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang.
| | - Hui-Juan Ma
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang.
| | - Bo-Qing Ma
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang.
| | - Shu-Chun Chen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang.
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Schneider R, Kraljević M, Peterli R, Rohm TV, Klasen JM, Cavelti-Weder C, Delko T. GLP-1 Analogues as a Complementary Therapy in Patients after Metabolic Surgery: a Systematic Review and Qualitative Synthesis. Obes Surg 2020; 30:3561-3569. [PMID: 32500274 DOI: 10.1007/s11695-020-04750-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/25/2020] [Accepted: 05/28/2020] [Indexed: 12/25/2022]
Abstract
The evidence is strong that bariatric surgery is superior to medical treatment in terms of weight loss and comorbidities in patients with severe obesity. However, a considerable part of patients presents with unsatisfactory response in the long term. It remains unclear whether postoperative administration of glucagon-like peptide-1 analogues can promote additional benefits. Therefore, a systematic review of the current literature on the management of postoperative GLP-1 analogue usage after metabolic surgery was performed. From 4663 identified articles, 6 met the inclusion criteria, but only one was a randomized controlled trial. The papers reviewed revealed that GLP-1 analogues may have beneficial effects on additional weight loss and T2D remission postoperatively. Thus, the use of GLP-1 analogues in addition to surgery promises good results concerning weight loss and improvements of comorbidities and can be used in patients with unsatisfactory results after bariatric surgery.
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Affiliation(s)
- Romano Schneider
- Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, P.O. BOX, CH-4002, Basel, Switzerland.
| | - Marko Kraljević
- Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, P.O. BOX, CH-4002, Basel, Switzerland
| | - Ralph Peterli
- Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, P.O. BOX, CH-4002, Basel, Switzerland
| | - Theresa V Rohm
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031, Basel, Switzerland
- Department of Biomedicine, University of Basel, University Hospital Basel, CH-4031, Basel, Switzerland
| | - Jennifer M Klasen
- Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, P.O. BOX, CH-4002, Basel, Switzerland
| | - Claudia Cavelti-Weder
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031, Basel, Switzerland
- Department of Biomedicine, University of Basel, University Hospital Basel, CH-4031, Basel, Switzerland
| | - Tarik Delko
- Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, P.O. BOX, CH-4002, Basel, Switzerland
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42
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Shiomi M, Tanaka Y, Takada T, Otori K. Determining whether the effect of liraglutide on non-alcoholic fatty liver disease depends on reductions in the body mass index. JGH OPEN 2020; 4:995-1001. [PMID: 33102775 PMCID: PMC7578289 DOI: 10.1002/jgh3.12384] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023]
Abstract
Background and Aim Non‐alcoholic fatty liver disease (NAFLD) initially presents as steatosis, which can progress to non‐alcoholic steatohepatitis (NASH), and often presents clinically alongside metabolic syndromes. Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are regularly utilized to treat type 2 diabetes mellitus. The GLP‐1 RA—liraglutide—ameliorates liver enzymes, histological features, and liver fat content of patients with NASH. However, few studies have examined whether the effect of GLP‐1 RAs depends on changes in the patient's body mass index (BMI). Therefore, this retrospective study aimed to investigate whether the efficacy of liraglutide depended on the baseline BMI or a reduction in BMI. Methods Fifty‐five Japanese patients with type 2 diabetes mellitus and NAFLD who received liraglutide treatment for 24 weeks were assessed. The association between BMI and liver function or fibrosis was evaluated based on the aspartate aminotransferase, alanine aminotransferase, and fibrosis‐4 indices. Results We found that 24 weeks of liraglutide treatment improved liver function and fibrosis in patients with type 2 diabetes mellitus and NAFLD, regardless of BMI changes or obesity status. Conclusions Our findings provide important insight into the impact of BMI on liver function and fibrosis in patients with type 2 diabetes mellitus and NAFLD who are treated with liraglutide.
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Affiliation(s)
- Megumi Shiomi
- Department of Clinical Pharmacy, School of Pharmacy Kitasato University Minato-ku Japan.,Department of Pharmacy Kitasato University Medical Center Saitama Japan
| | - Yoichi Tanaka
- Department of Clinical Pharmacy, School of Pharmacy Kitasato University Minato-ku Japan
| | - Tesshu Takada
- Department of Endocrinology, Diabetes, and Metabolism, School of Medicine Kitasato University Sagamihara Japan
| | - Katsuya Otori
- Department of Clinical Pharmacy, School of Pharmacy Kitasato University Minato-ku Japan.,Department of Pharmacy Kitasato University Medical Center Saitama Japan
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Zhang Q, Zhang XF, Niu CY. Application prospects of glucagon-like peptide-1 receptor agonists in treatment of metabolic diseases. Shijie Huaren Xiaohua Zazhi 2020; 28:393-400. [DOI: 10.11569/wcjd.v28.i11.393] [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] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome [overweight, obesity, type 2 diabetes mellitus (T2DM), and lipid metabolism disorder] is directly related to cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), tumors, and other diseases, and its prevalence has been increasing sharply, bringing an increasingly heavy burden on society. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a novel class of glucose-dependent hypoglycemic drugs modified from glucagon-like peptide-1. Since their mechanism of action is different from that of traditional insulin and oral secretagogues, they overcome the adverse reactions associated with traditional oral medications and insulin, can improve the success rate of T2DM control, and has been widely used in the treatment of T2DM. Recent studies have found that, in addition to hypoglycemic effect, GLP-1RAs can improve metabolic diseases, such as diabetes-related complications, NAFLD, and cardiovascular diseases, and therefore have broad application prospects. This paper reviews the potential role of GLP-1RAs in these diseases.
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Affiliation(s)
- Qiang Zhang
- School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Xiu-Fang Zhang
- Department of Pediatrics, Xiang'an Hospital of Xiamen University, Xiamen 361101, Fujian Province, China
| | - Chun-Yan Niu
- Department of Gastroenterology, Nanjing Lishui People's Hospital (Zhongda Hospital Lishui Branch, Southeast University), Nanjing 211200, Jiangsu Province, China
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44
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Yang M, Ma X, Xuan X, Deng H, Chen Q, Yuan L. Liraglutide Attenuates Non-Alcoholic Fatty Liver Disease in Mice by Regulating the Local Renin-Angiotensin System. Front Pharmacol 2020; 11:432. [PMID: 32322207 PMCID: PMC7156971 DOI: 10.3389/fphar.2020.00432] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 03/20/2020] [Indexed: 12/14/2022] Open
Abstract
The renin-angiotensin system (RAS) is involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and represents a potential therapeutic target for NAFLD. Glucagon-like peptide-1 (GLP-1) signaling has been shown to regulate the RAS within various local tissues. In this study, we aimed to investigate the functional relationship between GLP-1 and the local RAS in the liver during NAFLD. Wild-type and ACE2 knockout mice were used to establish a high-fat-induced NAFLD model. After the mice were treated with liraglutide (a GLP-1 analogue) for 4 weeks, the key RAS component genes were up-regulated in the liver of NAFLD mice. Liraglutide treatment regulated the RAS balance, preventing a reduction in fatty acid oxidation gene expression and increasing gluconeogenesis and the expression of inflammation-related genes caused by NAFLD, which were impaired in ACE2 knockout mice. Liraglutide-treated HepG2 cells exhibited activation of the ACE2/Ang1-7/Mas axis, increased fatty acid oxidation gene expression, and decreased inflammation, which could be reversed by A779 and AngII. These results indicate that the local RAS in the liver becomes overactivated in response to NAFLD. Moreover, ACE2 knockout increases the severity of liver steatosis. Liraglutide has a negative and antagonistic effect on the ACE/AngII/AT1R axis, a positive impact on the ACE2/Ang1-7/Mas axis, and is mediated through the PI3K/AKT pathway. This may represent a potential new mechanism by which liraglutide improves NAFLD.
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Affiliation(s)
- Mengying Yang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyi Ma
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiuping Xuan
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongjun Deng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Yuan
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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45
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Dei Cas M, Paroni R, Saccardo A, Casagni E, Arnoldi S, Gambaro V, Saresella M, Mario C, La Rosa F, Marventano I, Piancone F, Roda G. A straightforward LC-MS/MS analysis to study serum profile of short and medium chain fatty acids. J Chromatogr B Analyt Technol Biomed Life Sci 2020; 1154:121982. [PMID: 32862023 DOI: 10.1016/j.jchromb.2020.121982] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 11/26/2019] [Accepted: 01/11/2020] [Indexed: 12/22/2022]
Abstract
Short and medium fatty acids derived from either dietary sources, gut microbiota, and liver production might play a role in the modulation of metabolism and inflammation. The outcome of different autoimmune or inflammatory diseases could be related to microbiota composition and consequently fatty acids production. Their analytical detection, historically completed by GC, was herein investigated using a sensitive approach of LC-MS/MS with straightforward chemical derivatization, using 3-NPH, to the respective acylhydrazines. An isopropanol protein precipitation coupled to LC-MS/MS analysis allowed to separate and quantify butyric, valeric, hexanoic acid and their branched forms. The serum physiological ranges of short and medium chain fatty acids were determined in a heterogeneous healthy population (n = 54) from 18 to 85 years finding a concentration of 935.6 ± 246.5 (butyric), 698.8 ± 204.7 (isobutyric), 62.9 ± 15.3 (valeric), 1155.0 ± 490.4 (isovaleric) and 468.7 ± 377.5 (hexanoic) ng/mL respectively (mean ± SD). As expected, the biological levels in human serum are reasonably wide-ranging depending on several factors such as body-weight, gut microbiome dysbiosis, gut permeability, cardiometabolic dysregulation, and diet.
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Affiliation(s)
- Michele Dei Cas
- Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Rita Paroni
- Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Anna Saccardo
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Eleonora Casagni
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Sebastiano Arnoldi
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Veniero Gambaro
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Marina Saresella
- Laboratory of Molecular Medicine and Biotechnology, IRCCS Fondazione don Carlo Gnocchi, Milan, Italy
| | - Clerici Mario
- Laboratory of Molecular Medicine and Biotechnology, IRCCS Fondazione don Carlo Gnocchi, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Francesca La Rosa
- Laboratory of Molecular Medicine and Biotechnology, IRCCS Fondazione don Carlo Gnocchi, Milan, Italy
| | - Ivana Marventano
- Laboratory of Molecular Medicine and Biotechnology, IRCCS Fondazione don Carlo Gnocchi, Milan, Italy
| | - Federica Piancone
- Laboratory of Molecular Medicine and Biotechnology, IRCCS Fondazione don Carlo Gnocchi, Milan, Italy
| | - Gabriella Roda
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy.
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Pan CS, Stanley TL. Effect of Weight Loss Medications on Hepatic Steatosis and Steatohepatitis: A Systematic Review. Front Endocrinol (Lausanne) 2020; 11:70. [PMID: 32153507 PMCID: PMC7046622 DOI: 10.3389/fendo.2020.00070] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 02/03/2020] [Indexed: 12/25/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in individuals with obesity. Although multiple pharmacotherapeutics are in development, currently there are limited strategies specifically targeting NAFLD. This systematic review summarizes the existing literature on hepatic effects of medications used for weight loss. Glucagon-like peptide 1 (GLP-1) agonists are the best-studied in this regard, and evidence consistently demonstrates reduction in liver fat content, sometimes accompanied by improvements in histological features of steatohepatitis and reductions in serum markers of hepatic injury such as alanine aminotransferase (ALT). It remains unclear whether these benefits are independent of the weight loss caused by these agents. Literature is limited regarding effects of orlistat, but a small number of reports suggest that orlistat reduces liver fat content and improves histologic features of NASH, benefits which may also be driven primarily by weight loss. A sizeable body of literature on hepatic effects of metformin yields mixed results, with a probability of modest benefit, but no consistent signal for strong benefit. There are insufficient data on hepatic effects of topiramate, phentermine, naltrexone, bupropion, and lorcaserin. Finally, a few studies to date suggest that sodium-glucose co-transporter-2 (SGLT2) inhibitors may reduce liver fat content and cause modest reductions in ALT, but further study is needed to better characterize these effects. Based on available data, GLP-1 agonists have the strongest evidence base demonstrating beneficial effects on NAFLD, but it is not clear if any weight loss medication has effects on NAFLD superior to those of nutritional modification and exercise alone.
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Affiliation(s)
- Chelsea S. Pan
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Takara L. Stanley
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Pediatric Endocrine Division, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA, United States
- *Correspondence: Takara L. Stanley
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ten Hove M, Pater L, Storm G, Weiskirchen S, Weiskirchen R, Lammers T, Bansal R. The hepatic lipidome: From basic science to clinical translation. Adv Drug Deliv Rev 2020; 159:180-197. [PMID: 32615143 DOI: 10.1016/j.addr.2020.06.027] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 06/05/2020] [Accepted: 06/25/2020] [Indexed: 02/07/2023]
Abstract
The liver is the key organ involved in lipid metabolism and transport. Excessive lipid accumulation due to dysregulated lipid metabolism predisposes the liver to steatosis, cirrhosis, and hepatocellular carcinoma. Lipids are generally compartmentalized in specialized organelles called lipid droplets that enable cells to store and release lipids in a regulated manner. However, during flux-in and flux-out of droplets, lipids are converted into toxic species leading to lipid-mediated liver damage. Lipids are categorized into 'toxic' or 'healthy' lipids that are involved in liver disease pathogenesis or resolution, respectively. Lipidomic analysis have revealed unique lipid signature that correlates with the disease progression therefore being used for disease diagnosis. In this comprehensive review, we provide an overview on hepatic lipid homeostasis, lipid compartmentalization mechanisms and lipidomic profiles in different liver diseases. We further discuss promising therapeutics targeting the hepatic lipidome including pro-resolving lipids, liposomes, and small-molecule inhibitors for the treatment of liver diseases.
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Amelioration of diet-induced metabolic syndrome and fatty liver with sitagliptin via regulation of adipose tissue inflammation and hepatic Adiponectin/AMPK levels in mice. Biochimie 2020; 168:198-209. [DOI: 10.1016/j.biochi.2019.11.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 11/06/2019] [Indexed: 02/08/2023]
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Cardiovascular, renal and liver protection with novel antidiabetic agents beyond blood glucose lowering in type 2 diabetes: consensus article from the European Society of Hypertension Working Group on Obesity, Diabetes and the High-risk Patient. J Hypertens 2019; 38:377-386. [PMID: 31764586 DOI: 10.1097/hjh.0000000000002279] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
: The prevalence of type 2 diabetes (T2D) has increased over the past few decades. T2D has a strong genetic propensity that becomes overt when a patient is exposed to a typical Western lifestyle, gain weight and becomes obese, whereas weight loss protects from the development of T2D. Except of lifestyle modifications, the choice of the appropriate treatment is essential in the management of patients with T2D and appears critical for the obese population with T2D. The new pharmacological approach for the treatment of T2D, sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, seems to be effective not only in the management of T2D but also for weight loss, reduction of blood pressure and improvement of nonalcoholic fatty liver disease. Sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 analogues reduced cardiovascular risk, prevented cardiovascular disease and mortality, thereby playing an important role in the treatment of obese patients with hypertension and T2D.
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Abstract
Nonalcoholic steatohepatitis (NASH) is the second leading cause of liver transplantation in the US with a high risk of liver-related morbidities and mortality. Given the global burden of NASH, development of appropriate therapeutic strategies is an important clinical need. Where applicable, lifestyle modification remains the primary recommendation for the treatment of NASH, even though such changes are difficult to sustain and even insufficient to cure NASH. Bariatric surgery resolves NASH in such patients where lifestyle modifications have failed, and is recommended for morbidly obese patients with NASH. Thus, pharmacotherapies are of high value for NASH treatment. Though no drug has been approved by the US Food and Drug Administration for treatment of NASH, substantial progress in pharmacological development has been made in the last few years. Agents such as vitamin E and pioglitazone are recommended in patients with NASH, and yet concerns about their side effects remain. Many agents targeting various vital molecules and pathways, including those impacting metabolic perturbations, inflammatory cascades, and oxidative stress, are in clinical trials for the treatment of NASH. Some agents have shown promising results in phase II or III clinical trials, but more studies are required to assess their long-term effects. Herein, we review the potential strategies and challenges in therapeutic approaches to treating NASH.
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Affiliation(s)
- Ming-Ming Chen
- *Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
| | - Jing-Jing Cai
- †Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, P.R. China
| | - Yao Yu
- ‡Institute of Model Animals of Wuhan University, Wuhan, P.R. China
| | - Zhi-Gang She
- *Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
- ‡Institute of Model Animals of Wuhan University, Wuhan, P.R. China
- §Basic Medical School, Wuhan University, Wuhan, P.R. China
- ¶Medical Research Institute, School of Medicine, Wuhan University, Wuhan, P.R. China
| | - Hongliang Li
- *Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
- ‡Institute of Model Animals of Wuhan University, Wuhan, P.R. China
- §Basic Medical School, Wuhan University, Wuhan, P.R. China
- ¶Medical Research Institute, School of Medicine, Wuhan University, Wuhan, P.R. China
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