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Muir KC, Harris DD, Stone C, Kanuparthy M, Broadwin M, Hamze J, Abid MR, Sellke FW. Linagliptin Modulation of Inflammation in Chronic Coronary Artery Disease. J Surg Res 2025; 309:146-155. [PMID: 40253935 DOI: 10.1016/j.jss.2025.03.036] [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: 11/25/2024] [Revised: 03/04/2025] [Accepted: 03/22/2025] [Indexed: 04/22/2025]
Abstract
INTRODUCTION Coronary artery disease (CAD) confers a continued challenge to healthcare necessitating innovative therapies. Linagliptin, a dipeptidyl peptidase 4 inhibitor, has been shown in preclinical and clinical studies to have cardioprotective effects independent of its glycemic control. An important pathway by which linagliptin has been described to induce these effects is due to its immune regulation. This study aims to evaluate the immune modulation by linagliptin treatment in a porcine model of chronic myocardial ischemia. METHODS Yorkshire swine underwent ameroid constrictor placement to the left circumflex artery, which induced chronic myocardial ischemia. Two wk later, swine either received no drug (n = 8) or 2.5 mg linagliptin daily (n = 8). Five weeks later, swine were sacrificed and left ventricular tissue was harvested. Protein expression and immune cell count was measured with immunoblotting and immunofluorescence, respectively. Data were statistically analyzed via Wilcoxon rank-sum test. RESULTS Linagliptin treatment was associated with decreased expression of inflammatory markers interleukin (IL)-1β (P = 0.0012), IL-6 (P = 0.0073), nuclear factor kappa B (NFκB) (P = 0.0106), transforming growth factor beta (P = 0.001), and IL-4 (P = 0.0419) in chronically ischemic myocardium. There was increased expression of phosphorylated NFκB at Ser536 (p=<0.0001) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (P = 0.0167). Interestingly, there was increased expression of cluster of differentiation (CD) 11c (P = 0.0002) and increased cell count of CD11c dendritic cells (P = 0.014). CONCLUSIONS Linagliptin treatment was associated with a reduction of proinflammatory cytokines in the setting of chronically ischemic myocardium, with identified modulation of the NFκB pathway. Following treatment, there was found to be an increase in CD11c expression, demonstrating an increase in dendritic cells as a possible immune modulating cell population within the ischemic myocardium.
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Affiliation(s)
- Kelsey C Muir
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island.
| | - Dwight D Harris
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - Christopher Stone
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - Meghamsh Kanuparthy
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - Mark Broadwin
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - Jad Hamze
- Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - M Ruhul Abid
- Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - Frank W Sellke
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
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Cheraghpour M, Hatami B, Singal AG. Lifestyle and Pharmacologic Approaches to Prevention of Metabolic Dysfunction-associated Steatotic Liver Disease-related Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2025; 23:685-694.e6. [PMID: 39800201 DOI: 10.1016/j.cgh.2024.09.041] [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: 08/03/2024] [Revised: 09/19/2024] [Accepted: 09/30/2024] [Indexed: 01/15/2025]
Abstract
Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns (eg, high consumption of vegetables, whole grains, fish and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate pharmacologic approach for individuals with MASLD may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time, given a dearth of data defining their risk-benefit ratio.
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Affiliation(s)
- Makan Cheraghpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
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Man A, Knüsel L, Graf J, Lali R, Le A, Di Scipio M, Mohammadi-Shemirani P, Chong M, Pigeyre M, Kutalik Z, Paré G. Identification of effect modifiers using a stratified Mendelian randomization algorithmic framework. Eur J Epidemiol 2025:10.1007/s10654-025-01213-0. [PMID: 40072671 DOI: 10.1007/s10654-025-01213-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/21/2025] [Indexed: 03/14/2025]
Abstract
Mendelian randomization (MR) is a technique which uses genetic data to uncover causal relationships between variables. With the growing availability of large-scale biobank data, there is increasing interest in elucidating nuances in these relationships using MR. Stratified MR techniques such as doubly-ranked MR (DRMR) and residual stratification MR have been developed to identify nonlinearity in causal relationships. These methods calculate causal estimates within strata of the exposure adjusted to mitigate the impact of collider bias. However, their application to scenarios using a stratifying variable other than the exposure to identify the presence of effect modifiers has been limited. The reliable identification of effect modifiers is key to identifying subgroups of patients differentially affected by risk and protective factors. In this study, we present a stratified MR algorithm capable of identifying effect modifiers of causal relationships using adapted forms of DRMR and residual stratification MR. Through simulations, the algorithm was found to be robust at handling nonlinear relationships and forms of collider bias, accommodating both binary and continuous outcomes. Application of the stratified MR algorithm to 1,715 exposure-stratifying variable-outcome combinations identified two Bonferroni significant effect modifiers of causal relationships in the UK Biobank. The causal effect of body mass index on type 2 diabetes mellitus was attenuated with age, while the effect of LDL cholesterol on coronary artery disease was exacerbated with increased serum urate. Overall, we introduce a tool for detecting effect modifiers of causal relationships, and present two cases with clinical implications for personalized risk assessment of cardiometabolic diseases.
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Affiliation(s)
- Alice Man
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
- Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
| | - Leona Knüsel
- Department of Computational Biology, University of Lausanne, CH-1015, Lausanne, Switzerland
- Center for Primary Care and Public Health, University of Lausanne, 1010, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland
| | - Josef Graf
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Computing and Software, Faculty of Engineering, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
| | - Ricky Lali
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
| | - Ann Le
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
| | - Matteo Di Scipio
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
- Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
| | | | - Michael Chong
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
- Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
| | - Marie Pigeyre
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
| | - Zoltán Kutalik
- Department of Computational Biology, University of Lausanne, CH-1015, Lausanne, Switzerland
- Center for Primary Care and Public Health, University of Lausanne, 1010, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland
| | - Guillaume Paré
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada.
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
- Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada.
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Nassar M, Nassar O, Abosheaishaa H, Misra A. Comparative outcomes of systemic diseases in people with type 2 diabetes, or obesity alone treated with and without GLP-1 receptor agonists: a retrospective cohort study from the Global Collaborative Network : Author list. J Endocrinol Invest 2025; 48:483-497. [PMID: 39302577 DOI: 10.1007/s40618-024-02466-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 09/04/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used to manage type 2 diabetes (T2D) and obesity. Despite their recognized benefits in glycemic control and weight management, their impact on broader systemic has been less explored. OBJECTIVE This study aimed to evaluate the impact of GLP-1RAs on a variety of systemic diseases in people with T2D or obesity. METHODS We conducted a retrospective cohort study using data from the Global Collaborative Network, accessed through the TriNetX analytics platform. The study comprised two primary groups: individuals with T2D and those with obesity. Each group was further divided into subgroups based on whether they received GLP-1RA treatment or not. Data were analyzed over more than a 5-year follow-up period, comparing incidences of systemic diseases; systemic lupus erythematosus (SLE), systemic sclerosis (SS), rheumatoid arthritis (RA), ulcerative colitis (UC), crohn's disease (CD), alzheimer's disease (AD), parkinson's disease (PD), dementia, bronchial asthma (BA), osteoporosis, and several cancers. RESULTS In the T2D cohorts, GLP-1RA treatment was associated with significantly lower incidences of several systemic and metabolic conditions as compared to those without GLP-1RA, specifically, dementia (Risk Difference (RD): -0.010, p < 0.001), AD (RD: -0.003, p < 0.001), PD (RD: -0.002, p < 0.001), and pancreatic cancer (RD: -0.003, p < 0.001). SLE and SS also saw statistically significant reductions, though the differences were minor in magnitude (RD: -0.001 and - 0.000 respectively, p < 0.001 for both). Conversely, BA a showed a slight increase in risk (RD: 0.002, p < 0.001). CONCLUSIONS GLP-1RAs demonstrate potential benefits in reducing the risk of several systemic conditions in people with T2D or obesity. Further prospective studies are needed to confirm these effects fully and understand the mechanisms.
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Affiliation(s)
- Mahmoud Nassar
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
| | - Omar Nassar
- Williamsville East High School, Buffalo, NY, USA
| | - Hazem Abosheaishaa
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anoop Misra
- Fortis-C-DOC Centre of Excellence for Diabetes, Metabolic Diseases and Endocrinology, New Delhi, India
- National Diabetes, Obesity and Cholesterol Foundation (N-DOC), New Delhi, India
- Diabetes Foundation (India) (DFI) India, New Delhi, India
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Rossetti CL, Andrade IS, Fonte Boa LF, Neves MB, Fassarella LB, Bertasso IM, Souza MDGCD, Bouskela E, Lisboa PC, Takyia CM, Trevenzoli IH, Fortunato RS, Carvalho DPD. Liraglutide prevents body and fat mass gain in ovariectomized Wistar rats. Mol Cell Endocrinol 2024; 594:112374. [PMID: 39306226 DOI: 10.1016/j.mce.2024.112374] [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: 03/28/2024] [Revised: 09/03/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024]
Abstract
Estrogens exert beneficial metabolic effects by reducing food intake and enhancing energy expenditure through both central and peripheral mechanisms. The decrease of estrogen, as occurs in ovariectomy (OVX), leads to metabolic disturbances, such as increased body weight, adipose tissue mass, basal blood glucose, and impaired glucose tolerance. These effects can be reversed by reintroducing estrogen. GLP-1 and its receptor agonists, known for their antihyperglycemic properties, also exhibit anorexigenic effects. Besides that, research indicates that GLP-1 analogs can induce metabolic changes peripherally, such as increased fatty acid oxidation and inhibited lipogenesis. Given the shared metabolic actions of GLP-1 and estrogens, we explored whether liraglutide, a GLP-1 agonist, could mitigate the metabolic effects of estrogen deficiency. We tested this hypothesis using ovariectomized rats, a model that simulates menopausal estrogen deficiency, and treated them with either liraglutide or 17β-Estradiol benzoate for 21 days. Ovariectomy resulted in elevated DPP-IV activity in both plasma and inguinal white adipose tissue (iWAT). While estrogen replacement effectively countered the DPP-IV increase in both plasma and iWAT, liraglutide only prevented the rise in iWAT DPP-IV activity. Liraglutide prevented body weight and fat mass gain after ovariectomy to the same extent as estradiol treatment. This can be explained by the lower food intake and food efficiency caused by estradiol and liraglutide. However, liraglutide was associated with increased pro-inflammatory cytokines and inflammatory cells in white adipose tissue. Further research is crucial to fully understand the potential benefits and risks of using GLP-1 receptor agonists in the context of menopause.
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Affiliation(s)
- Camila Lüdke Rossetti
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil; Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, USA
| | - Iris Soares Andrade
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luiz Fernando Fonte Boa
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcelo Barbosa Neves
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Larissa Brito Fassarella
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Iala Milene Bertasso
- Laboratorio de Fisiologia Endócrina, Instituto de Biologia, Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maria das Graças Coelho de Souza
- Laboratório de Pesquisa Clínica e Experimental em Biologia Vascular (BioVasc), Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Eliete Bouskela
- Laboratório de Pesquisa Clínica e Experimental em Biologia Vascular (BioVasc), Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Patrícia Cristina Lisboa
- Laboratorio de Fisiologia Endócrina, Instituto de Biologia, Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Christina Maeda Takyia
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil; Programa de Pós-Graduação em Ciências Cirúrgicas, Faculdade de Medicina, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Isis Hara Trevenzoli
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rodrigo Soares Fortunato
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Denise Pires de Carvalho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
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Höfling C, Donkersloot P, Ulrich L, Burghardt S, Opitz M, Geissler S, Schilling S, Cynis H, Michalski D, Roßner S. Dipeptidyl peptidase 4 deficiency improves survival after focal cerebral ischemia in mice and ameliorates microglia activation and specific inflammatory markers. Neurobiol Dis 2024; 201:106671. [PMID: 39293688 DOI: 10.1016/j.nbd.2024.106671] [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: 06/17/2024] [Revised: 09/11/2024] [Accepted: 09/15/2024] [Indexed: 09/20/2024] Open
Abstract
Dipeptidyl peptidase 4 (DPP4; CD26) is involved in the regulation of various metabolic, immunological, and neurobiological processes in healthy individuals. Observations based on epidemiological data indicate that DPP4 inhibition by gliptins, typically used in patients with diabetes, may reduce the risk for cerebral ischemia and may also improve related outcomes. However, as DPP4 inhibitor application is neither complete nor specific for suppression of DPP4 enzymatic activity and DPP4 has non-enzymatic functions as well, the variety of consequences is a matter of debate. Therefore, we here used DPP4 knock-out (KO) mice to analyze the specific contribution of DPP4 to cellular, immunological, and functional consequences of experimental focal cerebral ischemia. We observed a significantly higher survival rate of DPP4 KO mice after ischemia, which was accompanied by a lower abundance of the pro-inflammatory chemokine CCL2 and reduced activation of Iba1-positive microglia cells in brain tissue of DPP4 KO mice. In addition, after ischemia for 24 h to 72 h, decreased concentrations of CCL5 and CCL12 in plasma and of CCL17 in brain tissue of DPP4 KO mice were observed when compared to wild type mice. Other aspects analyzed, such as the functional Menzies score, astrocyte activation and chemokine levels in plasma and brain tissue were affected by ischemia but appeared to be unaffected by the DPP4 KO genotype. Taken together, experimental ablation of DPP4 functions in mice improves survival and ameliorates aspects of cellular and molecular inflammation after focal cerebral ischemia.
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Affiliation(s)
- Corinna Höfling
- Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany; Department of Neurology, University of Leipzig, 04103 Leipzig, Germany
| | - Philippa Donkersloot
- Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany
| | - Luise Ulrich
- Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany
| | - Sina Burghardt
- Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany
| | - Michael Opitz
- Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany
| | - Stefanie Geissler
- Fraunhofer Institute for Cell Therapy and Immunology, Department of Molecular Drug Design and Target Validation, 06120 Halle (Saale), Germany
| | - Stephan Schilling
- Fraunhofer Institute for Cell Therapy and Immunology, Department of Molecular Drug Design and Target Validation, 06120 Halle (Saale), Germany; Anhalt University of Applied Sciences, Faculty of Applied Biosciences and Process Engineering, 06366 Köthen, Germany
| | - Holger Cynis
- Fraunhofer Institute for Cell Therapy and Immunology, Department of Molecular Drug Design and Target Validation, 06120 Halle (Saale), Germany; Junior Research Group "Immunomodulation in Pathophysiological Processes" Faculty of Medicine, Martin Luther University Halle-Wittenberg, Germany
| | - Dominik Michalski
- Department of Neurology, University of Leipzig, 04103 Leipzig, Germany
| | - Steffen Roßner
- Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany.
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Taylor R. Understanding the cause of type 2 diabetes. Lancet Diabetes Endocrinol 2024; 12:664-673. [PMID: 39038473 DOI: 10.1016/s2213-8587(24)00157-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/23/2024] [Accepted: 05/23/2024] [Indexed: 07/24/2024]
Abstract
Type 2 diabetes has long been thought to have heterogenous causes, even though epidemiological studies uniformly show a tight relationship with overnutrition. The twin cycle hypothesis postulated that interaction of self-reinforcing cycles of fat accumulation inside the liver and pancreas, driven by modest but chronic positive calorie balance, could explain the development of type 2 diabetes. This hypothesis predicted that substantial weight loss would bring about a return to the non-diabetic state, permitting observation of the pathophysiology determining the transition. These changes were postulated to reflect the basic mechanisms of causation in reverse. A series of studies over the past 15 years has elucidated these underlying mechanisms. Together with other research, the interaction of environmental and genetic factors has been clarified. This knowledge has led to successful implementation of a national programme for remission of type 2 diabetes. This Review discusses the paucity of evidence for heterogeneity in causes of type 2 diabetes and summarises the in vivo pathophysiological changes, which cause this disease of overnutrition. Type 2 diabetes has a homogenous cause expressed in genetically heterogenous individuals.
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Affiliation(s)
- Roy Taylor
- Newcastle Magnetic Resonance Centre, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
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8
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Yang M, Yan R, Sha R, Wang X, Zhou S, Li B, Zheng Q, Cao Y. Epigallocatechin gallate alleviates non-alcoholic fatty liver disease through the inhibition of the expression and activity of Dipeptide kinase 4. Clin Nutr 2024; 43:1769-1780. [PMID: 38936303 DOI: 10.1016/j.clnu.2024.06.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent glocal cause of chronic hepatic disease, with incidence rates that continue to rise steadily. Treatment options for affected patients are currently limited to dietary changes and exercise interventions, with no drugs having been licensed for the treatment of this disease. There is thus a pressing need for the development of novel therapeutic strategies. Work from our group suggests that the primary bioactive ingredient in green tea, epigallocatechin gallate (EGCG), may help reduce liver fat content and protect against hepatic injury through the inhibition of dipeptidyl peptidase 4 (DPP4) expression and activity. The study investigated the potential pathways by which EGCG may improve NAFLD, identified the sites of interaction between EGCG and DPP4, and proposed novel clinical treatment strategies. METHODS A clinical randomized controlled trial was conducted to investigate the potential efficacy of EGCG in NAFLD patients. The study compared relevant indices before and after EGCG administration. Animal models of NAFLD were constructed using male C57BL/6J mice fed a high-fat diet to observe the ameliorative effects of EGCG on the livers of the model mice and to investigate the potential pathways by which EGCG alleviates NAFLD. The interaction mechanism between EGCG and DPP4 was investigated using oleic acid and palmitic acid-treated HepG2 cell lines. Plasmids in which different sites had been disrupted were used to identify the effective interaction sites. RESULTS ECGC was found to suppress the accumulation of lipids, inhibit inflammation, remediate dysregulated lipid metabolism, and improve the pathogenesis of NAFLD via the inhibition of the expression and activity of DPP4. CONCLUSIONS The study results indicate that EGCG has a positive impact on improving NAFLD. These results highlight promising new opportunities to safely and effectively treat NAFLD in the clinic. STUDY ID NUMBER ChiCTR2300076741; https://www.chictr.org.cn/.
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Affiliation(s)
- Mingfeng Yang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, PR China
| | - Ruike Yan
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, PR China
| | - Ruohe Sha
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, PR China
| | - Xinxin Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, PR China
| | - Shiting Zhou
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, PR China
| | - Baifeng Li
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
| | - Qianqian Zheng
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University 110122, Shenyang, Liaoning Province, PR China.
| | - Yanli Cao
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, PR China.
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Pelluri R, Kongara S, Nagasubramanian VR, Mahadevan S, Chimakurthy J. Effect of Teneligliptin 20 mg Twice Daily on Glucagon-Like Peptide-1 Levels and Its Influence on Non-Glycemic Components in Non-Diabetic Obese Individuals. Metab Syndr Relat Disord 2024; 22:90-96. [PMID: 38165660 DOI: 10.1089/met.2023.0218] [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] [Indexed: 01/04/2024] Open
Abstract
Background and Aims: Teneligliptin is an oral antidiabetic agent, it can persevere glucagon-like peptide-1 (GLP-1) by inhibiting dipeptidyl peptidase enzyme. In addition, it has rare incidence of hypoglycemia. Hence, this study aimed to test the effect of teneligliptin 20 mg twice daily along with low carbohydrate diet and physical exercise on change of body weight and insulin resistance in nondiabetic obese subjects. Materials and Methods: It is a prospective, randomized, double-blind, placebo-controlled, parallel group study carried out at outpatient department of an endocrinology hospital over the period of 48 weeks. Teneligliptin 20 mg twice daily 30 min before food (low carbohydrate diet [LCD]) with regular physical exercise, and control group was kept with placebo twice daily 30 min before food LCD with regular physical exercise. This study was registered in clinical trial registry of India [CTRI/2020/02/023329]. Results: A total of 150 nondiabetic obese subjects were randomized into test (n = 75) and control groups (n = 75). At the end of 48 weeks there was significant improvement in GLP-1, simplified nutrition assessment questionnaire (SNAQ) score, homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), and body weight. The mean difference and 95% confidence interval of GLP-1 (pg/mL) was 76.42 (44.42-148.41) (P = 0.37); SNAQ score, -1.64 (-2.48 to -0.81) (P = 0.000); HOMA-IR, -0.9 (-0.59 to -0.38) (P = 0.000); TG (mg/dL) -29.37 (-44.46 to -14.07) (P = 0.000); reduction of body weight (kilograms) -3.09 (-6.11 to -0.07) (P = 0.043). Conclusion: Findings of this study reveals that teneligliptin-treated group showed significant improvement in GLP-1 levels, reduced insulin resistance, body weight, TG, appetite, and metabolic syndrome. Teneligliptin is well tolerated, except in upper respiratory tract infections. CTR number: CTRI/2020/02/023329.
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Affiliation(s)
- Ranakishor Pelluri
- Department of Pharmacy Practice, Sri Ramachandra Institute of Higher Education Research, (Deemed to be University), Chennai, India
- Department of Endocrinology and Metabolism, Endolife Speciality Hospital, Guntur, India
- Department of Pharmaceutical Sciences, Vignan's Foundation for Science Technology and Research, (Deemed to be University), Guntur, India
| | - Srikanth Kongara
- Department of Endocrinology and Metabolism, Endolife Speciality Hospital, Guntur, India
| | | | - Shriraam Mahadevan
- Department of Endocrinology and Metabolism, Sri Ramachandra Institute of Higher Education and Research, (Deemed to be University), Chennai, India
| | - Jithendra Chimakurthy
- Department of Pharmaceutical Sciences, Vignan's Foundation for Science Technology and Research, (Deemed to be University), Guntur, India
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10
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Song Y, Yang H, Kim J, Lee Y, Kim SH, Do IG, Park CY. Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy. Mol Metab 2023; 78:101806. [PMID: 37739179 PMCID: PMC10542016 DOI: 10.1016/j.molmet.2023.101806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/16/2023] [Accepted: 09/11/2023] [Indexed: 09/24/2023] Open
Abstract
OBJECTIVE Abnormal autophagic function and activated inflammasomes are typical features in the liver of patients with non-alcoholic steatohepatitis (NASH). Here, we explored whether gemigliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor for treatment of type 2 diabetes, can induce autophagy and regulate inflammasome activation as a potential NASH treatment independent of its anti-diabetic effect. METHODS Expression analysis was performed using human liver samples obtained from 18 subjects who underwent hepatectomy. We explored the function and mechanism of gemigliptin using a methionine- and choline-deficient diet (MCD)-induced NASH mouse model and HepG2 cells cultured in MCD-mimicking medium. RESULTS Autophagy was suppressed by marked decreases in the expression of ULK1 and LC3II/LC3I ratio in human NAFLD/NASH patients, a NASH mouse model, and HepG2 cells cultured with MCD-mimicking media. Surprisingly, we found that the expression of p-AMPK decreased in liver tissues from patients with steatosis but was restored in NASH patients. The expression of p-AMPK in the NASH mouse model was similar to that of the control group. Hence, these results indicate that autophagy was reduced in NASH via an AMPK-independent pathway. However, gemigliptin treatment attenuated lipid accumulation, inflammation, and fibrosis in the liver of MCD diet-fed mice with restoration of ULK1 expression and autophagy induction. In vitro, gemigliptin alleviated inflammasome activation through induction of ULK1-dependent autophagy. Furthermore, gemigliptin treatment upregulated ULK1 expression and activated AMPK even after siRNA-mediated knockdown of AMPKα1/2 and ULK1, respectively. CONCLUSIONS Collectively, these results suggest that gemigliptin ameliorated NASH via AMPK-independent, ULK1-mediated effects on autophagy.
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Affiliation(s)
- Youngmi Song
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hyekyung Yang
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Juhee Kim
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yoonjin Lee
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sung-Ho Kim
- LG Chem Life Sciences, Gangseo-gu, Seoul, South Korea
| | - In-Gu Do
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Cheol-Young Park
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.
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11
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Xie D, Wang Q, Huang W, Zhao L. Dipeptidyl-peptidase-4 inhibitors have anti-inflammatory effects in patients with type 2 diabetes. Eur J Clin Pharmacol 2023; 79:1291-1301. [PMID: 37493797 DOI: 10.1007/s00228-023-03541-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 07/16/2023] [Indexed: 07/27/2023]
Abstract
AIMS Systematic low-grade inflammation is considered to be an important factor leading to the development of T2DM and the progression of its complications. Dipeptidyl-peptidase-4 (DPP-4) inhibitors show potential anti-inflammatory effects in patients with T2DM. This meta-analysis aimed to evaluate the anti-inflammatory effects of DPP-4 inhibitors in patients with T2DM. METHODS A comprehensive search was performed in PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials to identify randomized controlled trials that assess the anti-inflammatory effects of DPP-4 inhibitors. Quantitative data analysis was conducted by a random-effects model. Sensitivity analyses were conducted to determine the robustness of the pooled results. RESULTS Twenty-two studies with 1595 patients with T2DM were included. Pooled results showed that DPP-4 inhibitor therapy was significantly associated with the reduction of C-reactive protein (CRP) (SMD, - 0.56, p < 0.01), TNF-α (SMD, - 1.69, p < 0.01), IL-6 (SMD, - 0.67, p < 0.01), and IL-1β (WMD, - 8.21 pg/ml, p < 0.01). Leave-one-out meta-analysis showed no significant change in the pooled results of CRP and TNF-α. CONCLUSION This meta-analysis demonstrated that DPP-4 inhibitors can significantly attenuate low-grade inflammatory state in patients with T2DM. In addition to improving glycemic control, DDP-4 inhibitors might offer extra therapeutic value by controlling inflammation.
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Affiliation(s)
- Dengpiao Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Qiqi Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Wei Huang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China.
| | - Liangbin Zhao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China.
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12
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Mohammed OA. Alogliptin exhibits multifaceted effects in thioacetamide-insulted rats: A novel approach to combating hepatic inflammation and fibrogenesis. Pathol Res Pract 2023; 250:154833. [PMID: 37769397 DOI: 10.1016/j.prp.2023.154833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 09/21/2023] [Accepted: 09/23/2023] [Indexed: 09/30/2023]
Abstract
Hepatic fibrosis arising from chronic liver injury is characterized by dysregulated healing, including hepatic stellate cell activation and excessive deposition of extracellular matrix proteins. Administration of the hepatotoxin thioacetamide (TAA) induces liver injury coupled to fibrogenesis in rodents, mimicking aspects of human disease. Alogliptin is a highly selective inhibitor of dipeptidyl peptidase-4 with purported antifibrotic actions. We investigated the protective effects of alogliptin against TAA-mediated hepatic fibrosis in rats. Adult male Sprague-Dawley rats received intraperitoneal injections of TAA (150 mg/kg) twice weekly for 6 weeks to induce liver fibrosis. A subset of rats also received daily oral alogliptin (20 mg/kg). At 6 weeks, liver injury and fibrosis were assessed by histology, hydroxyproline content, serum liver enzymes, inflammatory cytokines, oxidative stress markers, and genes related to inflammation, apoptosis, and fibrosis. TAA elicited necroinflammation, oxidative stress, upregulation of pro-fibrogenic mediators, increased hydroxyproline content, and excessive collagen deposition, indicating hepatic fibrosis. The administration of Alogliptin led to notable enhancements in liver histology, an extension in survival time, a decrease in hydroxyproline levels and the expression of fibrogenic genes, a reduction in inflammatory cytokines and oxidative stress, and mitigation of hepatocellular apoptosis in rats subjected to TAA treatment. Alogliptin displayed potent antifibrotic, antioxidant, and hepatoprotective properties in this model of toxic liver damage, likely by impeding NFκB while enhanced Nrf2 DNA binding activity which together modulate oxidative stress, inflammation, myofibroblast activation, and apoptosis. These results highlight the potential therapeutic value of alogliptin offering hope for improved treatment of hepatic fibrosis.
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Affiliation(s)
- Osama A Mohammed
- Department of Clinical Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
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13
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Saini K, Sharma S, Khan Y. DPP-4 inhibitors for treating T2DM - hype or hope? an analysis based on the current literature. Front Mol Biosci 2023; 10:1130625. [PMID: 37287751 PMCID: PMC10242023 DOI: 10.3389/fmolb.2023.1130625] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 05/08/2023] [Indexed: 06/09/2023] Open
Abstract
DPP-4 inhibition is an interesting line of therapy for treating Type 2 Diabetes Mellitus (T2DM) and is based on promoting the incretin effect. Here, the authors have presented a brief appraisal of DPP-4 inhibitors, their modes of action, and the clinical efficiency of currently available drugs based on DPP-4 inhibitors. The safety profiles as well as future directions including their potential application in improving COVID-19 patient outcomes have also been discussed in detail. This review also highlights the existing queries and evidence gaps in DPP-4 inhibitor research. Authors have concluded that the excitement surrounding DPP-4 inhibitors is justified because in addition to controlling blood glucose level, they are good at managing risk factors associated with diabetes.
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14
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Chen J, Mei A, Wei Y, Li C, Qian H, Min X, Yang H, Dong L, Rao X, Zhong J. GLP-1 receptor agonist as a modulator of innate immunity. Front Immunol 2022; 13:997578. [PMID: 36569936 PMCID: PMC9772276 DOI: 10.3389/fimmu.2022.997578] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a 30-amino acid hormone secreted by L cells in the distal ileum, colon, and pancreatic α cells, which participates in blood sugar regulation by promoting insulin release, reducing glucagon levels, delaying gastric emptying, increasing satiety, and reducing appetite. GLP-1 specifically binds to the glucagon-like peptide-1 receptor (GLP-1R) in the body, directly stimulating the secretion of insulin by pancreatic β-cells, promoting proliferation and differentiation, and inhibiting cell apoptosis, thereby exerting a glycemic lowering effect. The glycemic regulating effect of GLP-1 and its analogues has been well studied in human and murine models in the circumstance of many diseases. Recent studies found that GLP-1 is able to modulate innate immune response in a number of inflammatory diseases. In the present review, we summarize the research progression of GLP-1 and its analogues in immunomodulation and related signal pathways.
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Affiliation(s)
- Jun Chen
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Aihua Mei
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Yingying Wei
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chunlei Li
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Hang Qian
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Xinwen Min
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Handong Yang
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, China
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoquan Rao
- Department of Cardiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Jixin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
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15
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Wang Q, An Y, Zhang L, Zhang Y, Wang G, Liu J. Regulation of Adropin by Sitagliptin monotherapy in participants with newly diagnosed type 2 Diabetes. BMC Endocr Disord 2022; 22:306. [PMID: 36476135 PMCID: PMC9727947 DOI: 10.1186/s12902-022-01233-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 10/17/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Adropin is a potent metabolic regulator of insulin sensitivity and glycolipid metabolism. The present study investigated the effects of sitagliptin on adropin and metabolic parameters in participants with newly diagnosed type 2 diabetes (T2D). METHODS Thirty-five participants newly-diagnosed with T2D were prescribed sitagliptin 100 mg once daily for 17 weeks. Twenty-eight age-, sex-, and BMI-matched healthy subjects were included as the control group. Adropin and clinical parameters were assessed at baseline and after treatment. RESULTS At baseline, serum adropin levels were lower in T2D participants than in the healthy individuals (3.12 ± 0.73 vs. 5.90 ± 1.22 ng/ml, P < 0.01). Serum adropin levels were significantly higher in T2D patients after sitagliptin treatment (4.97 ± 1.01 vs. 3.12 ± 0.73 ng/ml, P < 0.01). The changes in serum adropin levels after sitagliptin treatment were associated with the improvements of fasting blood glucose (FBG) (β = - 0.71, P < 0.01), glycosylated hemoglobin (HbA1c) (β = - 0.44, P < 0.01) and homeostatic model assessment of β-cell function (HOMA-β) (β = 9.02, P < 0.01). CONCLUSIONS Sitagliptin treatment could significantly increase serum adropin levels in participants with newly diagnosed T2D. The increase in serum adropin levels could be associated with the amelioration of glucose metabolism, which might be involved in beneficial glucose-lowering mechanisms of sitagliptin. TRIAL REGISTRATION Clinicaltrials.gov , NCT04495881 . Retrospectively registered on 03/08/2020.
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Affiliation(s)
- Qiu Wang
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Yu An
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Lin Zhang
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Yuanying Zhang
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China.
| | - Jia Liu
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China.
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16
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AlZaim I, Eid AH, Abd-Elrahman KS, El-Yazbi AF. Adipose Tissue Mitochondrial Dysfunction and Cardiometabolic Diseases: On the Search for Novel Molecular Targets. Biochem Pharmacol 2022; 206:115337. [DOI: 10.1016/j.bcp.2022.115337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 10/17/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022]
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17
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Shirakawa J, Togashi Y, Basile G, Okuyama T, Inoue R, Fernandez M, Kyohara M, De Jesus DF, Goto N, Zhang W, Tsuno T, Kin T, Pan H, Dreyfuss JM, Shapiro AMJ, Yi P, Terauchi Y, Kulkarni RN. E2F1 transcription factor mediates a link between fat and islets to promote β cell proliferation in response to acute insulin resistance. Cell Rep 2022; 41:111436. [PMID: 36198264 PMCID: PMC9617565 DOI: 10.1016/j.celrep.2022.111436] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/21/2022] [Accepted: 09/08/2022] [Indexed: 02/03/2023] Open
Abstract
Prevention or amelioration of declining β cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by β cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced β cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks β-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of β cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables β cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote β cell compensation.
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Affiliation(s)
- Jun Shirakawa
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA; Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 3718512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan.
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan
| | - Giorgio Basile
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan
| | - Ryota Inoue
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 3718512, Japan
| | - Megan Fernandez
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan
| | - Dario F De Jesus
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Nozomi Goto
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan
| | - Wei Zhang
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Takahiro Tsuno
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 3718512, Japan
| | - Tatsuya Kin
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Hui Pan
- Bioinformatics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jonathan M Dreyfuss
- Bioinformatics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - A M James Shapiro
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Peng Yi
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 2360004, Japan
| | - Rohit N Kulkarni
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA.
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18
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Barchetta I, Cimini FA, Dule S, Cavallo MG. Dipeptidyl Peptidase 4 (DPP4) as A Novel Adipokine: Role in Metabolism and Fat Homeostasis. Biomedicines 2022; 10:biomedicines10092306. [PMID: 36140405 PMCID: PMC9496088 DOI: 10.3390/biomedicines10092306] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Dipeptidyl peptidase 4 (DPP4) is a molecule implicated in the regulation of metabolic homeostasis and inflammatory processes, and it exerts its main action through its enzymatic activity. DPP4 represents the enzyme most involved in the catabolism of incretin hormones; thus, its activity impacts appetite, energy balance, and the fine regulation of glucose homeostasis. Indeed, DPP4 inhibitors represent a class of antidiabetic agents widely used for the treatment of Type 2 diabetes mellitus (T2DM). DPP4 also acts as an adipokine and is mainly secreted by the adipose tissue, mostly from mature adipocytes of the visceral compartment, where it exerts autocrine and paracrine activities. DPP4 can disrupt insulin signaling within the adipocyte and in other target cells and tissues, where it also favors the development of a proinflammatory environment. This is likely at the basis of the presence of elevated circulating DPP4 levels in several metabolic diseases. In this review, we summarize the most recent evidence of the role of the DPP4 as an adipokine-regulating glucose/insulin metabolism and fat homeostasis, with a particular focus on clinical outcomes associated with its increased secretion in the presence of adipose tissue accumulation and dysfunction.
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Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways. Clin Sci (Lond) 2022; 136:1347-1366. [PMID: 36148775 PMCID: PMC9508552 DOI: 10.1042/cs20220572] [Citation(s) in RCA: 154] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 01/30/2023]
Abstract
The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight or obesity and insulin resistance. It is also associated with an increased cardiovascular disease risk, including hypertension and atherosclerosis. Hepatic lipid metabolism is regulated by a combination of the uptake and export of fatty acids, de novo lipogenesis, and fat utilization by β-oxidation. When the balance between these pathways is altered, hepatic lipid accumulation commences, and long-term activation of inflammatory and fibrotic pathways can progress to worsen the liver disease. This review discusses the details of the molecular mechanisms regulating hepatic lipids and the emerging therapies targeting these pathways as potential future treatments for MAFLD.
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20
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Pathak R, Kumar A, Palfrey HA, Stone KP, Raju NR, Gettys TW, Murthy SN. Prolonged effects of DPP-4 inhibitors on steato-hepatitic changes in Sprague-Dawley rats fed a high-cholesterol diet. Inflamm Res 2022; 71:711-722. [PMID: 35578028 PMCID: PMC10154130 DOI: 10.1007/s00011-022-01572-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/28/2022] [Accepted: 04/03/2022] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE Sitagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors/gliptins are antidiabetic drugs known to improve lipid profile, and confer anti-inflammatory and anti-fibrotic effects, which are independent of their hypoglycemic effects. However, in our previous short-term (35 days) studies, we showed that sitagliptin accentuates the hepato-inflammatory effects of high dietary cholesterol (Cho) in male Sprague-Dawley rats. Since most type 2 diabetics also present with lipid abnormalities and use DPP-4 inhibitors for glucose management, the present study was conducted to assess the impact of sitagliptin during long-term (98 days) feeding of a high Cho diet. An additional component of the present investigation was the inclusion of other gliptins to determine if hepatic steatosis, necro-inflammation, and fibrosis were specific to sitagliptin or are class effects. METHODS Adult male Sprague-Dawley rats were fed control or high Cho (2.0%) diets, and gavaged daily (from day 30 through 98) with vehicle or DPP-4 inhibitors (sitagliptin or alogliptin or saxagliptin). On day 99 after a 4 h fast, rats were euthanized. Blood and liver samples were collected to measure lipids and cytokines, and for histopathological evaluation, determination of hepatic lesions (steatosis, necrosis, inflammation, and fibrosis) using specific staining and immunohistochemical methods. RESULTS Compared to controls, the high Cho diet produced a robust increase in NASH like phenotype that included increased expression of hepatic (Tnfa, Il1b, and Mcp1) and circulatory (TNFα and IL-1β) markers of inflammation, steatosis, necrosis, fibrosis, and mononuclear cell infiltration. These mononuclear cells were identified as macrophages and T cells, and their recruitment in the liver was facilitated by marked increases in endothelium-expressed cell adhesion molecules. Importantly, treatment with DPP-4 inhibitors (3 tested) neither alleviated the pathologic responses induced by high Cho diet nor improved lipid profile. CONCLUSIONS The potential lipid lowering effects of DPP-4 inhibitors were diminished by high Cho (a significant risk factor for inducing liver damage). The robust inflammatory responses induced by high Cho feeding in long-term experiment were not exacerbated by DPP-4 inhibitors and a consistent hepatic inflammatory environment persisted, implying a prospective physiological adaptation.
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Affiliation(s)
- Rashmi Pathak
- Department of Environmental Toxicology, Southern University and A&M College, 209, Lee Hall, Baton Rouge, LA, 70813, USA.,Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, 70803, USA
| | - Avinash Kumar
- Department of Environmental Toxicology, Southern University and A&M College, 209, Lee Hall, Baton Rouge, LA, 70813, USA.,Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA.,Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA
| | - Henry A Palfrey
- Department of Environmental Toxicology, Southern University and A&M College, 209, Lee Hall, Baton Rouge, LA, 70813, USA
| | - Kirsten P Stone
- Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Narayan R Raju
- Pathology Research Laboratory Inc, South San Francisco, CA, USA
| | - Thomas W Gettys
- Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Subramanyam N Murthy
- Department of Environmental Toxicology, Southern University and A&M College, 209, Lee Hall, Baton Rouge, LA, 70813, USA.
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21
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Barkondaj B, Nargis T, Chakrabarti P, Mukhopadhyay S, Biswas K, Ganguly D, Chaterjee C, Sengupta N, Hazra A. An Observational Study showing Dipeptidyl Peptidase-4 (DPP-4) Activity and Gene Expression Variation in Chronic Liver Disease (CLD) Patients from a Tertiary Care Hospital of Eastern India. Indian J Endocrinol Metab 2022; 26:245-251. [PMID: 36248034 PMCID: PMC9555384 DOI: 10.4103/ijem.ijem_139_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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 04/15/2022] [Accepted: 04/22/2022] [Indexed: 11/06/2022] Open
Abstract
INTRODUCTION The studies in animal models of cirrhosis suggest that dipeptidyl peptidase type 4 (DPP-4) enzymes play a crucial role in disease pathogenesis. In this clinical observational study, activity of DPP-4 and related gene expression were analysed in chronic liver disease patients. OBJECTIVES To understand the DPP-4 enzyme activity variation in the common types of chronic liver disease by assessing plasma and peripheral blood mononuclear cell (PBMC) DPP-4 activity and comparing with healthy controls and to explore DPP-4 gene expression in PBMC. METHODS We recruited 130 study subjects in four cohorts-46 nonalcoholic fatty liver disease (NAFLD), 23 non-alcoholic cirrhosis (NAC) excluding viral aetiology, 21 alcoholic liver disease (ALC), and 40 control subjects. Blood samples were analysed for relevant biochemical parameters and plasma DPP-4 activity. PBMC fraction was used for the DPP-4 activity assay and gene expression analysis. RESULTS We found that lower plasma DPP-4 activity among patient cohorts but this was not statistically significant. The PBMC DPP-4 activity was significantly lower in NAFLD cohort. In the same cohort, DPP-4 gene expression in PBMC fraction was significantly increased (P < 0.05). There was significant correlation between plasma DPP-4 activity and liver injury marker alanine aminotransferase (ALT) among NAFLD (rho = 0.459, P < 0.01), NAC (rho = 0.475, P < 0.05), and ALC (rho = -0.572, P < 0.01) patients. Plasma DPP-4 activity modestly predicted ALT plasma level (beta coefficient = 0.489, P < 0.01). CONCLUSIONS The PBMC DPP-4 activity and DPP-4 gene expression gets significantly altered in NAFLD patients. Plasma DPP-4 activity also shows correlation with ALT levels in CLD patients. The role of DPP-4 in disease pathology in NAFLD and other forms of CLD needs to be explored.
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Affiliation(s)
- Bikramjit Barkondaj
- Department of Pharmacology, ESI-PGIMSR, ESIC Medical College, Kolkata, West Bengal, India
| | - Titli Nargis
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India
| | - Partha Chakrabarti
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India
| | - Satinath Mukhopadhyay
- Department of Endocrinology & Metabolism, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
| | - Kalidas Biswas
- Department of Medical Gastroenterology, Medical College and Hospital Kolkata, Kolkata, West Bengal, India
| | - Dipyaman Ganguly
- Division of Cancer Biology and Inflammatory Disorder, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India
| | - Chandan Chaterjee
- Department of Pharmacology, ESI-PGIMSR, ESIC Medical College, Kolkata, West Bengal, India
| | - Nilanjan Sengupta
- Department of Endocrinology, NRS Medical College, Kolkata, West Bengal, India
| | - Avijit Hazra
- Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
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22
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Efficacy of Sitagliptin on Nonalcoholic Fatty Liver Disease in High-fat-diet-fed Diabetic Mice. Curr Med Sci 2022; 42:513-519. [PMID: 35451807 DOI: 10.1007/s11596-022-2573-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/25/2022] [Indexed: 11/03/2022]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is a common cause of clinical liver dysfunction and an important prepathological change of liver cirrhosis. Central obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome are the major risk factors for NAFLD. Sitagliptin (Sig) is a novel hypoglycemic agent that improves blood glucose levels by increasing the level of active incretin. Sig has been shown to prevent the development of fatty livers in mice on a fructose-rich diet. The purpose of this study was to observe the efficacy of Sig on NAFLD in type 2 diabetic mice. METHODS The diet-induced obesity mouse model was established, and the diabetic mice were screened by an intraperitoneal glucose tolerance trial. The mice were randomly divided into four groups for 8 weeks of intervention: high-fat diet (HFD) group, Sig group, metformin (Met) group, and Sig+Met group. After the intervention, the liver function indexes as well as the blood glucose and blood lipid levels of the mice were measured. In addition, the wet weight of the liver was measured; the pathological sections of the liver tissues were stained to observe the hepatocyte fatty degeneration, inflammation, necrosis, and fibrosis; and the hepatic histological injury was recorded as the NAFLD activity score (NAS). RESULTS Compared with the normal control group, the body weight, liver weight, blood glucose level, insulin resistance (IR), blood lipid level, and transaminase level of the mice in the HFD group were significantly increased, showing typical metabolic syndrome. After treatment with Sig and/or Met, the mice gained less weight, had lower levels of blood glucose, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and transaminase, and had improved IR compared with the HFD group. The liver pathological NASs in the Sig group (P=0.01), Met group (P=0.028), and Sig+Met group (P<0.001) were lower than those in the HFD group (P<0.05), suggesting that the use of the two drugs alone or in combination can improve the state of liver inflammation. In terms of fibrosis, there was no fibrosis in the control group but there was significant fibrosis in the HFD group (P<0.001). There was no significant difference between the drug intervention groups and the HFD group, indicating that the drug therapy (Sig and/or Met) did not significantly improve the pre-existing fibrosis. CONCLUSION Our experiment proved that Sig can improve NAFLD, including improvement of the serum transaminase level, hepatic pathological inflammation level, and hepatocyte adiposis, suggesting that Sig may play a role by improving glucose and lipid metabolism, reducing the body weight and liver weight, improving insulin sensitivity, and inhibiting fatty liver inflammation. Sig may be a new direction for the treatment of patients with a nonalcoholic fatty liver and diabetes, delaying the progression of NAFLD.
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23
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Cariou B. The metabolic triad of non-alcoholic fatty liver disease, visceral adiposity and type 2 diabetes: Implications for treatment. Diabetes Obes Metab 2022; 24 Suppl 2:15-27. [PMID: 35014161 DOI: 10.1111/dom.14651] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 01/06/2022] [Accepted: 01/06/2022] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with visceral obesity, insulin resistance, type 2 diabetes (T2D) and has been often considered as the hepatic expression of the metabolic syndrome (MetS). Epidemiological studies highlight a bidirectional relationship of NAFLD with T2D in which NAFLD increases the risk of incident T2D and T2D increases the risk of severe non-alcoholic steatohepatitis (NASH) and liver fibrosis. Regarding the molecular determinants of NAFLD, we specifically focused in this review on adipocyte dysfunction as a key molecular link between visceral adipose tissue, MetS and NAFLD. Notably, the subcutaneous white adipose tissue expandability appears a critical adaptive buffering mechanism to prevent lipotoxicity and its related metabolic complications, such as NAFLD and T2D. There is a clinical challenge to consider therapeutic strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis. Strategies that promote significant and sustained weight loss (~10% of total body weight) such as metabolic and bariatric surgery or incretin-based therapies (GLP-1 receptor agonists or dual GLP-1/GIP or GLP-1/glucagon receptor co-agonists) are among the most efficient ones. In addition, insulin sensitizers such as PPARγ (pioglitazone) and pan-PPARs agonists (lanifibranor) have shown some beneficial effects on both NASH and liver fibrosis. Since NASH is a complex and multifactorial disease, it is conceivable that targeting different pathways, not only insulin resistance but also inflammation and fibrotic processes, is required to achieve NASH resolution.
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Affiliation(s)
- Bertrand Cariou
- Université de Nantes, Inserm, CNRS, CHU Nantes, l'institut du thorax, Nantes, France
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24
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Lee N, Heo YJ, Choi SE, Jeon JY, Han SJ, Kim DJ, Kang Y, Lee KW, Kim HJ. Hepatoprotective effects of gemigliptin and empagliflozin in a murine model of diet-induced non-alcoholic fatty liver disease. Biochem Biophys Res Commun 2022; 588:154-160. [PMID: 34971904 DOI: 10.1016/j.bbrc.2021.12.065] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/14/2021] [Accepted: 12/18/2021] [Indexed: 12/19/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver diseases characterized by steatosis, inflammation, and fibrosis. This study aimed to investigate the potential of dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors in alleviating the progression of NAFLD. The NAFLD model was generated by feeding male C57BL/6J mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 7 weeks. After 2 weeks of CDAHFD feeding, the NAFLD model mice were assigned to four groups, namely (ⅰ) VEHICLE, (ⅱ) gemigliptin (GEMI), (ⅲ) empagliflozin (EMPA), and (ⅳ) GEMI + EMPA. For the next 5 weeks, mice received the vehicle or the drug based upon the group to which they belonged. Thereafter, the triglyceride concentration, extent of fibrosis, and the expression of genes encoding inflammatory cytokines, chemokines, and antioxidant enzymes were analyzed in the livers of mice. The NAFLD activity score and hepatic fibrosis grade were assessed via hematoxylin and eosin and Sirius Red staining of the liver tissue samples. All mice belonging to the GEMI, EMPA, and GEMI + EMPA groups showed improvements in the accumulation of liver triglycerides and the expression of inflammatory cytokines and chemokines. Additionally, the oxidative stress was reduced due to inhibition of the c-Jun N-terminal kinase pathway and upregulation of the antioxidant enzymes. Furthermore, in these three groups, the galectin-3 and interleukin 33-induced activity of tumor necrosis factor-α was inhibited, thereby preventing the progression of liver fibrosis. These findings suggest that the GEMI, EMPA, and GEMI + EMPA treatments ameliorate hepatic steatosis, inflammation, oxidative stress, and fibrosis in CDAHFD-induced NAFLD mouse models.
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Affiliation(s)
- Nami Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Yu Jung Heo
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Sung-E Choi
- Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Ja Young Jeon
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Seung Jin Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Yup Kang
- Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Kwan Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea.
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25
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Sharma A, Virmani T, Sharma A, Chhabra V, Kumar G, Pathak K, Alhalmi A. Potential Effect of DPP-4 Inhibitors Towards Hepatic Diseases and Associated Glucose Intolerance. Diabetes Metab Syndr Obes 2022; 15:1845-1864. [PMID: 35733643 PMCID: PMC9208633 DOI: 10.2147/dmso.s369712] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/10/2022] [Indexed: 11/23/2022] Open
Abstract
Dipeptidyl-peptidase-4 (DPP-4) is an enzyme having various properties and physiological roles in lipid accumulation, resistance to anticancer agents, and immune stimulation. DPP-4 includes membrane-bound peptidases and is a kind of enzyme that cleaves alanine or proline-containing peptides such as incretins, chemokines, and appetite-suppressing hormones (neuropeptide) at their N-terminal dipeptides. DPP-4 plays a role in the final breakdown of peptides produced by other endo and exo-peptidases from nutritious proteins and their absorption in these tissues. DPP-4 enzyme activity has different modes of action on glucose metabolism, hunger regulation, gastrointestinal motility, immune system function, inflammation, and pain regulation. According to the literature survey, as DPP-4 levels increase in individuals with liver conditions, up-regulation of hepatic DPP-4 expression is likely to be the cause of glucose intolerance or insulin resistance. This review majorly focuses on the cleavage of alanine or proline-containing peptides such as incretins by the DPP-4 and its resulting conditions like glucose intolerance and cause of DPP-4 level elevation due to some liver conditions. Thus, we have discussed the various effects of DPP-4 on the liver diseases like hepatitis C, non-alcoholic fatty liver, hepatic regeneration and stem cell, hepatocellular carcinoma, and the impact of elevated DPP-4 levels in association with liver diseases as a cause of glucose intolerance and their treatment drug of choices. In addition, the effect of DPP-4 inhibitors on obesity and their negative aspects are also discussed in brief.
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Affiliation(s)
- Ashwani Sharma
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Tarun Virmani
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Anjali Sharma
- Freelancer, Pharmacovigilance Expert, Uttar Pradesh, India
| | - Vaishnavi Chhabra
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Girish Kumar
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Kamla Pathak
- Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Uttar Pradesh, 206130, India
| | - Abdulsalam Alhalmi
- Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen
- Correspondence: Abdulsalam Alhalmi, Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen, Email
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26
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18:0 Lyso PC Derived by Bioactivity-Based Molecular Networking from Lentil Mutant Lines and Its Effects on High-Fat Diet-Induced Obese Mice. Molecules 2021; 26:molecules26247547. [PMID: 34946633 PMCID: PMC8707596 DOI: 10.3390/molecules26247547] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/07/2021] [Accepted: 12/08/2021] [Indexed: 01/12/2023] Open
Abstract
Lentil (Lens culinaris; Fabaceae), one of the major pulse crops in the world, is an important source of proteins, prebiotics, lipids, and essential minerals as well as functional components such as flavonoids, polyphenols, and phenolic acids. To improve crop nutritional and medicinal traits, hybridization and mutation are widely used in plant breeding research. In this study, mutant lentil populations were generated by γ-irradiation for the development of new cultivars by inducing genetic diversity. Molecular networking via Global Natural Product Social Molecular Networking web platform and dipeptidyl peptide-IV inhibitor screening assay were utilized as tools for structure-based discovery of active components in active mutant lines selected among the lentil population. The bioactivity-based molecular networking analysis resulted in the annotation of the molecular class of phosphatidylcholine (PC) from the most active mutant line. Among PCs, 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (18:0 Lyso PC) was selected for further in vivo study of anti-obesity effect in a high-fat diet (HFD)-induced obese mouse model. The administration of 18:0 Lyso PC not only prevented body weight gain and decreased relative gonadal adipose tissue weight, but also attenuated the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and leptin in the sera of HFD-induced obese mice. Additionally, 18:0 Lyso PC treatment inhibited the increase of adipocyte area and crown-like structures in adipose tissue. Therefore, these results suggest that 18:0 Lyso PC is a potential compound to have protective effects against obesity, improving obese phenotype induced by HFD.
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27
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Shirakawa J. Translational research on human pancreatic β-cell mass expansion for the treatment of diabetes. Diabetol Int 2021; 12:349-355. [PMID: 34567917 DOI: 10.1007/s13340-021-00531-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 08/15/2021] [Indexed: 11/27/2022]
Abstract
The structural, functional, and pathological differences between human islets and rodent islets, such as mouse or rat islets, have been clarified, and research using human islets is becoming more important for elucidating the pathophysiology of diabetes and developing therapeutic strategies for diabetes. Increasing the functional human β-cell mass is a feasible method for the treatment of both type 1 and type 2 diabetes. The glucokinase-mediated glucose signaling pathway is known to promote β-cell proliferation not only in rodent models but also in humans. However, little is known about the signaling components of glucose- or glucokinase-mediated signaling pathways. Studies have gradually revealed the involvement of ER stress-related molecules, cell cycle regulators, inflammatory proteins, extracellular matrix proteins, and neurotransmitters in the glucokinase-mediated signaling pathway in β-cells. Unraveling the mechanisms of those molecules in the regulation of human β-cell mass will provide new insights into how the functional β-cell mass can be increased. The human islet distribution program is essential for human islet research. However, human islets for research are only available by import from Europe and America into Japan or Asia. Since Japanese or Asian diabetes patients possibly show different features compared with European or American diabetes patients, studies using human islets from Japanese or Asian populations have become important for the elucidation of pathophysiology in these specific population groups. This review outlines new pathways important for the regulation of human pancreatic β-cell mass and expectations regarding the establishment of a human islet distribution program in Japan.
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Affiliation(s)
- Jun Shirakawa
- Laboratory and Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, 371-8510 Japan
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28
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Anti-fibrotic activity of sitagliptin against concanavalin A-induced hepatic fibrosis. Role of Nrf2 activation/NF-κB inhibition. Int Immunopharmacol 2021; 100:108088. [PMID: 34454288 DOI: 10.1016/j.intimp.2021.108088] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 12/23/2022]
Abstract
Sitagliptin is known for its anti-diabetic activity though it has other pleiotropic pharmacological actions. Its effect against concanavalin A (Con A)-induced hepatic fibrosis has not been investigated yet. Our target was to test whether sitagliptin can suppress the development of Con A-induced hepatic fibrosis and if so, what are the mechanisms involved? Con A (6 mg/kg) was injected once weekly to male Swiss albino mice for four weeks. Sitagliptin was daily administered concurrently with Con A. Results have shown the potent hepatoprotective activity of sitagliptin against Con A-induced hepatitis and fibrosis. That was evident through the amelioration of hepatotoxicity serum parameters (ALT, AST, ALP, and LDH) and the increase in the level of serum albumin in sitagliptin treated mice. Simultaneously, there was amendment of the Con A-induced hepatic lesions and repression of fibrosis in sitagliptin-treated animals. Hydroxyproline, collagen content and the immuno-expression of the fibrotic markers, TGF-β and α-SMA were depressed upon sitagliptin treatment. Sitagliptin suppressed Con A-induced oxidative stress and increased antioxidants. RT-PCR analysis showed enhancement of mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes (GCLc, GCLm, NQO-1, HO-1) by sitagliptin. Furthermore, sitagliptin ameliorated the level and immuno-expression of nuclear factor kappa-B (NF-κB) alongside the immuno-expression of the inflammatory cytokine, TNF-α. Taken together, this study demonstrates the hepatoprotective activity of sitagliptin which may be in part related to enhancement of Nrf2 signaling pathway and inhibition of NF-κB which interact inflammatory response in liver. Sitagliptin might be a new candidate to suppress hepatitis-associated fibrosis.
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29
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Xing X, Guo S, Liu Y, Kuang J, Huang Z, Wang X, Lu Q. Saxagliptin protects against diabetic nephropathy by inhibiting caspase 3/PARP-1-dependent nephrocyte apoptosis. Exp Ther Med 2021; 22:990. [PMID: 34345272 PMCID: PMC8311252 DOI: 10.3892/etm.2021.10422] [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: 06/25/2019] [Accepted: 06/08/2021] [Indexed: 11/16/2022] Open
Abstract
Saxagliptin (SAX) can protect against tissue damage caused by diabetic nephropathy. However, whether this compound can restore kidney function, and its specific mechanism of action remain unclear. The present study explored the therapeutic effects and mechanisms of SAX. Male Wistar rats (8 weeks old) were randomly divided into the following groups: A control group (n=10); a group with streptozocin-induced diabetes mellitus (DM) treated with saline (n=20); and a group with streptozocin-induced DM treated with SAX (n=20). Following 20 weeks of treatment, renal function and the extent of renal damage were assessed based on histological staining using hematoxylin and eosin, periodic acid-Schiff and Masson's trichrome staining. The experimental results indicated that Streptozocin induction of DM led to thicker basement membranes in mesangial cells and a more abundant extracellular matrix. These changes were ameliorated following treatment with SAX. The data demonstrated that renal tissue and renal cell apoptosis were ameliorated significantly following treatment with SAX. Furthermore, the expression levels of the apoptotic genes poly (ADP-ribose) polymerase-1 (PARP-1) and caspase 3 were significantly decreased following treatment with SAX. Therefore, SAX may reduce the extent of renal apoptosis and pathological outcomes in diabetic nephropathy by downregulating the expression of caspase 3 and PARP-1 in the death receptor pathway of apoptosis.
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Affiliation(s)
- Xiaowei Xing
- Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Shuang Guo
- Department of Gastroenterology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yusheng Liu
- Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Jiangying Kuang
- Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Zhiwei Huang
- Department of Hematology, The Qilu Children's Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Xin Wang
- Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Qinghua Lu
- Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
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30
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Smati S, Canivet CM, Boursier J, Cariou B. Anti-diabetic drugs and NASH: from current options to promising perspectives. Expert Opin Investig Drugs 2021; 30:813-825. [PMID: 34214406 DOI: 10.1080/13543784.2021.1951701] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Accumulating evidence supports a bidirectional association between nonalcoholic steatohepatitis (NASH) and type 2 diabetes (T2D). There is a clinical challenge to consider pharmaceutical strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis.Areas covered: By using PubMed, we performed a literature search to review the potential beneficial effect of anti-diabetic and metabolic investigational drugs on NASH.Expert opinion: Since insulin resistance is central in the pathophysiology of both T2D and NASH, there is an urgent need for new insulin sensitizers. Peroxisome proliferator-activated receptor (PPAR) agonists, especially PPARγ and pan-PPARs agonists, have shown some beneficial effects on both NASH and liver fibrosis, but their routine use should be limited by their safety profile. Incretin-based therapies, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and the polyagonists (GLP-1, GIP, glucagon) under development are the most promising anti-diabetic drugs for NASH treatment, mainly due to their action on body weight loss. Preliminary, preclinical and early phase studies suggest that SGLT2 inhibitors and fibroblast growth factor (FGF)19 and FGF21-based therapies are promising targets for NASH and T2D treatment. The common weakness for all of these drugs is their limited effect on liver fibrosis, potentially due to short-term trial design.
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Affiliation(s)
- Sarra Smati
- Department of Endocrinology, Université De Nantes, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, Nantes, France
| | - Clémence M Canivet
- Hepato-Gastroenterology department, University Hospital, Angers, France.,HIFIH Laboratory, EA 3859, University of Angers, Angers, France
| | - Jérôme Boursier
- Hepato-Gastroenterology department, University Hospital, Angers, France.,HIFIH Laboratory, EA 3859, University of Angers, Angers, France
| | - Bertrand Cariou
- Department of Endocrinology, Université De Nantes, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, Nantes, France
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Zhao J, Zhao Y, Hu Y, Peng J. Targeting the GPR119/incretin axis: a promising new therapy for metabolic-associated fatty liver disease. Cell Mol Biol Lett 2021; 26:32. [PMID: 34233623 PMCID: PMC8265056 DOI: 10.1186/s11658-021-00276-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/02/2021] [Indexed: 12/22/2022] Open
Abstract
In the past decade, G protein-coupled receptors have emerged as drug targets, and their physiological and pathological effects have been extensively studied. Among these receptors, GPR119 is expressed in multiple organs, including the liver. It can be activated by a variety of endogenous and exogenous ligands. After GPR119 is activated, the cell secretes a variety of incretins, including glucagon-like peptide-1 and glucagon-like peptide-2, which may attenuate the metabolic dysfunction associated with fatty liver disease, including improving glucose and lipid metabolism, inhibiting inflammation, reducing appetite, and regulating the intestinal microbial system. GPR119 has been a potential therapeutic target for diabetes mellitus type 2 for many years, but its role in metabolic dysfunction associated fatty liver disease deserves further attention. In this review, we discuss relevant research and current progress in the physiology and pharmacology of the GPR119/incretin axis and speculate on the potential therapeutic role of this axis in metabolic dysfunction associated with fatty liver disease, which provides guidance for transforming experimental research into clinical applications.
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Affiliation(s)
- Jianan Zhao
- Institute of Liver Diseases, Shuguang Hospital Affiliated To Shanghai, University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China
| | - Yu Zhao
- Institute of Liver Diseases, Shuguang Hospital Affiliated To Shanghai, University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine), Ministry of Education, 528 Zhangheng Road, Pudong District, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528, Zhangheng Road, Shanghai, China
| | - Yiyang Hu
- Institute of Clinical Pharmacology, Shuguang Hospital Affiliated To Shanghai, University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China.
- Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine), Ministry of Education, 528 Zhangheng Road, Pudong District, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528, Zhangheng Road, Shanghai, China.
| | - Jinghua Peng
- Institute of Liver Diseases, Shuguang Hospital Affiliated To Shanghai, University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China.
- Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine), Ministry of Education, 528 Zhangheng Road, Pudong District, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528, Zhangheng Road, Shanghai, China.
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Kitaura H, Ogawa S, Ohori F, Noguchi T, Marahleh A, Nara Y, Pramusita A, Kinjo R, Ma J, Kanou K, Mizoguchi I. Effects of Incretin-Related Diabetes Drugs on Bone Formation and Bone Resorption. Int J Mol Sci 2021; 22:ijms22126578. [PMID: 34205264 PMCID: PMC8234693 DOI: 10.3390/ijms22126578] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Patients with type 2 diabetes have an increased risk of fracture compared to the general population. Glucose absorption is accelerated by incretin hormones, which induce insulin secretion from the pancreas. The level of the incretin hormone, glucagon-like peptide-1 (GLP-1), shows an immediate postprandial increase, and the circulating level of intact GLP-1 is reduced rapidly by dipeptidyl peptidase-4 (DPP-4)-mediated inactivation. Therefore, GLP-1 receptor agonists and DPP-4 inhibitors are effective in the treatment of type 2 diabetes. However, these incretin-related diabetic agents have been reported to affect bone metabolism, including bone formation and resorption. These agents enhance the expression of bone markers, and have been applied to improve bone quality and bone density. In addition, they have been reported to suppress chronic inflammation and reduce the levels of inflammatory cytokine expression. Previously, we reported that these incretin-related agents inhibited both the expression of inflammatory cytokines and inflammation-induced bone resorption. This review presents an overview of current knowledge regarding the effects of incretin-related diabetes drugs on osteoblast differentiation and bone formation as well as osteoclast differentiation and bone resorption. The mechanisms by which incretin-related diabetes drugs regulate bone formation and bone resorption are also discussed.
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Stojsavljevic-Shapeski S, Duvnjak M, Virovic-Jukic L, Hrabar D, Smircic Duvnjak L. New Drugs on the Block-Emerging Treatments for Nonalcoholic Steatohepatitis. J Clin Transl Hepatol 2021; 9:51-59. [PMID: 33604255 PMCID: PMC7868699 DOI: 10.14218/jcth.2020.00057] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 09/18/2020] [Accepted: 10/21/2020] [Indexed: 12/12/2022] Open
Abstract
Patients with nonalcoholic steatohepatitis (NASH) are at higher risk of progression to advanced stages of fibrosis, cirrhosis, hepatocellular carcinoma and other end-stage liver disease complications. When addressing treatment of NASH, we have limited approved options, and the mainstay of therapy is lifestyle intervention. Extensive research and revelation in the field of pathogenesis of NASH has offered new possibilities of treatment and emerging new drugs that are being tested currently in numerous preclinical and clinical trials. These drugs target almost all steps in the pathogenesis of NASH to improve insulin sensitivity, glucose and lipid metabolism, to inhibit de novo lipogenesis and delivery of lipids to the liver, and to influence apoptosis, inflammation and fibrogenesis. Although NASH is a multifactorial disease, in the future we could identify the predominating pathological mechanism and, by choosing the most appropriate specific medication, tailor the treatment for every patient individually.
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Affiliation(s)
| | - Marko Duvnjak
- Polyclinic Duvnjak, Zagreb, Croatia
- University of Applied Health Science, Zagreb, Croatia
| | - Lucija Virovic-Jukic
- Department of Gastroenterology and Hepatology, Clinical Hospital Center Sestre Milosrdnice, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Davor Hrabar
- Department of Gastroenterology and Hepatology, Clinical Hospital Center Sestre Milosrdnice, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Lea Smircic Duvnjak
- University of Applied Health Science, Zagreb, Croatia
- Vuk Vrhovac University Clinic-UH Merkur, Zagreb, Croatia
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Pezhman L, Tahrani A, Chimen M. Dysregulation of Leukocyte Trafficking in Type 2 Diabetes: Mechanisms and Potential Therapeutic Avenues. Front Cell Dev Biol 2021; 9:624184. [PMID: 33692997 PMCID: PMC7937619 DOI: 10.3389/fcell.2021.624184] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 02/04/2021] [Indexed: 12/18/2022] Open
Abstract
Type 2 Diabetes Mellitus (T2DM) is a chronic inflammatory disorder that is characterized by chronic hyperglycemia and impaired insulin signaling which in addition to be caused by common metabolic dysregulations, have also been associated to changes in various immune cell number, function and activation phenotype. Obesity plays a central role in the development of T2DM. The inflammation originating from obese adipose tissue develops systemically and contributes to insulin resistance, beta cell dysfunction and hyperglycemia. Hyperglycemia can also contribute to chronic, low-grade inflammation resulting in compromised immune function. In this review, we explore how the trafficking of innate and adaptive immune cells under inflammatory condition is dysregulated in T2DM. We particularly highlight the obesity-related accumulation of leukocytes in the adipose tissue leading to insulin resistance and beta-cell dysfunction and resulting in hyperglycemia and consequent changes of adhesion and migratory behavior of leukocytes in different vascular beds. Thus, here we discuss how potential therapeutic targeting of leukocyte trafficking could be an efficient way to control inflammation as well as diabetes and its vascular complications.
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Affiliation(s)
- Laleh Pezhman
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Abd Tahrani
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.,Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, United Kingdom.,University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Myriam Chimen
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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35
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Pan K, Ohnuma K, Morimoto C, Dang NH. CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions. Cureus 2021; 13:e13495. [PMID: 33777580 PMCID: PMC7990348 DOI: 10.7759/cureus.13495] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
CD26/Dipeptidyl peptidase IV (DPPIV) is a cell surface glycoprotein with numerous roles including glucose metabolism, immunomodulation, and tumorigenesis. CD26/DPPIV is well recognized in diabetes, with DPPIV inhibitors being a class of oral hypoglycemic drugs called gliptins that are commonly used to treat type two diabetes mellitus. Recent work also indicated a potential role for CD26 in infectious diseases, including COVID-19, and immune-mediated disorders such as rheumatoid arthritis, inflammatory bowel disease, and graft-versus-host disease. In cancer, CD26/DPPIV expression has been characterized in numerous tumors such as hematologic malignancies, malignant pleural mesothelioma (MPM), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastrointestinal stromal tumor (GIST), and prostate, lung, colorectal, and ovarian (PLCO) cancer. Hence, CD26 has been frequently studied as a tumor biomarker and therapeutic target. CD26/DPPIV-targeted therapies have been evaluated in various cancers, including the use of anti-CD26 monoclonal antibodies as anticancer treatment in selected neoplasms. This review highlights our current understanding of the role of CD26 in cancer, diabetes, immune-mediated diseases, and infectious diseases. Enhanced understanding of CD26 biology and function may lead to novel therapeutic approaches in multiple human diseases.
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Affiliation(s)
- Kelsey Pan
- Internal Medicine, University of Florida, Gainesville, USA
| | - Kei Ohnuma
- Department of Therapy Development and Innovation for Immune Disorders and Cancers, Juntendo University, Tokyo, JPN
| | - Chikao Morimoto
- Department of Therapy Development and Innovation for Immune Disorders and Cancers, Juntendo University, Tokyo, JPN
| | - Nam H Dang
- Oncology, University of Florida, Gainesville, USA
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Herz CT, Brix JM, Ludvik B, Schernthaner G, Schernthaner GH. Decrease of dipeptidyl peptidase 4 activity is associated with weight loss after bariatric surgery. Obes Surg 2021; 31:2545-2550. [PMID: 33538983 PMCID: PMC8113172 DOI: 10.1007/s11695-020-05200-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/22/2020] [Accepted: 12/29/2020] [Indexed: 12/13/2022]
Abstract
Purpose Dipeptidyl peptidase 4 (DPP4) is expressed and secreted by adipocytes. DPP4 induces insulin resistance independently of its effect on glucagon-like peptide 1, thus it is conceivable that DPP4 directly contributes to metabolic dysfunction in patients with morbid obesity. The aim of this study was to investigate the impact of weight loss induced by bariatric surgery on DPP4 activity, and whether these changes are associated with improvements in markers of metabolic dysfunction and fatty liver disease. Materials and Methods We included 68 non-diabetic patients who underwent bariatric surgery. Serum DPP4 activity was measured using a fluorogenic substrate before and after surgery. Results Results: After a median follow-up period of 12 (IQR 11-17) months, median serum DPP4 activity decreased from 230 (IQR: 194-273) to 193 (164-252) pmol/min (p=0.012). The decrease in DPP4 activity was significantly correlated with decreases in BMI, improved cholesterol levels, reduced hepatic injury markers as well as improved post-prandial insulin sensitivity. After multivariable adjustment, ΔDPP4 activity remained significantly associated with Δcholesterol (beta=0.341, p=0.025), ΔLDL cholesterol (beta=0.350, p=0.019), Δgamma-glutamyltransferase (beta=0.323, p=0.040) and ΔMatsuda index (beta=-0.386, p=0.045). Conclusion We demonstrated that weight loss induced by bariatric surgery results in decreased circulating DPP4 activity beyond the initial phase of weight loss. The associations between decreased DPP4 activity and improved cholesterol levels as well as hepatic injury markers point towards pleiotropic effects of DPP4 beyond glucose metabolism which warrant further investigation.
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Affiliation(s)
- Carsten T Herz
- Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Medicine I, Klinik Landstraße, Vienna, Austria.,Division of Angiology, Department of Medicine II, Medical University of Vienna, Vienna, Austria
| | - Johanna M Brix
- Department of Medicine I, Klinik Landstraße, Vienna, Austria.,Karl Landsteiner Institute for Obesity and Metabolic Disorders, Vienna, Austria
| | - Bernhard Ludvik
- Department of Medicine I, Klinik Landstraße, Vienna, Austria.,Karl Landsteiner Institute for Obesity and Metabolic Disorders, Vienna, Austria
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Yang F, Dang S, Lv H, Shi B. Combined treatment with a gastric inhibitory polypeptide receptor antagonist and a peptidyl peptidase-4 inhibitor improves metabolic abnormalities in diabetic mice. J Int Med Res 2021; 49:300060520985664. [PMID: 33512261 PMCID: PMC7871083 DOI: 10.1177/0300060520985664] [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] [Indexed: 01/01/2023] Open
Abstract
Objectives Dipeptidyl peptidase-4 inhibition and gastric inhibitory polypeptide (GIP) receptor antagonism have therapeutic effects in type 2 diabetes mellitus. We assessed the effects of sitagliptin and Pro3(GIP) in a mouse model of diabetes. Methods Diabetes was induced in C57BL/6J mice by a high-fat diet and intraperitoneal injection of streptozocin. Blood glucose was assessed weekly. Six weeks later, serum triglycerides, total cholesterol and glucose tolerance were assessed and pancreatic and adipose tissues were collected. Results Combination therapy with sitagliptin and Pro3(GIP) resulted in significantly greater reductions of blood glucose and triglycerides than either monotherapy. Combination therapy also improved insulin sensitivity and glucose tolerance. β-cell mass and insulin-positive cell percentage in the pancreas was higher in mice receiving combination therapy compared with either monotherapy. Crown-like structures, inflammatory markers in adipose tissue, and serum leptin concentrations were decreased in mice receiving combination therapy compared with either monotherapy. Conclusions Combination therapy with Pro3(GIP) and sitagliptin improved metabolic abnormalities in diabetic mice. Changes in serum leptins and reduced inflammatory cell infiltration in adipose tissue might account for the observed effects.
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Affiliation(s)
- Fei Yang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Medical University, Xi'an Shaanxi Province, China
| | - Shan Dang
- Department of Gastroenterology, Shaanxi Provincial Peoplès Hospital, Xi'an Shaanxi Province, China
| | - Hongjun Lv
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Bingyin Shi
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
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Fu ZD, Cai XL, Yang WJ, Zhao MM, Li R, Li YF. Novel glucose-lowering drugs for non-alcoholic fatty liver disease. World J Diabetes 2021; 12:84-97. [PMID: 33520110 PMCID: PMC7807257 DOI: 10.4239/wjd.v12.i1.84] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/22/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The efficacy of novel glucose-lowering drugs in treating non-alcoholic fatty liver disease (NAFLD) is unknown.
AIM To evaluate the efficacy of glucose-lowering drugs dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors in treating NAFLD and to perform a comparison between these treatments.
METHODS Electronic databases were systematically searched. The inclusion criteria were: Randomized controlled trials comparing DPP-4 inhibitors, GLP-1 RAs, or SGLT2 inhibitors against placebo or other active glucose-lowering drugs in NAFLD patients, with outcomes of changes in liver enzyme [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] from baseline.
RESULTS Nineteen studies were finally included in this meta-analysis. Compared with placebo or other active glucose-lowering drug treatment, treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors all led to a significant decrease in ALT change and AST change from baseline. The difference between the DPP-4 inhibitor and SGLT2 inhibitor groups in ALT change was significant in favor of DPP-4 inhibitor treatment (P < 0.05). The trends of reduction in magnetic resonance imaging proton density fat fraction and visceral fat area changes were also observed in all the novel glucose-lowering agent treatment groups.
CONCLUSION Treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors resulted in improvements in serum ALT and AST levels and body fat composition, indicating a beneficial effect in improving liver injury and reducing liver fat in NAFLD patients.
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Affiliation(s)
- Zuo-Di Fu
- Department of Endocrinology, Beijing Friendship Hospital Pinggu Campus, Beijing 101200, China
| | - Xiao-Ling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Wen-Jia Yang
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Ming-Ming Zhao
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100079, China
| | - Ran Li
- Sport Science School, Beijing Sport University, Beijing 100078, China
| | - Yu-Feng Li
- Department of Endocrinology, Beijing Friendship Hospital Pinggu Campus, Capital Medical University, Beijing 101200, China
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Maroni L, Fianchi F, Miele L, Svegliati Baroni G. The pathophysiology of gut–liver connection. THE COMPLEX INTERPLAY BETWEEN GUT-BRAIN, GUT-LIVER, AND LIVER-BRAIN AXES 2021:97-122. [DOI: 10.1016/b978-0-12-821927-0.00002-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Kjær MB, George J, Kazankov K, Grønbæk H. Current perspectives on the pathophysiology of metabolic associated fatty liver disease: are macrophages a viable target for therapy? Expert Rev Gastroenterol Hepatol 2021; 15:51-64. [PMID: 32878486 DOI: 10.1080/17474124.2020.1817740] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Metabolic associated fatty liver disease (MAFLD) is a new nomenclature for fatty liver replacing nonalcoholic fatty liver disease (NAFLD). MAFLD has emerged as the leading cause of liver-related morbidity and mortality with increasing incidence due to its close association with the global epidemic of obesity and type 2 diabetes mellitus. Macrophages play a key role in MAFLD development and progression of steatohepatitis and fibrosis. Therefore, targeting macrophages may be a new therapeutic approach for MAFLD and MAFLD with steatohepatitis. AREAS COVERED We provide a comprehensive review of the significant role of macrophages in MAFLD. Further, we evaluate the current status of lifestyle interventions and pharmacological treatments with a focus on effects mediated through direct or indirect targeting of macrophages. EXPERT OPINION Targeting macrophages holds promise as a treatment option for the management of MAFLD and steatohepatitis. Improved stratification of patients according to MAFLD phenotype would contribute to more adequate design enhancing the yield of clinical trials ultimately leading to personalized medicine for patients with MAFLD. Furthermore, reflecting the multifactorial pathogenesis of MAFLD, combination therapies based on the various pathophysiological driver events including as pertinent to this review, macrophage recruitment, polarization and action, present an intriguing target for future investigation.
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Affiliation(s)
- Mikkel Breinholt Kjær
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney , Sydney, Australia
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
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Jakhmola-Mani R, Islam A, Katare DP. Liver-Brain Axis in Sporadic Alzheimer's Disease: Role of Ten Signature Genes in a Mouse model. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2020; 20:871-885. [PMID: 33297922 DOI: 10.2174/1871527319666201209111006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 08/23/2020] [Accepted: 09/08/2020] [Indexed: 12/12/2022]
Abstract
AIM Poor nutritional effect of junk food induces injurious adversities to the liver and brain but still most of the developing nations survives on these diets to compensate for fast-paced lifestyle. Aim of the study is to infer the proteinconnections behind liver-brain axis and identify the role of these proteins in causing neurodegenerative disorders. BACKGROUND Chronic consumption of fructose and fat rich food works as a toxin in body and have the ability to cause negative metabolic shift. Recently a study was published in Annals of Internal Medicine (2019) citing the loss of vision and hearing in a 14-year-old boy whose diet was strictly restricted to fries and junk-food for almost a decade. This puts the entire body on insulin resistance and related co-morbidities and causes simultaneous damaging effects in liver as well brain. This work provides insights into liver-brain axis and explains how liver is involved in brain related disorders. OBJECTIVE In this study transcriptomic data relating to chronic eating of junk-food was analyzed and simultaneous damage that happens in liver and brain was assessed at molecular level. METHOD Transcriptomic study was taken from GEO database and analysed to find out the genes dysregulated in both liver and brain during this metabolic stress. Cytoscapev3.7 was used to decipher the signalling between liver and brain. This connection between both was called as Liver-Brain axis. RESULT The results obtained from our study indicates the role of TUBB5-HYOU1-SDF2L1-DECR1-CDH1-EGFR-SKP2- SOD1-IRAK1-FOXO1 gene signature towards the decline of concurrent liver and brain health. Dysregulated levels of these genes are linked to molecular processes like cellular senescence, hypoxia, glutathione synthesis, amino acid modification, increased nitrogen content, synthesis of BCAAs, cholesterol biosynthesis, steroid hormone signalling and VEGF pathway. CONCLUSION We strongly advocate that prolonged consumption of junk food is a major culprit in brain related disorders like Alzheimer's disease and propose that receptors for brain diseases lie outside the brain and aiming them for drug discovery and design may be beneficial in future clinical studies. This study also discusses the connection between NAFLD (nonalcoholic fatty liver disease) and sAD (sporadic Alzheimer's disease) owing to liver-brain axis.
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Affiliation(s)
- Ruchi Jakhmola-Mani
- Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida. India
| | - Anam Islam
- Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida. India
| | - Deepshikha Pande Katare
- Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida. India
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Vincent RK, Williams DM, Evans M. A look to the future in non-alcoholic fatty liver disease: Are glucagon-like peptide-1 analogues or sodium-glucose co-transporter-2 inhibitors the answer? Diabetes Obes Metab 2020; 22:2227-2240. [PMID: 32945071 DOI: 10.1111/dom.14196] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/19/2020] [Accepted: 09/03/2020] [Indexed: 12/18/2022]
Abstract
The increasing prevalence of diabetes and non-alcoholic fatty liver disease (NAFLD) is a growing public health concern associated with significant morbidity, mortality and economic cost, particularly in those who progress to cirrhosis. Medical treatment is frequently limited, with no specific licensed treatments currently available for people with NAFLD. Its association with diabetes raises the possibility of shared mechanisms of disease progression and treatment. With the ever-growing interest in the non-glycaemic effects of diabetes medications, studies and clinical trials have investigated hepatic outcomes associated with the use of drug classes used for people with type 2 diabetes (T2D), such as glucagon-like peptide-1 (GLP-1) analogues or sodium-glucose co-transporter-2 (SGLT2) inhibitors. Studies exploring the use of GLP-1 analogues or SGLT2 inhibitors in people with NAFLD have observed improved measures of hepatic inflammation, liver enzymes and radiological features over short periods. However, these studies tend to have variable study populations and inconsistent reported outcomes, limiting comparison between drugs and drug classes. As these drugs appear to improve biomarkers of NAFLD, clinicians should consider their use in patients with NAFLD and T2D. However, further evidence with greater participant numbers and longer trial durations is required to support specific licensing for people with NAFLD. Larger trials would allow reporting of major adverse hepatic events, akin to cardiovascular and renal outcome trials, to be determined. This would provide a more meaningful evaluation of the impact of these drugs in NAFLD. Nevertheless, these drugs represent a future potential therapeutic avenue in this difficult-to-treat population and may beget significant health and economic impacts.
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Affiliation(s)
- Rebecca K Vincent
- Department of Gastroenterology, University Hospital Llandough, Cardiff, UK
| | - David M Williams
- Department of Diabetes and Endocrinology, University Hospital Llandough, Cardiff, UK
| | - Marc Evans
- Department of Diabetes and Endocrinology, University Hospital Llandough, Cardiff, UK
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Okuyama T, Shirakawa J, Tajima K, Ino Y, Vethe H, Togashi Y, Kyohara M, Inoue R, Miyashita D, Li J, Goto N, Ichikawa T, Yamasaki S, Ohnuma H, Takayanagi R, Kimura Y, Hirano H, Terauchi Y. Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor. Int J Mol Sci 2020; 21:ijms21217815. [PMID: 33105604 PMCID: PMC7672621 DOI: 10.3390/ijms21217815] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 10/19/2020] [Accepted: 10/19/2020] [Indexed: 12/21/2022] Open
Abstract
Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.
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Affiliation(s)
- Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
| | - Jun Shirakawa
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
- Laboratory and Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8510, Japan
- Correspondence: ; Tel.: +81-27-220-8850
| | - Kazuki Tajima
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
| | - Yoko Ino
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan; (Y.I.); (Y.K.)
| | - Heidrun Vethe
- Department of Clinical Medicine, University of Bergen, P.O. Box 7803 Bergen, Norway;
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
| | - Ryota Inoue
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
- Laboratory and Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8510, Japan
| | - Daisuke Miyashita
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
| | - Jinghe Li
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
- Laboratory and Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8510, Japan
| | - Nozomi Goto
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
| | - Taiga Ichikawa
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
| | - Shingo Yamasaki
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
| | - Haruka Ohnuma
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
| | - Rie Takayanagi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
| | - Yayoi Kimura
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan; (Y.I.); (Y.K.)
| | - Hisashi Hirano
- Graduate School of Health Science, Gunma Paz University, Takasaki 370-0006, Japan;
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (T.O.); (K.T.); (Y.T.); (M.K.); (R.I.); (D.M.); (J.L.); (N.G.); (T.I.); (S.Y.); (H.O.); (R.T.); (Y.T.)
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Noureddin M, Muthiah MD, Sanyal AJ. Drug discovery and treatment paradigms in nonalcoholic steatohepatitis. Endocrinol Diabetes Metab 2020; 3:e00105. [PMID: 33102791 PMCID: PMC7576222 DOI: 10.1002/edm2.105] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 11/05/2019] [Accepted: 11/09/2019] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western populations, and is closely associated with features of the metabolic syndrome. The burden of disease is set to rise exponentially, and this is further compounded by the lack of good medications. In addition, these patients tend to have multiple comorbidities that may not be adequately managed. In this article, we review the biological basis of potential therapies in nonalcoholic steatohepatitis (NASH), the current drugs being tested in clinical trials, as well some practical considerations in managing patients in the clinic.
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Affiliation(s)
- Mazen Noureddin
- Division of Digestive and Liver DiseasesComprehensive Transplant CenterCedars Sinai Medical CenterLos AngelesCalifornia
| | - Mark D. Muthiah
- Department of MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and HepatologyNational University HospitalNational University Health SystemSingapore
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and NutritionVirginia Commonwealth University School of MedicineRichmondVirginia
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Gut-Pancreas-Liver Axis as a Target for Treatment of NAFLD/NASH. Int J Mol Sci 2020; 21:ijms21165820. [PMID: 32823659 PMCID: PMC7461212 DOI: 10.3390/ijms21165820] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/04/2020] [Accepted: 08/09/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide. Due to its association with obesity and diabetes and the fall in hepatitis C virus morbidity, cirrhosis in NAFLD is becoming the most frequent indication to liver transplantation, but the pathogenetic mechanisms are still not completely understood. The so-called gut-liver axis has gained enormous interest when data showed that its alteration can lead to NAFLD development and might favor the occurrence of non-alcoholic steatohepatitis (NASH). Moreover, several therapeutic approaches targeting the gut-pancreas-liver axis, e.g., incretins, showed promising results in NASH treatment. In this review, we describe the role of incretin hormones in NAFLD/NASH pathogenesis and treatment and how metagenomic/metabolomic alterations in the gut microbiota can lead to NASH in the presence of gut barrier modifications favoring the passage of bacteria or bacterial products in the portal circulation, i.e., bacterial translocation.
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Zha H, Fang DQ, van der Reis A, Chang K, Yang LY, Xie JJ, Shi D, Xu QM, Li YT, Li LJ. Vital members in the gut microbiotas altered by two probiotic Bifidobacterium strains against liver damage in rats. BMC Microbiol 2020; 20:144. [PMID: 32503418 PMCID: PMC7275491 DOI: 10.1186/s12866-020-01827-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 05/19/2020] [Indexed: 02/07/2023] Open
Abstract
Background Probiotics are effective to rectify the imbalanced gut microbiota in the diseased cohorts. Two Bifidobacterium strains (LI09 and LI10) were found to alleviate D-galactosamine-induced liver damage (LD) in rats in our previous work. A series of bioinformatic and statistical analyses were performed to determine the vital bacteria in the gut microbiotas altered by the LI09 or LI10 in rats. Results Two groups of representative phylotypes could distinguish the gut microbiotas of LI09 or LI10 groups from the other groups. Among them, OTU170_Porphyromonadaceae acted as a gatekeeper in LI09 group, while OTU12_Bacteroides was determined with multiple correlations in the gut network of LI10 group. Multiple reduced OTUs associated with LC and increased OTUs associated with health were determined in LI09 or LI10 groups, among which, increased OTU51_Barnesiella and reduced OTU99_Barnesiella could be associated with the protective effects of both the two probiotics. The gut microbiotas in LI09, LI10 and positive control groups were clustered into three clusters, i.e., Cluster_1_Microbiota, Cluster_2_Microbiota and Cluster_3_Microbiota, by Partition Around Medoids clustering analysis. Cluster_2_Microbiota was determined at least dysbiotic status due to its greatest LD dysbiosis ratio, lowest levels of liver function variables and plasma cytokines compared with the two other clustered microbiotas, suggesting the treated rats in Cluster_2 were at better health status. Conclusion Our findings suggest that OTU170_Porphyromonadaceae and OTU12_Bacteroides are vital in the gut microbiotas altered by LI09 and LI10. Characteristics of the LD cohorts treated by LI09 or LI10 at different gut microbial colonization states could help monitor the cohorts’ health status.
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Affiliation(s)
- Hua Zha
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310000, China.,School of Biological Sciences, The University of Auckland, Auckland, New Zealand.,Institute of Marine Science, The University of Auckland, Auckland, New Zealand
| | - Dai-Qiong Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310000, China
| | - Aimee van der Reis
- Institute of Marine Science, The University of Auckland, Auckland, New Zealand
| | - Kevin Chang
- Department of Statistics, The University of Auckland, Auckland, New Zealand
| | - Li-Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310000, China
| | - Jiao-Jiao Xie
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310000, China
| | - Ding Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310000, China
| | - Qiao-Mai Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310000, China
| | - Ya-Ting Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310000, China
| | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310000, China.
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Li YP, Xiao J, Liang X, Pei Y, Han XF, Li CX, Tian H. DPP-4 inhibition resembles exercise in preventing type 2 diabetes development by inhibiting hepatic protein kinase C ε expression in a mouse model of hyperinsulinemia. J Int Med Res 2020; 48:300060520934635. [PMID: 32588693 PMCID: PMC7323281 DOI: 10.1177/0300060520934635] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/26/2020] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE Interventions for hyperinsulinemia (HINS), an early indicator of type 2 diabetes mellitus (T2DM), can significantly reduce the T2DM risk. This study aims to determine how dipeptidyl peptidase-4 (DPP-4) inhibition prevents HINS progression to T2DM through ameliorating hepatic steatosis. METHODS KKay mice were used as a HINS model and they underwent exercise or received a DPP-4 inhibitor, MK0626. Hepatic steatosis was examined and liver diacylglycerol levels were determined. Human hepatic cells (LO2) were treated with MK0626 or transfected with DPP-4 siRNA. Protein kinase C ε isoform (PKCε) and DPP-4 expression and insulin receptor substrate 1 (IRS-1) phosphorylation were assessed using immunohistochemistry and western blot. RESULTS KKay mice developed HINS spontaneously at 7 weeks of age. Similar to exercise, MK0626 ameliorated hepatic steatosis and reduced the liver triglyceride and diacylglycerol content. Both exercise and MK0626 suppressed diacylglycerol-induced PKCε expression and restored insulin signaling, which was shown by tyrosine phosphorylation of IRS-1, in the livers of KKay mice. Additionally, silencing DPP-4 or MK0626 treatment decreased PKCε expression in LO2 cells. CONCLUSIONS Our data demonstrate that DPP-4 inhibition resembles exercise and effectively delays T2DM onset by suppressing hepatic PKCε expression in the HINS mouse model.
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Affiliation(s)
- Yu-peng Li
- Tianjin Medical University Chu Hsien-I Memorial Hospital (Tianjin Medical University Metabolic Diseases Hospital), Tianjin, China. NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
| | - Jing Xiao
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
| | - Xu Liang
- Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China; Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China
| | - Yu Pei
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
| | - Xiao-fei Han
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
| | - Chen-xi Li
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
| | - Hui Tian
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
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Abstract
Insulin secretion by the pancreatic β-cells is elicited in response to elevated extracellular glucose concentration. In addition to triggering insulin secretion, glucose-induced signal regulates β-cell proliferation and survival. However, the molecular mechanism underlying the effects of glucose on the β-cell functionality still remains unclear. Glucokinase, a hexokinase isozyme that catalyzes the phosphorylation of glucose, acts as the glucose sensor in the β-cells. To investigate the mechanisms of glucose signaling in the regulation of β-cell functions, we analyzed the role of glucokinase in insulin secretion, β-cell proliferation and β-cell apoptosis, using β-cell-specific glucokinase-haploinsufficient (Gck+/-) mice and allosteric glucokinase activators (GKAs). Glucokinase-mediated glucose metabolism (1) suppresses endoplasmic reticulum (ER) stress-induced β-cell apoptosis via inducing insulin receptor substrate-2 (IRS-2) expression and expression of ER stress-related molecules, (2) promotes adaptive β-cell proliferation through activation of the Forkhead Box M1 (FoxM1)/polo-like kinase-1 (PLK1)/centromere protein-A (CENP-A) pathway, (3) induces islet inflammation by promoting interaction of islet-derived S100 calcium-binding protein A8 (S100A8) with macrophages, (4) induces the expression of Fibulin-5 (Fbln5), an extracellular matrix protein to regulate β-cell functions, and (5) activates other unknown pathways. Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors have been found to possibly compensate for dysregulation of glucose metabolism in the β-cells. This review provides an update and overview of the recent advances in the study of β-cell pathophysiology and some therapeutic possibilities focusing on glucose-/glucokinase-mediated signaling.
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Affiliation(s)
- Jun Shirakawa
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Wang Z, Park H, Bae EJ. Efficacy of evogliptin and cenicriviroc against nonalcoholic steatohepatitis in mice: a comparative study. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2019; 23:459-466. [PMID: 31680767 PMCID: PMC6819900 DOI: 10.4196/kjpp.2019.23.6.459] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/15/2019] [Accepted: 08/26/2019] [Indexed: 12/16/2022]
Abstract
Dipeptidyl peptidase (DPP)-4 inhibitors, or gliptins, are a class of oral hypoglycemic drugs that have been widely used as a second-line treatment for type 2 diabetes. Gliptins, which were introduced for clinical use a decade ago, have been shown to be beneficial against nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) in animals and humans. Cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor type 2 and 5, is currently under investigation against NASH and fibrosis. It was previously discovered that evogliptin (EVO) reduces hepatic steatosis in diet-induced obese animals but the effectiveness of EVO on NASH remains unexplored. Here, we compared the effectiveness of EVO and CVC against NASH and fibrosis in mice fed a high-fat and high-fructose diet (HFHF). Biochemical and histological analyses showed that mice fed a HFHF for 20 weeks developed severe hepatic steatosis and inflammation with mild fibrosis. Administration of EVO (0.2% wt/wt) for the last 8 weeks of HFHF feeding significantly reduced hepatic triglyceride accumulation, inflammation, and fibrosis as well as restored insulin sensitivity, as evidenced by lowered plasma insulin levels and the improvement in insulin tolerance test curves. Treatment of mice with CVC (0.1% wt/wt) inhibited hepatic inflammation and fibrogenesis with similar efficacy to that of EVO, without affecting hepatic steatosis. CVC treatment also reduced plasma insulin concentrations, despite no improvement in insulin tolerance. In conclusion, EVO administration efficiently ameliorated the development of NASH and fibrosis in HFHF-fed mice, corroborating its therapeutic potential.
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Affiliation(s)
- Zheng Wang
- College of Pharmacy, Woosuk University, Wanju 55338, Korea
| | - Hansu Park
- Dong-A Socio Research Center, Dong-A ST Co., Ltd., Yongin 17073, Korea
| | - Eun Ju Bae
- College of Pharmacy, Chonbuk National University, Jeonju 54896, Korea
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Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options. JHEP Rep 2019; 1:312-328. [PMID: 32039382 PMCID: PMC7001557 DOI: 10.1016/j.jhepr.2019.07.002] [Citation(s) in RCA: 280] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 06/14/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to have reached 25% or more in adults. NAFLD is prevalent in obese individuals, but may also affect non-obese insulin-resistant individuals. NAFLD is associated with a 2- to 3-fold increased risk of developing type 2 diabetes (T2D), which may be higher in patients with more severe liver disease - fibrosis increases this risk. In NAFLD, not only the close association with obesity, but also the impairment of many metabolic pathways, including decreased hepatic insulin sensitivity and insulin secretion, increase the risk of developing T2D and related comorbidities. Conversely, patients with diabetes have a higher prevalence of steatohepatitis, liver fibrosis and end-stage liver disease. Genetics and mechanisms involving dysfunctional adipose tissue, lipotoxicity and glucotoxicity appear to play a role. In this review, we discuss the altered pathophysiological mechanisms that underlie the development of T2D in NAFLD and vice versa. Although there is no approved therapy for the treatment of NASH, we discuss pharmacological agents currently available to treat T2D that could potentially be useful for the management of NASH.
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Affiliation(s)
- Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, The University of Florida, and Malcom Randall Veterans Administration Medical Center, Gainesville, Florida
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