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Quagliariello V, Canale ML, Bisceglia I, Iovine M, Giordano V, Giacobbe I, Scherillo M, Gabrielli D, Maurea C, Barbato M, Inno A, Berretta M, Tedeschi A, Oliva S, Greco A, Maurea N. Glucagon-like Peptide 1 Receptor Agonists in Cardio-Oncology: Pathophysiology of Cardiometabolic Outcomes in Cancer Patients. Int J Mol Sci 2024; 25:11299. [PMID: 39457081 PMCID: PMC11508560 DOI: 10.3390/ijms252011299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/16/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
Cancer patients, especially long cancer survivors, are exposed to several cardio-metabolic diseases, including diabetes, heart failure, and atherosclerosis, which increase their risk of cardiovascular mortality. Therapy with glucagon-like peptide 1 (GLP1) receptor agonists demonstrated several beneficial cardiovascular effects, including atherosclerosis and heart failure prevention. Cardiovascular outcome trials (CVOTs) suggest that GLP-1 RA could exert cardiorenal benefits and systemic anti-inflammatory effects in patients with type-2 diabetes through the activation of cAMP and PI3K/AkT pathways and the inhibition of NLRP-3 and MyD88. In this narrative review, we highlight the biochemical properties of GLP-1 RA through a deep analysis of the clinical and preclinical evidence of the primary prevention of cardiomyopathies. The overall picture of this review encourages the study of GLP-1 RA in cancer patients with type-2 diabetes, as a potential primary prevention strategy against heart failure and atherosclerosis.
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Affiliation(s)
- Vincenzo Quagliariello
- Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy; (M.I.); (V.G.); (I.G.); (M.B.); (N.M.)
| | | | - Irma Bisceglia
- Servizi Cardiologici Integrati, Dipartimento Cardio-Toraco-Vascolare, Azienda Ospedaliera San Camillo Forlanini, 00148 Rome, Italy;
| | - Martina Iovine
- Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy; (M.I.); (V.G.); (I.G.); (M.B.); (N.M.)
| | - Vienna Giordano
- Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy; (M.I.); (V.G.); (I.G.); (M.B.); (N.M.)
| | - Ilaria Giacobbe
- Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy; (M.I.); (V.G.); (I.G.); (M.B.); (N.M.)
| | - Marino Scherillo
- Division of Cardiology, Hospital San Pio Benevento (BN), 82100 Benevento, Italy;
| | - Domenico Gabrielli
- U.O.C. Cardiologia, Dipartimento Cardio-Toraco-Vascolare, Azienda Ospedaliera San Camillo Forlanini, 00152 Rome, Italy;
| | - Carlo Maurea
- Department of Medicine, University of Salerno, 84084 Fisciano, Italy;
| | - Matteo Barbato
- Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy; (M.I.); (V.G.); (I.G.); (M.B.); (N.M.)
| | - Alessandro Inno
- Medical Oncology, IRCCS Ospedale Sacro Cuore Don Calabria, 37024 Negrar di Valpolicella, Italy;
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy;
| | - Andrea Tedeschi
- Cardiology Unit of Emergency Department, Guglielmo da Saliceto Hospital, 29121 Piacenza, Italy;
| | - Stefano Oliva
- UOSD Cardiologia di Interesse Oncologico IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | - Alessandra Greco
- Divisione di Cardiologia, Fondazione IRCCS San Matteo Hospital, Viale Golgi 19, 27100 Pavia, Italy;
| | - Nicola Maurea
- Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy; (M.I.); (V.G.); (I.G.); (M.B.); (N.M.)
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Perez-Frances M, Bru-Tari E, Cohrs C, Abate MV, van Gurp L, Furuyama K, Speier S, Thorel F, Herrera PL. Regulated and adaptive in vivo insulin secretion from islets only containing β-cells. Nat Metab 2024; 6:1791-1806. [PMID: 39169271 PMCID: PMC11422169 DOI: 10.1038/s42255-024-01114-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 07/22/2024] [Indexed: 08/23/2024]
Abstract
Insulin-producing β-cells in pancreatic islets are regulated by systemic cues and, locally, by adjacent islet hormone-producing 'non-β-cells' (namely α-cells, δ-cells and γ-cells). Yet whether the non-β-cells are required for accurate insulin secretion is unclear. Here, we studied mice in which adult islets are exclusively composed of β-cells and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation, enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under a high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was comparable to that in intact islets. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of entire islets. The findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. These results support efforts aimed at developing diabetes treatments by generating β-like clusters devoid of non-β-cells, such as from pluripotent stem cells differentiated in vitro or by reprograming non-β-cells into insulin producers in situ.
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Affiliation(s)
- Marta Perez-Frances
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Eva Bru-Tari
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christian Cohrs
- Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany
| | - Maria Valentina Abate
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Léon van Gurp
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Kenichiro Furuyama
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Stephan Speier
- Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany
| | - Fabrizio Thorel
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Pedro L Herrera
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
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Yu B, Wang D, Zhou J, Huang R, Cai T, Hu Y, Zhou Y, Ma J. Diabetes Pharmacotherapy and its effects on the Skeletal Muscle Energy Metabolism. Mini Rev Med Chem 2024; 24:1470-1480. [PMID: 38549524 DOI: 10.2174/0113895575299439240216081711] [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: 12/19/2023] [Revised: 02/04/2024] [Accepted: 02/07/2024] [Indexed: 08/07/2024]
Abstract
The disorders of skeletal muscle metabolism in patients with Type 2 diabetes mellitus (T2DM), such as mitochondrial defection and glucose transporters (GLUTs) translocation dysfunctions, are not uncommon. Therefore, when anti-diabetic drugs were used in various chronic diseases associated with hyperglycemia, the impact on skeletal muscle should not be ignored. However, current studies mainly focus on muscle mass rather than metabolism or functions. Anti-diabetic drugs might have a harmful or beneficial impact on skeletal muscle. In this review, we summarize the upto- date studies on the effects of anti-diabetic drugs and some natural compounds on skeletal muscle metabolism, focusing primarily on emerging data from pre-clinical to clinical studies. Given the extensive use of anti-diabetic drugs and the common sarcopenia, a better understanding of energy metabolism in skeletal muscle deserves attention in future studies.
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Affiliation(s)
- Baowen Yu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Dong Wang
- Department of Otolaryngology Head and Neck, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Junming Zhou
- Department of Cadre Gastroenterology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Rong Huang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Tingting Cai
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yonghui Hu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yunting Zhou
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jianhua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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Mahalingam S, Bellamkonda R, Arumugam MK, Perumal SK, Yoon J, Casey C, Kharbanda K, Rasineni K. Glucagon-like peptide 1 receptor agonist, exendin-4, reduces alcohol-associated fatty liver disease. Biochem Pharmacol 2023; 213:115613. [PMID: 37209859 PMCID: PMC10351880 DOI: 10.1016/j.bcp.2023.115613] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/06/2023] [Accepted: 05/15/2023] [Indexed: 05/22/2023]
Abstract
Fatty liver is the earliest response to excessive ethanol consumption, which increases the susceptibility of the liver to develop advanced stage of liver disease. Our previous studies have revealed that chronic alcohol administration alters metabolic hormone levels and their functions. Of current interest to our laboratory is glucagon-like peptide 1 (GLP-1), a widely studied hormone known to reduce insulin resistance and hepatic fat accumulation in patients with metabolic-associated fatty liver disease. In this study, we examined the beneficial effects of exendin-4 (a GLP-1 receptor agonist) in an experimental rat model of ALD. Male Wistar rats were pair-fed the Lieber-DeCarli control or ethanol diet. After 4 weeks of this feeding regimen, a subset of rats in each group were intraperitoneally injected every other day with either saline or exendin-4 at a dose of 3 nmol/kg/day (total 13 doses) while still being fed their respective diet. At the end of the treatment, rats were fasted for 6 h and glucose tolerance test was conducted. The following day, the rats were euthanized, and the blood and tissue samples collected for subsequent analysis. We found that exendin-4 treatment had no significant effect on body weight gain among the experimental groups. Exendin-4-treated ethanol rats exhibited improved alcohol-induced alterations in liver/body weight and adipose/body weight ratio, serum ALT, NEFA, insulin, adiponectin and hepatic triglyceride levels. Reduction in indices of hepatic steatosis in exendin-4 treated ethanol-fed rats was attributed to improved insulin signaling and fat metabolism. These results strongly suggest that exendin-4 mitigates alcohol-associated hepatic steatosis by regulating fat metabolism.
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Affiliation(s)
- Sundararajan Mahalingam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Ramesh Bellamkonda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Sathish Kumar Perumal
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Jessica Yoon
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Carol Casey
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kusum Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States.
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Li R, Mai T, Zheng S, Zhang Y. Effect of metformin and exenatide on pregnancy rate and pregnancy outcomes in overweight or obese infertility PCOS women: long-term follow-up of an RCT. Arch Gynecol Obstet 2022; 306:1711-1721. [PMID: 35829765 DOI: 10.1007/s00404-022-06700-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 07/03/2022] [Indexed: 11/27/2022]
Abstract
PURPOSE The majority of Polycystic ovary syndrome (PCOS) are overweight or obese with increased infertility and high risk of pregnancy complications. We aim to compare efficacy of metformin and exenatide on spontaneous pregnancy rate, overall pregnancy rate after assisted reproductive technology treatment (ART) and pregnancy outcomes in overweight or obese infertility PCOS. METHODS In this long-term follow-up study, 160 overweight or obese infertility Chinese PCOS were randomized to exenatide or metformin treatment for 12 weeks. Afterward, all were treated with metformin alone until pregnancy confirmed and followed until delivery. If patients failed spontaneous pregnancy during the second 12 weeks, ART could be offered until end of 64 weeks. The primary outcome was spontaneous pregnancy rate. RESULTS At week 24, 29.2% of women in exenatide group conceived spontaneously while 14.7% in metformin group (p = 0.03). At week 64, total pregnancy rates were 79.2% in exenatide group and 76% in metformin group without significant difference (p = 0.65). Between two groups, there was no significant difference of pregnancy outcomes (p > 0.05). A stepwise logistic regression showed that spontaneous pregnancy was positively associated with body weight reduction and HOMA-IR improvement in either group. CONCLUSION In overweight or obese infertility Chinese PCOS, 12 weeks pregestational exenatide treatment resulted in more spontaneous pregnancy likely due to greater weight reduction and improvement of insulin resistance compared with metformin treatment without obvious benefit on overall pregnancy rate after ART or pregnancy outcomes of successful conceived women. TRIAL REGISTRATION This clinical trial was registered at Chinese Clinical Trials Registry (ChiCTR-IIR-16008084) on 13/3/2016.
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Affiliation(s)
- Renyuan Li
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.,Key Laboratory for Major Obstetric Diseases of Guangdong Higher Education Institutes, Guangzhou, Guangdong, People's Republic of China
| | - Tingting Mai
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.,Key Laboratory for Major Obstetric Diseases of Guangdong Higher Education Institutes, Guangzhou, Guangdong, People's Republic of China
| | - Siyuan Zheng
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.,Key Laboratory for Major Obstetric Diseases of Guangdong Higher Education Institutes, Guangzhou, Guangdong, People's Republic of China
| | - Ying Zhang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China. .,Key Laboratory for Major Obstetric Diseases of Guangdong Higher Education Institutes, Guangzhou, Guangdong, People's Republic of China.
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Incretin-induced changes in the transcriptome of skeletal muscles of fa/fa Zucker rat (ZFR) with obesity, without diabetes. Int J Obes (Lond) 2022; 46:1311-1318. [PMID: 35383269 DOI: 10.1038/s41366-022-01114-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 03/09/2022] [Accepted: 03/21/2022] [Indexed: 11/08/2022]
Abstract
INTRODUCTION Glucagon-like peptide-1 receptor agonists (GLP-1ra) are increasingly used in treating type 2 diabetes and obesity. Exendin-4 (Ex-4), a long acting GLP-1ra, was previously reported to decrease oxidative stress in hepatocytes, adipocytes and skeletal muscle cells in obese nondiabetic fa/fa Zucker rats (ZFR), thereby improving insulin resistance. AIM We aimed first to identify Ex-4-induced changes in the transcriptome of skeletal muscle cells in ZFR. RESULTS Ontology analysis of differentially expressed genes (DEGs) in ZFR versus lean animals (LR) showed that the extracellular matrix (ECM) is the first most affected cellular compartment, followed by myofibrils and endoplasmic reticulum (ER). Interestingly, among 15 genes regulated in ZFR versus LR, 14 of them were inversely regulated by Ex-4, as further confirmed by RT-qPCR. Picro-Sirius red histological staining showed that decreased ECM fiber area in ZFR is partially restored by Ex-4. Ontology analysis of the myofibril compartment revealed that decreased muscle contractile function in ZFR is partially restored by Ex-4, as confirmed by Phalloidin histological staining that showed a partial restoration by Ex-4 of altered contractile apparatus in ZFR. Ontology analysis of ER DEGs in ZFR versus LR showed that some of them are related to the AMP-activated protein kinase (AMPK) signaling pathway. Phosphorylated AMPK levels were strongly increased in Ex-4-treated ZFR. CONCLUSION Altogether, our results suggest that GLP-1ra strongly restructure ECM and reinforce contractile capabilities in ZFR, while optimizing the cellular metabolism through AMPK.
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Wang S, Xu Z, Cai B, Chen Q. Berberine as a Potential Multi-Target Agent for Metabolic Diseases: A Review of Investigations for Berberine. Endocr Metab Immune Disord Drug Targets 2020; 21:971-979. [PMID: 32914727 DOI: 10.2174/1871530320666200910105612] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/19/2020] [Accepted: 08/10/2020] [Indexed: 11/22/2022]
Abstract
Berberine (BBR) is a botanic alkaloid extracted from Coptis chinensis (Huanglian), which has various properties, compassing anti-hyperglycemia, anti-obesity, anti-inflammation, and improves insulin resistance, etc. Several researches have confirmed that BBR has effective actions in treating glycolipid metabolic abnormalities. BBR is also beneficial in regulating intestinal flora. Metabolic diseases are strongly associated with metabolic disorders, which are growing in the population and dramatically impacting human health, which also have been considered as a leading cause of diseases and death globally. This review is to evaluate the metabolic properties of BBR, and its potential application to the treatment of metabolic diseases by its effective actions on metabolic disorders.
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Affiliation(s)
- Shengju Wang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Zhang Xu
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Baochao Cai
- Endocrinology Department, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing 314001, China
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
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Bifari F, Manfrini R, Dei Cas M, Berra C, Siano M, Zuin M, Paroni R, Folli F. Multiple target tissue effects of GLP-1 analogues on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Pharmacol Res 2018; 137:219-229. [PMID: 30359962 DOI: 10.1016/j.phrs.2018.09.025] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 09/11/2018] [Accepted: 09/24/2018] [Indexed: 12/12/2022]
Abstract
Accumulating experimental and clinical evidences over the last decade indicate that GLP-1 analogues have a series of central nervous system and peripheral target tissues actions which are able to significantly influence the liver metabolism. GLP-1 analogues pleiotropic effects proved to be efficacious in T2DM subjects not only reducing liver steatosis and ameliorating NAFLD and NASH, but also in lowering plasma glucose and liver inflammation, improving cardiac function and protecting from kidney dysfunction. While the experimental and clinical data are robust, the precise mechanisms of action potentially involved in these protective multi-target effects need further investigation. Here we present a systematic review of the most recent literature data on the multi-target effects of GLP-1 analogues on the liver, on adipose and muscular tissue and on the nervous system, all capable of influencing significant aspects of the fatty liver disease physiopathology. From this analysis, we can conclude that the multi-target beneficial action of the GLP-1 analogues could explain the positive effects observed in animal and human models on progression of NAFLD to NASH.
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Affiliation(s)
- Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Roberto Manfrini
- Department of Internal Medicine ASST Santi Paolo e Carlo, Milan, Italy
| | - Michele Dei Cas
- Laboratory of Clinical Biochemistry and Mass Spectrometry, Department of Health Science, University of Milan, Milan, Italy
| | - Cesare Berra
- Metabolic Disease and Diabetes, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Matteo Siano
- Department of Internal Medicine ASST Santi Paolo e Carlo, Milan, Italy
| | - Massimo Zuin
- Unit of Medicine, Gastroenterology and Hepatology, Milan, Italy
| | - Rita Paroni
- Laboratory of Clinical Biochemistry and Mass Spectrometry, Department of Health Science, University of Milan, Milan, Italy
| | - Franco Folli
- Unit of Endocrinology and Metabolism ASST Santi Paolo e Carlo, Department of Health Science, University of Milan, Milan, Italy.
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Nakagawa R, Hosokawa-Tsuji A, Aoki Y, Takasawa K, Maru M, Nakajima K, Sutani A, Miyakawa Y, Tomizawa D, Kashimada K, Morio T. Total body irradiation for hematopoietic stem cell transplantation during early childhood is associated with the risk for diabetes mellitus. Endocrine 2018; 61:76-82. [PMID: 29691808 DOI: 10.1007/s12020-018-1595-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 04/09/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is a curative treatment for life-threatening malignancies and related diseases. Recently, the long-term prognosis of HSCT during childhood has greatly improved; however, the late adverse effects of HSCT have been found to cause substantial morbidity among long-term survivors. Although metabolic complications, such as diabetes mellitus (DM) and hyperlipidemia (HL), are the major late effects of pediatric HSCT, the clinical details are not clarified sufficiently. METHODS From 1983 to 2013, 75 participants underwent HSCT in our institute because of malignant or other related diseases. We retrospectively evaluated metabolic complications of eligible 22 participants (14 men and 8 women), and their clinical backgrounds. RESULTS Among 22 participants, 4 and 9 participants developed DM and HL after HSCT, respectively, and all participants with DM developed HL. None of the participants with DM were obese, and all had substantial insulin resistance. Total body irradiation (TBI) was performed in 10 participants, including 4 participants with DM and 5 participants with HL, revealing that TBI is an independent risk factor for DM. The age at TBI for participants with DM was significantly lower than that for participants without DM (p = 0.01), and all participants with DM received TBI before the age of 6. CONCLUSIONS Our data suggested that TBI was a risk factor for DM after HSCT, and TBI before the age of six increased the possibility of DM without obesity.
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Affiliation(s)
- Ryuichi Nakagawa
- Division of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan
| | - Atsumi Hosokawa-Tsuji
- Division of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan
| | - Yuki Aoki
- Division of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan
- Department of Pediatric Oncology, National Cancer Center Hospital, Chuou-Ward, Tokyo, 104-0045, Japan
| | - Kei Takasawa
- Division of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan
| | - Mitsue Maru
- School of Healthcare Science, Faculty of Medicine, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan
- International Nursing Development, Faculty of Nursing and Rehabilitation, Konan Women's University, Kobe City, Hyogo Prefecture, 658-0001, Japan
| | - Keisuke Nakajima
- Division of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan
| | - Akito Sutani
- Division of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan
| | - Yuichi Miyakawa
- Division of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan
| | - Daisuke Tomizawa
- Division of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan
- Children's Cancer Center, National Center for Child Health and Development, Setagaya-Ward, Tokyo, 157-8535, Japan
| | - Kenichi Kashimada
- Division of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan.
| | - Tomohiro Morio
- Division of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Bunkyo-Ward, Tokyo, 113-8510, Japan
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10
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Zhao L, Cang Z, Sun H, Nie X, Wang N, Lu Y. Berberine improves glucogenesis and lipid metabolism in nonalcoholic fatty liver disease. BMC Endocr Disord 2017; 17:13. [PMID: 28241817 PMCID: PMC5329945 DOI: 10.1186/s12902-017-0165-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 02/22/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is considered a critical hepatic manifestation of metabolic syndrome. Berberine (BBR) exerts anti-hyperglycemic and anti-dyslipidemic effects and can also ameliorate NAFLD. Thus, BBR might exert its therapeutic effect on NAFLD by improving glucolipid metabolism. Here, we investigated the aspects and extent to which glucolipid metabolism were affected by BBR in rats with NAFLD. METHODS Three groups of Sprague-Dawley rats were studied: a control group (n = 6) fed a normal chow diet and a NAFLD group (n = 6) and a NAFLD + BBR group (n = 6) fed a high-fat diet. Normal saline and BBR (150 mg/kg body weight/day for 16 weeks) were administered by gavage. All rats were infused with isotope tracers. The rates of glucose appearance (Raglu), gluconeogenesis (GNG) and glycerol appearance (Ragly) were assessed with 2H and 13C tracers, whereas the rates of hepatic lipogenesis and fatty acid β oxidation were measured using the 3H tracer. RESULTS When the NAFLD model was successfully induced by administering a high-fat diet, body weight, insulin resistance and dyslipidemia were significantly increased. After the BBR treatment, weight loss, decreased lipid profiles and HOMA-IR, and increased ISI were observed. Meanwhile, BBR reduced Raglu, GNG and hepatic lipogenesis, whereas the rate of fatty acid β oxidation in skeletal muscle showed an increasing trend. Ragly showed a decreasing trend. Based on the results of the histological analysis, BBR obviously attenuated the ectopic liver fat accumulation. CONCLUSIONS BBR improved NAFLD by inhibiting glucogenesis and comprehensively regulating lipid metabolism, and its effect on inhibiting hepatic lipogenesis was much stronger. The improvement may be partly mediated by weight loss. Berberine might be a good choice for patients with NAFLD and glucose metabolic disorder. Future clinical trials need to be conducted to confirm these effects.
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Affiliation(s)
- Li Zhao
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Zhen Cang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Honglin Sun
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Xiaomin Nie
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Ningjian Wang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Yingli Lu
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China.
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11
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Hira T, Suto R, Kishimoto Y, Kanahori S, Hara H. Resistant maltodextrin or fructooligosaccharides promotes GLP-1 production in male rats fed a high-fat and high-sucrose diet, and partially reduces energy intake and adiposity. Eur J Nutr 2017; 57:965-979. [PMID: 28161724 DOI: 10.1007/s00394-017-1381-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 01/10/2017] [Indexed: 12/12/2022]
Abstract
PURPOSE Increasing secretion and production of glucagon-like peptide-1 (GLP-1) by continuous ingestion of certain food components has been expected to prevent glucose intolerance and obesity. In this study, we examined whether a physiological dose (5% weight in diet) of digestion-resistant maltodextrin (RMD) has a GLP-1-promoting effect in rats fed a high-fat and high-sucrose (HFS) diet. METHODS Rats were fed a control diet or the HFS (30% fat, 40% sucrose wt/wt) diet supplemented with 5% RMD or fructooligosaccharides (FOS) for 8 weeks or for 8 days in separated experiments. Glucose tolerance, energy intake, plasma and tissue GLP-1 concentrations, and cecal short-chain fatty acids concentrations were assessed. RESULTS After 4 weeks of feeding, HFS-fed rats had significantly higher glycemic response to oral glucose than control rats, but rats fed HFS + RMD/FOS did not (approx. 50% reduction vs HFS rats). HFS + RMD/FOS-fed rats had higher GLP-1 responses (~twofold) to oral glucose, than control rats. After 8 weeks, visceral adipose tissue weight was significantly higher in HFS-fed rats than control rats, while HFS + RMD/FOS rats had a trend of reduced gain (~50%) of the tissue weight. GLP-1 contents and luminal propionate concentrations in the large intestine increased (>twofold) by adding RMD/FOS to HFS. Eight days feeding of RMD/FOS-supplemented diets reduced energy intake (~10%) and enhanced cecal GLP-1 production (~twofold), compared to HFS diet. CONCLUSIONS The physiological dose of a prebiotic fiber promptly (within 8 days) promotes GLP-1 production in rats fed an obesogenic diet, which would help to prevent excess energy intake and fat accumulation.
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Affiliation(s)
- Tohru Hira
- Laboratory of Nutritional Biochemistry, Research Faculty of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, 060-8589, Japan.
| | - Ryoya Suto
- Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
| | - Yuka Kishimoto
- Research & Development, Matsutani Chemical Industry Co., Ltd., Itami, Hyogo, Japan
| | - Sumiko Kanahori
- Research & Development, Matsutani Chemical Industry Co., Ltd., Itami, Hyogo, Japan
| | - Hiroshi Hara
- Laboratory of Nutritional Biochemistry, Research Faculty of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, 060-8589, Japan
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12
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Oliveira J, Lau E, Carvalho D, Freitas P. Glucagon-like peptide-1 analogues - an efficient therapeutic option for the severe insulin resistance of lipodystrophic syndromes: two case reports. J Med Case Rep 2017; 11:12. [PMID: 28086952 PMCID: PMC5237351 DOI: 10.1186/s13256-016-1175-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 12/11/2016] [Indexed: 11/29/2022] Open
Abstract
Background Lipodystrophic syndromes are uncommon medical conditions which are normally associated with metabolic disorders, such as diabetes mellitus, dyslipidemia, and fatty liver disease. These complications are generally difficult to treat, particularly diabetes, due to severe insulin resistance. We present two case reports of successful treatment of diabetes with glucagon-like peptide-1 analogues in patients with clinical features of lipodystrophic syndromes. Case presentation Two white women aged 49 and 60 years manifested marked central body fat deposition with severe lipoatrophy of their limbs and buttocks and pronounced acanthosis nigricans. They had hypertension, dyslipidemia, fatty liver disease, and poorly controlled diabetes (glycated hemoglobin 8.3% and 10.2%, respectively) despite the use of three classes of oral antidiabetic drugs taken in combination in the first case, and high doses of insulin in the second case. Four months after the addition of glucagon-like peptide-1 analogue to their previous treatment they both showed a pronounced improvement in metabolic control (glycated hemoglobin 5.6% and 6.2%, respectively). In the first case, a weight loss of nearly 30 kg was recorded. Conclusions We intend to demonstrate that glucagon-like peptide-1 analogues could be a valuable tool for patients with lipodystrophic disorders, probably by improving body fat distribution, with favorable results in insulin-sensitivity and glycemic control.
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Affiliation(s)
- Joana Oliveira
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar São João, Alameda Prof. Hernâni Monteiro, 4200, Porto, Portugal. .,Faculty of Medicine, University of Porto, Porto, Portugal.
| | - Eva Lau
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar São João, Alameda Prof. Hernâni Monteiro, 4200, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
| | - Davide Carvalho
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar São João, Alameda Prof. Hernâni Monteiro, 4200, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
| | - Paula Freitas
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar São João, Alameda Prof. Hernâni Monteiro, 4200, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
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13
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Chatterjee S, Ghosal S, Chatterjee S. Glucagon-like peptide-1 receptor agonists favorably address all components of metabolic syndrome. World J Diabetes 2016; 7:441-448. [PMID: 27795818 PMCID: PMC5065664 DOI: 10.4239/wjd.v7.i18.441] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Revised: 07/28/2016] [Accepted: 08/06/2016] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular death is the leading cause of mortality for patients with type 2 diabetes mellitus. The etiology of cardiovascular disease in diabetes may be divided into hyperglycemia per se and factors operating through components of metabolic syndrome (MetS). Hyperglycemia causes direct injury to vascular endothelium and possibly on cardiac myocytes. MetS is a cluster of risk factors like obesity, hyperglycemia, hypertension and dyslipidemia. The incidence of this syndrome is rising globally. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are a group of drugs, which address all components of this syndrome favorably. Experimental evidence suggests that they have favorable actions on myocardium as well. Several compounds belonging to GLP-1RA class are in market now and a large number awaiting their entry. Although, originally this class of drugs emerged as a treatment for type 2 diabetes mellitus, more recent data generated revealed beneficial effects on multiple metabolic parameters. We have studied literature published between 2000 and 2016 to look into effects of GLP-1RA on components of MetS. Results from recently concluded clinical trials suggest that some of the molecules in this class may have favorable effects on cardiovascular outcome.
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14
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Andreozzi F, Raciti GA, Nigro C, Mannino GC, Procopio T, Davalli AM, Beguinot F, Sesti G, Miele C, Folli F. The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism. J Transl Med 2016; 14:229. [PMID: 27473212 PMCID: PMC4967343 DOI: 10.1186/s12967-016-0985-7] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 07/20/2016] [Indexed: 01/11/2023] Open
Abstract
Aims/hypothesis Potentiation of glucose-induced insulin secretion is the main mechanism of exenatide (EXE) antidiabetic action, however, increased glucose utilization by peripheral tissues has been also reported. We here studied the effect of EXE on glucose uptake by skeletal muscle cells. Methods 2-deoxy-glucose (2DG) uptake and intracellular signal pathways were measured in rat L6 skeletal muscle myotubes exposed to 100 nmol/l EXE for up to 48 h. Mechanisms of EXE action were explored by inhibiting AMPK activity with compound C (CC, 40 μmol/l) or siRNAs (2 μmol/l). Results Time course experiments show that EXE increases glucose uptake up to 48 h achieving its maximal effect, similar to that induced by insulin, after 20 min (2- vs 2.5-fold-increase, respectively). Differently from insulin, EXE does not stimulate: (i) IR β-subunit- and IRS1 tyrosine phosphorylation and binding to p85 regulatory subunit of PI-3kinase; (ii) AKT activation; and (iii) ERK1/2 and JNK1/2 phosphorylation. Conversely, EXE increases phosphorylation of α-subunit of AMPK at Thr172 by 2.5-fold (p < 0.01). Co-incubation of EXE and insulin does not induce additive effects on 2DG-uptake. Inhibition of AMPK with CC, and reduction of AMPK protein expression by siRNA, completely abolish EXE-induced 2DG-uptake. Liraglutide, another GLP-1 receptor agonist, also stimulates AMPK phosphorylation and 2DG-uptake. Moreover, EXE stimulates 2DG-uptake also by L6 myotubes rendered insulin-resistant with methylglyoxal. Finally, EXE also induces glucose transporter Glut-4 translocation to the plasma membrane. Conclusions/interpretation In L6 myotubes, EXE and liraglutide increase glucose uptake in an insulin-independent manner by activating AMPK. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-0985-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Francesco Andreozzi
- Department of Medical and Surgical Sciences, University of Catanzaro "Magna-Graecia", Catanzaro, Italy. .,Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
| | - Gregory Alexander Raciti
- Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy.,Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy
| | - Cecilia Nigro
- Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy.,Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy
| | - Gaia Chiara Mannino
- Department of Medical and Surgical Sciences, University of Catanzaro "Magna-Graecia", Catanzaro, Italy
| | - Teresa Procopio
- Department of Medical and Surgical Sciences, University of Catanzaro "Magna-Graecia", Catanzaro, Italy
| | - Alberto M Davalli
- Department of Medicine Endocrinology Unit, Ospedale San Raffaele, Milan, Italy
| | - Francesco Beguinot
- Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy.,Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy
| | - Giorgio Sesti
- Department of Medical and Surgical Sciences, University of Catanzaro "Magna-Graecia", Catanzaro, Italy
| | - Claudia Miele
- Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy.,Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy
| | - Franco Folli
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA. .,Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
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15
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Smits MM, Tonneijck L, Muskiet MHA, Kramer MHH, Cahen DL, van Raalte DH. Gastrointestinal actions of glucagon-like peptide-1-based therapies: glycaemic control beyond the pancreas. Diabetes Obes Metab 2016; 18:224-35. [PMID: 26500045 DOI: 10.1111/dom.12593] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 09/22/2015] [Accepted: 10/17/2015] [Indexed: 12/23/2022]
Abstract
The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) lowers postprandial glucose concentrations by regulating pancreatic islet-cell function, with stimulation of glucose-dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP-1 are at least as important for glucose-lowering. GLP-1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP-1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP-1 receptor agonists, which mimic the effects of GLP-1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP-1 receptor agonists can be broadly categorized as short- or long-acting, with each having unique islet-cell and gastrointestinal effects that lower glucose levels. Short-acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long-acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual β-cell function.
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Affiliation(s)
- M M Smits
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - L Tonneijck
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - M H A Muskiet
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - M H H Kramer
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - D L Cahen
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - D H van Raalte
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
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16
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XiaoTian L, QiNan W, XiaGuang G, WuQuan D, Bing C, ZiWen L. Exenatide Activates the APPL1-AMPK-PPARα Axis to Prevent Diabetic Cardiomyocyte Apoptosis. J Diabetes Res 2015; 2016:4219735. [PMID: 26759813 PMCID: PMC4677202 DOI: 10.1155/2016/4219735] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 06/07/2015] [Accepted: 06/10/2015] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE To investigate the effect and mechanism of the exenatide on diabetic cardiomyopathy. METHODS Rats were divided into control group, diabetes group (D), diabetes treated with insulin (DI) group, and diabetes treat with exenatide (DE) group. We detected apoptosis rate by TUNEL, the adiponectin and high molecular weight adiponectin (HMW-adiponectin) by ELISA, and the expression of APPL1, p-AMPK/T-AMPK, PPARα, and NF-κB by immunohistochemistry and western blotting. RESULTS Compared with the D group, the apoptosis in the Control and DE groups was decreased (P < 0.05); the adiponectin and HMW-adiponectin were increased (P < 0.05); the APPL1, p-AMPK/T-AMPK, PPARα, and LV -dP/dt were increased (P < 0.05); and the NF-κB, GRP78, and LVEDP were decreased (P < 0.05). Compared with DE group, the glucose levels in the DI group were similar (P < 0.05); the apoptosis and LVEDP were increased; the APPL1, p-AMPK/T-AMPK, PPARα, and LV -dP/dt were decreased (P < 0.05); the NF-κB and GRP78 were increased (P < 0.05); the adiponectin and HMW-adiponectin were significantly decreased (P < 0.05). CONCLUSION Our model of diabetic cardiomyopathy was constructed successfully. After being treated with exenatide, the adiponectin and HMW-adiponectin and the APPL1-AMPK-PPARα axis were increased, the NF-κB and the apoptosis were decreased, the cardiac function of the diabetic rats was improved, and these effects were independent of glucose control.
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Affiliation(s)
- Lei XiaoTian
- Endocrine Department, The First Affiliated Hospital of the Third Military Medical University, Chongqing 400038, China
| | - Wu QiNan
- Endocrine Department, The First Affiliated Hospital of the Third Military Medical University, Chongqing 400038, China
| | - Gan XiaGuang
- Endocrine Department, The First Affiliated Hospital of the Third Military Medical University, Chongqing 400038, China
| | - Deng WuQuan
- Endocrine Department, The First Affiliated Hospital of the Third Military Medical University, Chongqing 400038, China
| | - Chen Bing
- Endocrine Department, The First Affiliated Hospital of the Third Military Medical University, Chongqing 400038, China
| | - Liang ZiWen
- Endocrine Department, The First Affiliated Hospital of the Third Military Medical University, Chongqing 400038, China
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17
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Kim TH, Kim MK, Cheong YH, Chae YN, Lee Y, Ka SO, Jung IH, Shin CY, Bae EJ, Son MH. Hepatic role in an early glucose-lowering effect by a novel dipeptidyl peptidase 4 inhibitor, evogliptin, in a rodent model of type 2 diabetes. Eur J Pharmacol 2015; 771:65-76. [PMID: 26621343 DOI: 10.1016/j.ejphar.2015.11.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 11/13/2015] [Accepted: 11/18/2015] [Indexed: 01/13/2023]
Abstract
Although multiple dipeptidyl peptidase 4 (DPP4) inhibitors have shown glucose-lowering effects by preserving pancreatic cells in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice, the hepatic role in regulation of glucose homeostasis by DPP4 inhibitors in HFD/STZ mice remains elusive. In herein study, parallel comparison of effects on the liver (expression of gluconeogenic genes and the linked signaling molecules) and pancreas (islet morphology and relative area of alpha or beta cells) in combination with glucose-lowering effects were made at the end of 2- and 10-week of evogliptin treatment in HFD/STZ mice. Significant control of hyperglycemia was observed from the second week and persisted during 10-week treatment of 0.3% evogliptin in HFD/STZ mice. This effect was accompanied by increased level of plasma glucagon-like peptide-1 and preserved pancreas islet structure. Furthermore, the hepatic increases in gluconeogenic gene expression in HFD/STZ mice was significantly reduced by evogliptin treatment, which was accompanied by the suppression of cAMP response element-binding protein (CREB) phosphorylation and expression of transducer of regulated CREB protein 2. This hepatic effect of evogliptin treatment was reproduced in 2-week study, however, pancreatic beta-cell area was not altered yet although the expression of pancreatic and duodenal homeobox protein 1 was increased. We conclude that the suppression of hepatic gluconeogenesis by evogliptin is followed by preservation of pancreatic islet, leading to remarkable and persistent glucose-lowering effect in HFD/STZ mice. Our findings provide further insight for the hepatic role in DPP4 inhibitor-mediated glucose control in diabetes.
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Affiliation(s)
- Tae-Hyoung Kim
- Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea
| | - Mi-Kyung Kim
- Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea
| | - Ye-Hwang Cheong
- Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea
| | - Yu-Na Chae
- Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea
| | - Youngyi Lee
- College of Pharmacy, Woosuk University, Wanju-gun, Jeollabuk-do, Republic of Korea
| | - Sun-O Ka
- Chonbuk National University Medical School, Jeonju-si, Jeollabuk-do, Republic of Korea
| | - Il-Hoon Jung
- Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea
| | - Chang-Yell Shin
- Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea
| | - Eun Ju Bae
- College of Pharmacy, Woosuk University, Wanju-gun, Jeollabuk-do, Republic of Korea.
| | - Moon-Ho Son
- Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea.
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18
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Deng W, Qiu S, Yang G, Chen B. Exenatide once-weekly injection for the treatment of type 2 diabetes in Chinese patients: current perspectives. Ther Clin Risk Manag 2015; 11:1153-62. [PMID: 26309403 PMCID: PMC4539087 DOI: 10.2147/tcrm.s81088] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) analogs, such as exenatide, have played an important role as antidiabetic medications in the treatment of type 2 diabetes (T2DM). Like most other hypoglycemic agents, exenatide has a number of actions, including lowering blood glucose, promoting weight loss, improving insulin resistance, and protecting islet β-cells. Although GLP-1 analogs, combined with other antidiabetic medications, have excellent performance in T2DM, some side effects and imperfections limit its use in clinical practice. Since 2012, a new generation GLP-1 agent, exenatide once weekly (QW), has been available for patients with T2DM in the USA, but not as yet in the People’s Republic of China. Previous data indicate that exenatide QW achieves better fasting glucose reductions than sitagliptin or exenatide twice daily, whilst appearing non-inferior to pioglitazone and achieving less reductions than insulin glargine. Exenatide QW was better at improving average postprandial glucose than sitagliptin or titrated insulin glargine, but was inferior to exenatide twice daily. Additionally exenatide QW has a better effect in terms of weight loss than other glycemic medications. Exenatide QW can also reduce blood lipids and lower blood pressure. Accordingly, exenatide QW is cost-effective, achieves good clinical outcomes, and has acceptable side effects, indicating that it has promising prospects for future use in the People’s Republic of China.
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Affiliation(s)
- Wuquan Deng
- Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China
| | - Sheng Qiu
- Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China
| | - Gangyi Yang
- Department of Endocrinology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Bing Chen
- Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China
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