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Hadid S, Frishman WH, Aronow WS. Advancing Diabetes Management and Glycemic Control While Exploring CagriSema's Impact on Obesity Management. Cardiol Rev 2025:00045415-990000000-00488. [PMID: 40327810 DOI: 10.1097/crd.0000000000000940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
Diabetes is a complex metabolic disorder affecting over 37 million people in the United States. Without proper management, diabetes can lead to a myriad of complications, including cardiovascular disease, kidney failure, and vision loss. Obesity is a major contributor to type 2 diabetes, but genetic and physiological factors make weight loss difficult, necessitating medication management for both conditions. Government-approved weight loss medications, including glucagon-like peptide-1 agonists and amylin analogs, have proven to be effective for both conditions. However, intensive glycemic control involving antidiabetic medications, while beneficial for reducing diabetic complications, can often precipitate hypoglycemic events, which are characterized by cardiac arrhythmias, coma, confusion, and even mortality. A new drug under investigation, CagriSema, combines cagrilintide, an amylin analog, with semaglutide, a glucagon-like peptide-1 agonist. This drug is being marketed as a safe and potentially superior medication to lower both Hemoglobin A1c and body weight. In this article, the pathophysiology, current guidelines, and management of diabetes will be reviewed, with an emphasis on the clinical evidence for tight glucose control and avoiding hypoglycemic events. Following this, an overview of recent trials on antidiabetic medications, including those involving CagriSema, will be presented, along with prospects for future trials in this promising area of research.
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Affiliation(s)
- Somar Hadid
- From the Department of Medicine, New York Medical College, Valhalla, NY
| | | | - Wilbert S Aronow
- Departments of Cardiology and Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY
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2
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Börchers S, Skibicka KP. GLP-1 and Its Analogs: Does Sex Matter? Endocrinology 2025; 166:bqae165. [PMID: 39715341 PMCID: PMC11733500 DOI: 10.1210/endocr/bqae165] [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: 11/20/2024] [Revised: 12/05/2024] [Accepted: 12/22/2024] [Indexed: 12/25/2024]
Abstract
While obesity and diabetes are prevalent in both men and women, some aspects of these diseases differ by sex. A new blockbuster class of therapeutics, glucagon-like peptide 1 (GLP-1) analogs (eg, semaglutide), shows promise at curbing both diseases. This review addresses the topic of sex differences in the endogenous and therapeutic actions of GLP-1 and its analogs. Work on sex differences in human studies and animal research is reviewed. Preclinical data on the mechanisms of potential sex differences in the endogenous GLP-1 system as well as the therapeutic effect of GLP-1 analogs, focusing on the effects of the drugs on the brain and behavior relating to appetite and metabolism, are highlighted. Moreover, recent clinical evidence of sex differences in the therapeutic effects of GLP-1 analogs in obesity, diabetes, and cardiovascular disease are discussed. Lastly, we review evidence for the role of GLP-1 analogs in mood and reproductive function, with particular attention to sex differences. Overall, while we did not find evidence for many qualitative sex differences in the therapeutic effect of clinically approved GLP-1 analogs, a growing body of literature highlights quantitative sex differences in the response to GLP-1 and its analogs as well as an interaction of these therapeutics with estrogens. What also clearly emerges is the paucity of data in female animal models or women in very basic aspects of the science of GLP-1-gaps that should be urgently mended, given the growing popularity of these medications, especially in women.
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Affiliation(s)
- Stina Börchers
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 41390 Gothenburg, Sweden
| | - Karolina P Skibicka
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 41390 Gothenburg, Sweden
- Nutritional Sciences Department, The Pennsylvania State University, University Park, PA 16803, USA
- Huck Institutes of Life Science, The Pennsylvania State University, University Park, PA 16803, USA
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3
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Deis T, Goetze JP, Kistorp C, Gustafsson F. Gut Hormones in Heart Failure. Circ Heart Fail 2024; 17:e011813. [PMID: 39498569 DOI: 10.1161/circheartfailure.124.011813] [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: 03/18/2024] [Accepted: 10/07/2024] [Indexed: 11/21/2024]
Abstract
Heart failure (HF) is a syndrome affecting all organ systems. While some organ interactions have been studied intensively in HF (such as the cardiorenal interaction), the endocrine gut has to some degree been overlooked. However, there is growing evidence of direct cardiac effects of several hormones secreted from the gastrointestinal tract. For instance, GLP-1 (glucagon-like peptide-1), an incretin hormone secreted from the distal intestine following food intake, has notable effects on the heart, impacting heart rate and contractility. GLP-1 may even possess cardioprotective abilities, such as inhibition of myocardial ischemia and cardiac remodeling. While other gut hormones have been less studied, there is evidence suggesting cardiostimulatory properties of several hormones. Moreover, it has been reported that patients with HF have altered bioavailability of numerous gastrointestinal hormones, which may have prognostic implications. This might indicate an important role of gut hormones in cardiac physiology and pathology, which may be of particular importance in the failing heart. We present an overview of the current knowledge on gut hormones in HF, focusing on HF with reduced ejection fraction, and discuss how these hormones may be regulators of cardiac function and central hemodynamics. Potential therapeutic perspectives are discussed, and knowledge gaps are highlighted herein.
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Affiliation(s)
- Tania Deis
- Department of Cardiology (T.D., F.G.), Rigshospitalet, Copenhagen, Denmark
| | - Jens P Goetze
- Department of Clinical Biochemistry (J.P.G.), Rigshospitalet, Copenhagen, Denmark
- Department of Biomedical Sciences (J.P.G.), University of Copenhagen, Denmark
| | - Caroline Kistorp
- Department of Endocrinology (C.K.), Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine (C.K., F.G.), University of Copenhagen, Denmark
| | - Finn Gustafsson
- Department of Cardiology (T.D., F.G.), Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine (C.K., F.G.), University of Copenhagen, Denmark
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Lymperopoulos A, Borges JI, Stoicovy RA. Cyclic Adenosine Monophosphate in Cardiac and Sympathoadrenal GLP-1 Receptor Signaling: Focus on Anti-Inflammatory Effects. Pharmaceutics 2024; 16:693. [PMID: 38931817 PMCID: PMC11206770 DOI: 10.3390/pharmaceutics16060693] [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: 04/20/2024] [Revised: 05/18/2024] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a multifunctional incretin hormone with various physiological effects beyond its well-characterized effect of stimulating glucose-dependent insulin secretion in the pancreas. An emerging role for GLP-1 and its receptor, GLP-1R, in brain neuroprotection and in the suppression of inflammation, has been documented in recent years. GLP-1R is a G protein-coupled receptor (GPCR) that couples to Gs proteins that stimulate the production of the second messenger cyclic 3',5'-adenosine monophosphate (cAMP). cAMP, acting through its two main effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), exerts several anti-inflammatory (and some pro-inflammatory) effects in cells, depending on the cell type. The present review discusses the cAMP-dependent molecular signaling pathways elicited by the GLP-1R in cardiomyocytes, cardiac fibroblasts, central neurons, and even in adrenal chromaffin cells, with a particular focus on those that lead to anti-inflammatory effects by the GLP-1R. Fully elucidating the role cAMP plays in GLP-1R's anti-inflammatory properties can lead to new and more precise targets for drug development and/or provide the foundation for novel therapeutic combinations of the GLP-1R agonist medications currently on the market with other classes of drugs for additive anti-inflammatory effect.
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Affiliation(s)
- Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA; (J.I.B.); (R.A.S.)
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Withaar C, Meems LM, Nollet EE, Schouten EM, Schroeder MA, Knudsen LB, Niss K, Madsen CT, Hoegl A, Mazzoni G, van der Velden J, Lam CS, Silljé HH, de Boer RA. The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF. JACC Basic Transl Sci 2023; 8:1298-1314. [PMID: 38094687 PMCID: PMC10714176 DOI: 10.1016/j.jacbts.2023.05.012] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 05/02/2023] [Accepted: 05/02/2023] [Indexed: 06/04/2024]
Abstract
Obesity-related heart failure with preserved ejection fraction (HFpEF) has become a well-recognized HFpEF subphenotype. Targeting the unfavorable cardiometabolic profile may represent a rational treatment strategy. This study investigated semaglutide, a glucagon-like peptide-1 receptor agonist that induces significant weight loss in patients with obesity and/or type 2 diabetes mellitus and has been associated with improved cardiovascular outcomes. In a mouse model of HFpEF that was caused by advanced aging, female sex, obesity, and type 2 diabetes mellitus, semaglutide, compared with weight loss induced by pair feeding, improved the cardiometabolic profile, cardiac structure, and cardiac function. Mechanistically, transcriptomic, and proteomic analyses revealed that semaglutide improved left ventricular cytoskeleton function and endothelial function and restores protective immune responses in visceral adipose tissue. Strikingly, treatment with semaglutide induced a wide array of favorable cardiometabolic effects beyond the effect of weight loss by pair feeding. Glucagon-like peptide-1 receptor agonists may therefore represent an important novel therapeutic option for treatment of HFpEF, especially when obesity-related.
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Affiliation(s)
- Coenraad Withaar
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
| | - Laura M.G. Meems
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
| | - Edgar E. Nollet
- Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Physiology, Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
| | - E. Marloes Schouten
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
| | | | - Lotte B. Knudsen
- Research and Early Development, Novo Nordisk A/S, Bagsvaerd, Denmark
| | - Kristoffer Niss
- Research and Early Development, Novo Nordisk A/S, Bagsvaerd, Denmark
| | | | | | - Gianluca Mazzoni
- Research and Early Development, Novo Nordisk A/S, Bagsvaerd, Denmark
| | - Jolanda van der Velden
- Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Physiology, Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
| | - Carolyn S.P. Lam
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
- National Heart Centre Singapore & Duke-National University of Singapore, Singapore
| | - Herman H.W. Silljé
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
| | - Rudolf A. de Boer
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
- Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands
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McLean BA, Wong CK, Kabir MG, Drucker DJ. Glucagon-like Peptide-1 receptor Tie2+ cells are essential for the cardioprotective actions of liraglutide in mice with experimental myocardial infarction. Mol Metab 2022; 66:101641. [PMID: 36396031 PMCID: PMC9706177 DOI: 10.1016/j.molmet.2022.101641] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/06/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce the rates of major cardiovascular events, including myocardial infarction in people with type 2 diabetes, and decrease infarct size while preserving ventricular function in preclinical studies. Nevertheless, the precise cellular sites of GLP-1R expression that mediate the cardioprotective actions of GLP-1 in the setting of ischemic cardiac injury are uncertain. METHODS Publicly available single cell RNA sequencing (scRNA-seq) datasets on mouse and human heart cells were analyzed for Glp1r/GLP1R expression. Fluorescent activated cell sorting was used to localize Glp1r expression in cell populations from the mouse heart. The importance of endothelial and hematopoietic cells for the cardioprotective response to liraglutide in the setting of acute myocardial infarction (MI) was determined by inactivating the Glp1r in Tie2+ cell populations. Cardiac gene expression profiles regulated by liraglutide were examined using RNA-seq to interrogate mouse atria and both infarcted and non-infarcted ventricular tissue after acute coronary artery ligation. RESULTS In mice, cardiac Glp1r mRNA transcripts were exclusively detected in endocardial cells by scRNA-seq. In contrast, analysis of human heart by scRNA-seq localized GLP1R mRNA transcripts to populations of atrial and ventricular cardiomyocytes. Moreover, very low levels of GIPR, GCGR and GLP2R mRNA transcripts were detected in the human heart. Cell sorting and RNA analyses detected cardiac Glp1r expression in endothelial cells (ECs) within the atria and ventricle in the ischemic and non-ischemic mouse heart. Transcriptional responses to liraglutide administration were not evident in wild type mouse ventricles following acute MI, however liraglutide differentially regulated genes important for inflammation, cardiac repair, cell proliferation, and angiogenesis in the left atrium, while reducing circulating levels of IL-6 and KC/GRO within hours of acute MI. Inactivation of the Glp1r within the Tie2+ cell expression domain encompassing ECs revealed normal cardiac structure and function, glucose homeostasis and body weight in Glp1rTie2-/- mice. Nevertheless, the cardioprotective actions of liraglutide to reduce infarct size, augment ejection fraction, and improve survival after experimental myocardial infarction (MI), were attenuated in Glp1rTie2-/- mice. CONCLUSIONS These findings identify the importance of the murine Tie2+ endothelial cell GLP-1R as a target for the cardioprotective actions of GLP-1R agonists and support the importance of the atrial and ventricular endocardial GLP-1R as key sites of GLP-1 action in the ischemic mouse heart. Hitherto unexplored species-specific differences in cardiac GLP-1R expression challenge the exclusive use of mouse models for understanding the mechanisms of GLP-1 action in the normal and ischemic human heart.
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Razavi M, Wei YY, Rao XQ, Zhong JX. DPP-4 inhibitors and GLP-1RAs: cardiovascular safety and benefits. Mil Med Res 2022; 9:45. [PMID: 35986429 PMCID: PMC9392232 DOI: 10.1186/s40779-022-00410-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 08/08/2022] [Indexed: 11/10/2022] Open
Abstract
Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus (T2DM). Both anti-diabetic treatments function by playing key modulatory roles in the incretin system. Though these drugs have been deemed effective in treating T2DM, the Food and Drug Administration (FDA) and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints. As a result, since 2008, the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety. The present review article strives to assess the safety and benefits of incretin-based therapy, a new class of antidiabetic drug, on the health of patient cardiovascular systems. In the process, this review will also provide a physiological overview of the incretin system and how key components function in T2DM.
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Affiliation(s)
- Michael Razavi
- Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Ying-Ying Wei
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430032, China
| | - Xiao-Quan Rao
- Department of Cardiovascular Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430032, China.
| | - Ji-Xin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430032, China.
- Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430032, China.
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8
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Zakaria EM, Tawfeek WM, Hassanin MH, Hassaballah MY. Cardiovascular protection by DPP-4 inhibitors in preclinical studies: an updated review of molecular mechanisms. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:1357-1372. [PMID: 35945358 PMCID: PMC9568460 DOI: 10.1007/s00210-022-02279-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 07/26/2022] [Indexed: 11/29/2022]
Abstract
Dipeptidyl peptidase 4 (DPP4) inhibitors are a class of antidiabetic medications that cause glucose-dependent increase in incretins in diabetic patients. One of the two incretins, glucagon-like peptide-1 (GLP-1), beside its insulinotropic activity, has been studied for extra pancreatic effects. Most of DPP4 inhibitors (DPP4i) have been investigated in in vivo and in vitro models of diabetic and nondiabetic cardiovascular diseases including heart failure, hypertension, myocardial ischemia or infarction, atherosclerosis, and stroke. Results of preclinical studies proved prominent therapeutic potential of DPP4i in cardiovascular diseases, regardless the presence of diabetes. This review aims to present an updated summary of the cardiovascular protective and therapeutic effects of DPP4 inhibitors through the past 5 years focusing on the molecular mechanisms beneath these effects. Additionally, based on the results summary presented here, future studies may be conducted to elucidate or illustrate some of these findings which can add clinical benefits towards management of diabetic cardiovascular complications.
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Affiliation(s)
- Esraa M Zakaria
- Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Walaa M Tawfeek
- Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
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Hu C, Zhang X, Hu M, Teng T, Yuan Y, Song P, Kong C, Xu S, Ma Z, Tang Q. Fibronectin type III domain-containing 5 improves aging-related cardiac dysfunction in mice. Aging Cell 2022; 21:e13556. [PMID: 35166002 PMCID: PMC8920441 DOI: 10.1111/acel.13556] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 12/17/2021] [Accepted: 01/05/2022] [Indexed: 12/14/2022] Open
Abstract
Aging is an important risk factor for cardiovascular diseases, and aging‐related cardiac dysfunction serves as a major determinant of morbidity and mortality in elderly populations. Our previous study has identified fibronectin type III domain‐containing 5 (FNDC5) and its cleaved form, irisin, as the cardioprotectant against doxorubicin‐induced cardiomyopathy. Herein, aging or matched young mice were overexpressed with FNDC5 by adeno‐associated virus serotype 9 (AAV9) vectors, or subcutaneously infused with irisin to uncover the role of FNDC5 in aging‐related cardiac dysfunction. To verify the involvement of nucleotide‐binding oligomerization domain‐like receptor with a pyrin domain 3 (NLRP3) and AMP‐activated protein kinase α (AMPKα), Nlrp3 or Ampkα2 global knockout mice were used. Besides, young mice were injected with AAV9‐FNDC5 and maintained for 12 months to determine the preventive effect of FNDC5. Moreover, neonatal rat cardiomyocytes were stimulated with tumor necrosis factor‐α (TNF‐α) to examine the role of FNDC5 in vitro. We found that FNDC5 was downregulated in aging hearts. Cardiac‐specific overexpression of FNDC5 or irisin infusion significantly suppressed NLRP3 inflammasome and cardiac inflammation, thereby attenuating aging‐related cardiac remodeling and dysfunction. In addition, irisin treatment also inhibited cellular senescence in TNF‐α‐stimulated cardiomyocytes in vitro. Mechanistically, FNDC5 activated AMPKα through blocking the lysosomal degradation of glucagon‐like peptide‐1 receptor. More importantly, FNDC5 gene transfer in early life could delay the onset of cardiac dysfunction during aging process. We prove that FNDC5 improves aging‐related cardiac dysfunction by activating AMPKα, and it might be a promising therapeutic target to support cardiovascular health in elderly populations.
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Affiliation(s)
- Can Hu
- Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
- Hubei Key Laboratory of Metabolic and Chronic Diseases Wuhan China
| | - Xin Zhang
- Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
- Hubei Key Laboratory of Metabolic and Chronic Diseases Wuhan China
| | - Min Hu
- Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
- Hubei Key Laboratory of Metabolic and Chronic Diseases Wuhan China
| | - Teng Teng
- Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
- Hubei Key Laboratory of Metabolic and Chronic Diseases Wuhan China
| | - Yu‐Pei Yuan
- Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
- Hubei Key Laboratory of Metabolic and Chronic Diseases Wuhan China
| | - Peng Song
- Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
- Hubei Key Laboratory of Metabolic and Chronic Diseases Wuhan China
| | - Chun‐Yan Kong
- Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
- Hubei Key Laboratory of Metabolic and Chronic Diseases Wuhan China
| | - Si‐Chi Xu
- Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
- Hubei Key Laboratory of Metabolic and Chronic Diseases Wuhan China
| | - Zhen‐Guo Ma
- Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
- Hubei Key Laboratory of Metabolic and Chronic Diseases Wuhan China
| | - Qi‐Zhu Tang
- Department of Cardiology Renmin Hospital of Wuhan University Wuhan China
- Hubei Key Laboratory of Metabolic and Chronic Diseases Wuhan China
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Li QX, Gao H, Guo YX, Wang BY, Hua RX, Gao L, Shang HW, Lu X, Xu JD. GLP-1 and Underlying Beneficial Actions in Alzheimer's Disease, Hypertension, and NASH. Front Endocrinol (Lausanne) 2021; 12:721198. [PMID: 34552561 PMCID: PMC8450670 DOI: 10.3389/fendo.2021.721198] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/23/2021] [Indexed: 12/24/2022] Open
Abstract
GLP-1 is derived from intestinal L cells, which takes effect through binding to GLP-1R and is inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). Since its discovery, GLP-1 has emerged as an incretin hormone for its facilitation in insulin release and reduction of insulin resistance (IR). However, GLP-1 possesses broader pharmacological effects including anti-inflammation, neuro-protection, regulating blood pressure (BP), and reducing lipotoxicity. These effects are interconnected to the physiological and pathological processes of Alzheimer's disease (AD), hypertension, and non-alcoholic steatohepatitis (NASH). Currently, the underlying mechanism of these effects is still not fully illustrated and a better understanding of them may help identify promising therapeutic targets of AD, hypertension, and NASH. Therefore, we focus on the biological characteristics of GLP-1, render an overview of the mechanism of GLP-1 effects in diseases, and investigate the potential of GLP-1 analogues for the treatment of related diseases in this review.
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Affiliation(s)
- Qiu-Xuan Li
- Clinical Medicine of “5+3” Program, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Han Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yue-Xin Guo
- Department of Oral Medicine, Basic Medical College, Capital Medical University, Beijing, China
| | - Bo-Ya Wang
- Eight Program of Clinical Medicine, Peking University Health Science Center, Beijing, China
| | - Rong-xuan Hua
- Clinical Medicine of “5+3” Program, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Lei Gao
- Department of Biomedical Informatics, School of Biomedical Engineering. Capital Medical University, Beijing, China
| | - Hong-Wei Shang
- Morphological Experiment Center, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xin Lu
- Morphological Experiment Center, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- *Correspondence: Jing-Dong Xu,
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11
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Siraj MA, Mundil D, Beca S, Momen A, Shikatani EA, Afroze T, Sun X, Liu Y, Ghaffari S, Lee W, Wheeler MB, Keller G, Backx P, Husain M. Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α. J Clin Invest 2020; 130:1392-1404. [PMID: 31985487 DOI: 10.1172/jci99934] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 11/13/2019] [Indexed: 01/02/2023] Open
Abstract
Mechanisms mediating the cardioprotective actions of glucagon-like peptide 1 (GLP-1) were unknown. Here, we show in both ex vivo and in vivo models of ischemic injury that treatment with GLP-1(28-36), a neutral endopeptidase-generated (NEP-generated) metabolite of GLP-1, was as cardioprotective as GLP-1 and was abolished by scrambling its amino acid sequence. GLP-1(28-36) enters human coronary artery endothelial cells (caECs) through macropinocytosis and acts directly on mouse and human coronary artery smooth muscle cells (caSMCs) and caECs, resulting in soluble adenylyl cyclase Adcy10-dependent (sAC-dependent) increases in cAMP, activation of protein kinase A, and cytoprotection from oxidative injury. GLP-1(28-36) modulates sAC by increasing intracellular ATP levels, with accompanying cAMP accumulation lost in sAC-/- cells. We identify mitochondrial trifunctional protein-α (MTPα) as a binding partner of GLP-1(28-36) and demonstrate that the ability of GLP-1(28-36) to shift substrate utilization from oxygen-consuming fatty acid metabolism toward oxygen-sparing glycolysis and glucose oxidation and to increase cAMP levels is dependent on MTPα. NEP inhibition with sacubitril blunted the ability of GLP-1 to increase cAMP levels in coronary vascular cells in vitro. GLP-1(28-36) is a small peptide that targets novel molecular (MTPα and sAC) and cellular (caSMC and caEC) mechanisms in myocardial ischemic injury.
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Affiliation(s)
- M Ahsan Siraj
- Ted Rogers Centre for Heart Research, University of Toronto, Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Dhanwantee Mundil
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Sanja Beca
- Heart and Stroke Richard Lewar Center of Excellence in Cardiovascular Research, and
| | - Abdul Momen
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Eric A Shikatani
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Talat Afroze
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Xuetao Sun
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Ying Liu
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Siavash Ghaffari
- Keenan Research Centre for Biomedical Research, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Warren Lee
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Keenan Research Centre for Biomedical Research, St. Michael's Hospital, Toronto, Ontario, Canada.,Department of Biochemistry.,Department of Medicine, and
| | - Michael B Wheeler
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Gordon Keller
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,McEwen Centre for Regenerative Medicine, and
| | - Peter Backx
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Mansoor Husain
- Ted Rogers Centre for Heart Research, University of Toronto, Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada.,Heart and Stroke Richard Lewar Center of Excellence in Cardiovascular Research, and.,Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Department of Medicine, and.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,McEwen Centre for Regenerative Medicine, and.,Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
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12
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Savarese G, Schrage B, Cosentino F, Lund LH, Rosano GMC, Seferovic P, Butler J. Non-insulin antihyperglycaemic drugs and heart failure: an overview of current evidence from randomized controlled trials. ESC Heart Fail 2020; 7:3438-3451. [PMID: 32909376 PMCID: PMC7755024 DOI: 10.1002/ehf2.12937] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/08/2020] [Accepted: 07/20/2020] [Indexed: 12/28/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is highly prevalent in the general population and especially in patients with heart failure (HF). It is not only a risk factor for incident HF, but is also associated with worse outcomes in prevalent HF. Therefore, antihyperglycaemic management in patients at risk of or with established HF is of importance to reduce morbidity/mortality. Following revision of the drug approval process in 2008 by the Food and Drug Administration and European Medicines Agency, several cardiovascular outcome trials on antihyperglycaemic drugs have recently investigated HF endpoints. Signals of harm in terms of increased risk of HF have been identified for thiazolidinediones and the dipeptidyl peptidase 4 inhibitor saxagliptin, and therefore, these drugs are not currently recommended in HF. Sulfonylureas also have an unfavourable safety profile and should be avoided in patients at increased risk of/with HF. Observational studies have assessed the use of metformin in patients with HF, showing potential safety and potential survival/morbidity benefits. Overall use of glucagon-like peptide 1 receptor agonists has not been linked with any clear benefit in terms of HF outcomes. Sodium-glucose cotransporter protein 2 inhibitors (SGLT2i) have consistently shown to reduce risk of HF-related outcomes in T2DM with and without HF and are thus currently recommended to lower risk of HF hospitalization in T2DM. Recent findings from the DAPA-HF trial support the use of dapagliflozin in patients with HF with reduced ejection fraction and, should ongoing trials with empagliflozin, sotagliflozin, and canagliflozin prove efficacy, will pave the way for SGLT2i as HF treatment regardless of T2DM.
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Affiliation(s)
- Gianluigi Savarese
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, 17176, Sweden
| | - Benedikt Schrage
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, 17176, Sweden
| | - Francesco Cosentino
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, 17176, Sweden
| | - Lars H Lund
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, 17176, Sweden
| | - Giuseppe M C Rosano
- Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy.,Cardiology Clinical Academic Group, St George's Hospitals NHS Trust University of London, London, UK
| | - Petar Seferovic
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia.,Serbian Academy of Sciences and Arts, Belgrade, Serbia
| | - Javed Butler
- Department of Medicine, University of Mississippi, Jackson, MS, USA
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13
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Cataldi M, Cignarelli A, Giallauria F, Muscogiuri G, Barrea L, Savastano S, Colao A. Cardiovascular effects of antiobesity drugs: are the new medicines all the same? INTERNATIONAL JOURNAL OF OBESITY SUPPLEMENTS 2020; 10:14-26. [PMID: 32714509 DOI: 10.1038/s41367-020-0015-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Waiting for a definite answer from well-designed randomized prospective clinical trials, the impact of the new antiobesity drugs -liraglutide, bupropion/naltrexone, phentermine/topiramate and lorcaserin- on cardiovascular outcomes remains uncertain. What has been learned from previous experience with older medicines is that antiobesity drugs may influence cardiovascular health not only causing weight reduction but also through direct actions on the cardiovascular system. Therefore, in the present review, we examine what is known, mainly from preclinical investigations, about the cardiovascular pharmacology of the new antiobesity medicines with the aim of highlighting potential mechanistic differences. We will show that the two active substances of the bupropion/naltrexone combination both exert beneficial and unwanted cardiovascular effects. Indeed, bupropion exerts anti-inflammatory effects but at the same time it does increase heart rate and blood pressure by potentiating catecholaminergic neurotransmission, whereas naltrexone reduces TLR4-dependent inflammation and has potential protective effects in stroke but also impairs cardiac adaption to ischemia and the beneficial opioid protective effects mediated in the endothelium. On the contrary, with the only exception of a small increase in heat rate, liraglutide only exerts favorable cardiovascular effects by protecting myocardium and brain from ischemic damage, improving heart contractility, lowering blood pressure and reducing atherogenesis. As far as the phentermine/topiramate combination is concerned, no direct cardiovascular beneficial effect is expected for phentermine (as this drug is an amphetamine derivative), whereas topiramate may exert cardioprotective and neuroprotective effects in ischemia and anti-inflammatory and antiatherogenic actions. Finally, lorcaserin, a selective 5HT2C receptor agonist, does not seem to exert significant direct effects on the cardiovascular system though at very high concentrations this drug may also interact with other serotonin receptor subtypes and exert unwanted cardiovascular effects. In conclusion, the final effect of the new antiobesity drugs on cardiovascular outcomes will be a balance between possible (but still unproved) beneficial effects of weight loss and "mixed" weight-independent drug-specific effects. Therefore comparative studies will be required to establish which one of the new medicines is more appropriate in patients with specific cardiovascular diseases.
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Affiliation(s)
- Mauro Cataldi
- Department of Neuroscience, Reproductive Sciences and Dentistry, Division of Pharmacology, Federico II University of Naples, Naples, Italy
| | - Angelo Cignarelli
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Francesco Giallauria
- Department of Translational Medical Sciences, Internal Medicine (Metabolic and Cardiac Rehabilitation Unit), Federico II University of Naples, Naples, Italy
| | - Giovanna Muscogiuri
- Department of Clinical Medicine and Surgery, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131 Naples, Italy
| | - Luigi Barrea
- Department of Clinical Medicine and Surgery, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131 Naples, Italy
| | - Silvia Savastano
- Department of Clinical Medicine and Surgery, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131 Naples, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131 Naples, Italy
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14
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Love KM, Liu J, Regensteiner JG, Reusch JE, Liu Z. GLP-1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes. J Diabetes 2020; 12:488-498. [PMID: 32274893 PMCID: PMC8393916 DOI: 10.1111/1753-0407.13045] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/24/2020] [Accepted: 03/31/2020] [Indexed: 12/25/2022] Open
Abstract
Muscle microvasculature critically regulates skeletal and cardiac muscle health and function. It provides endothelial surface area for substrate exchange between the plasma compartment and the muscle interstitium. Insulin fine-tunes muscle microvascular perfusion to regulate its own action in muscle and oxygen and nutrient supplies to muscle. Specifically, insulin increases muscle microvascular perfusion, which results in increased delivery of insulin to the capillaries that bathe the muscle cells and then facilitate its own transendothelial transport to reach the muscle interstitium. In type 2 diabetes, muscle microvascular responses to insulin are blunted and there is capillary rarefaction. Both loss of capillary density and decreased insulin-mediated capillary recruitment contribute to a decreased endothelial surface area available for substrate exchange. Vasculature expresses abundant glucagon-like peptide 1 (GLP-1) receptors. GLP-1, in addition to its well-characterized glycemic actions, improves endothelial function, increases muscle microvascular perfusion, and stimulates angiogenesis. Importantly, these actions are preserved in the insulin resistant states. Thus, treatment of insulin resistant patients with GLP-1 receptor agonists may improve skeletal and cardiac muscle microvascular perfusion and increase muscle capillarization, leading to improved delivery of oxygen, nutrients, and hormones such as insulin to the myocytes. These actions of GLP-1 impact skeletal and cardiac muscle function and systems biology such as functional exercise capacity. Preclinical studies and clinical trials involving the use of GLP-1 receptor agonists have shown salutary cardiovascular effects and improved cardiovascular outcomes in type 2 diabetes mellitus. Future studies should further examine the different roles of GLP-1 in cardiac as well as skeletal muscle function.
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Affiliation(s)
- Kaitlin M. Love
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
| | - Jia Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
| | - Judith G. Regensteiner
- Center for Women’s Health Research, University of Colorado School of Medicine, Aurora, Colorado
- Department of Medicine, University of Colorado, Aurora, Colorado
| | - Jane E.B. Reusch
- Center for Women’s Health Research, University of Colorado School of Medicine, Aurora, Colorado
- Department of Medicine, University of Colorado, Aurora, Colorado
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
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15
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PPG neurons in the nucleus of the solitary tract modulate heart rate but do not mediate GLP-1 receptor agonist-induced tachycardia in mice. Mol Metab 2020; 39:101024. [PMID: 32446875 PMCID: PMC7317700 DOI: 10.1016/j.molmet.2020.101024] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/13/2020] [Accepted: 05/13/2020] [Indexed: 01/07/2023] Open
Abstract
Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. Although the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects. Methods We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPGNTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA. Results Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPGNTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPGNTS neurons. PPGNTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPGNTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR. Conclusions These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPGNTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPGNTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.
Activation of PPG neurons triggers increases in heart rate in mice. PPG neurons do not provide a tonic sympathetic drive to the heart. The tachycardic effect of systemic Ex-4 is not mediated by PPG neurons. GLP-1 receptor activation has a sympathoexcitatory effect that increases heart rate. Local activation of GLP-1R in the spinal cord is sufficient to elicit tachycardia.
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16
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Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, Fritsche A, Gribble F, Grill HJ, Habener JF, Holst JJ, Langhans W, Meier JJ, Nauck MA, Perez-Tilve D, Pocai A, Reimann F, Sandoval DA, Schwartz TW, Seeley RJ, Stemmer K, Tang-Christensen M, Woods SC, DiMarchi RD, Tschöp MH. Glucagon-like peptide 1 (GLP-1). Mol Metab 2019; 30:72-130. [PMID: 31767182 PMCID: PMC6812410 DOI: 10.1016/j.molmet.2019.09.010] [Citation(s) in RCA: 1109] [Impact Index Per Article: 184.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/10/2019] [Accepted: 09/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. SCOPE OF REVIEW In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. MAJOR CONCLUSIONS Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.
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Affiliation(s)
- T D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany.
| | - B Finan
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | - S R Bloom
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - D D'Alessio
- Division of Endocrinology, Duke University Medical Center, Durham, NC, USA
| | - D J Drucker
- The Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, M5G1X5, Canada
| | - P R Flatt
- SAAD Centre for Pharmacy & Diabetes, Ulster University, Coleraine, Northern Ireland, UK
| | - A Fritsche
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany
| | - F Gribble
- Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - H J Grill
- Institute of Diabetes, Obesity and Metabolism, Department of Psychology, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - J F Habener
- Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard University, Boston, MA, USA
| | - J J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - W Langhans
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - J J Meier
- Diabetes Division, St Josef Hospital, Ruhr-University Bochum, Bochum, Germany
| | - M A Nauck
- Diabetes Center Bochum-Hattingen, St Josef Hospital (Ruhr-Universität Bochum), Bochum, Germany
| | - D Perez-Tilve
- Department of Internal Medicine, University of Cincinnati-College of Medicine, Cincinnati, OH, USA
| | - A Pocai
- Cardiovascular & ImmunoMetabolism, Janssen Research & Development, Welsh and McKean Roads, Spring House, PA, 19477, USA
| | - F Reimann
- Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - D A Sandoval
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - T W Schwartz
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DL-2200, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark
| | - R J Seeley
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - K Stemmer
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - M Tang-Christensen
- Obesity Research, Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | - S C Woods
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA
| | - R D DiMarchi
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA
| | - M H Tschöp
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany; Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
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17
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Lundgren JR, Færch K, Witte DR, Jonsson AE, Pedersen O, Hansen T, Lauritzen T, Holst JJ, Vistisen D, Jørgensen ME, Torekov SS, Johansen NB. Greater glucagon-like peptide-1 responses to oral glucose are associated with lower central and peripheral blood pressures. Cardiovasc Diabetol 2019; 18:130. [PMID: 31586493 PMCID: PMC6778378 DOI: 10.1186/s12933-019-0937-7] [Citation(s) in RCA: 2] [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: 07/08/2019] [Accepted: 09/27/2019] [Indexed: 12/25/2022] Open
Abstract
Background and aim Cardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD. Methods This cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m2, without antihypertensive treatment and known diabetes). All participants received an oral glucose tolerance test with measurements of GLP-1 at 0, 30 and 120 min. Aortic stiffness was assessed by pulse wave velocity (PWV). The associations between GLP-1 response and central and brachial blood pressure (BP) and PWV were assessed in linear regression models adjusting for age and sex. Results A greater GLP-1 response was associated with lower central systolic and diastolic BP of − 1.17 mmHg (95% confidence interval (CI) − 2.07 to − 0.27 mmHg, P = 0.011) and − 0.74 mmHg (95% CI − 1.29 to − 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of − 1.27 mmHg (95% CI − 2.20 to − 0.33 mmHg, P = 0.008) and − 1.00 (95% CI − 1.56 to − 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: − 4.94 (95% CI − 8.56 to − 1.31) mmHg, central diastolic BP: − 3.05 (95% CI − 5.29 to − 0.80) mmHg, brachial systolic BP: − 5.18 (95% CI − 8.94 to − 1.42) mmHg, and brachial diastolic BP: − 2.96 (95% CI − 5.26 to − 0.67) mmHg). Conclusion Greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality. Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005
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Affiliation(s)
- Julie R Lundgren
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark. .,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
| | | | - Daniel R Witte
- Aarhus University, Aarhus, Denmark.,Danish Diabetes Academy, Odense, Denmark
| | - Anna E Jonsson
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Oluf Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | | | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Signe S Torekov
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark. .,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
| | - Nanna B Johansen
- Steno Diabetes Center Copenhagen, Gentofte, Denmark.,Danish Diabetes Academy, Odense, Denmark
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18
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Sharma A, Verma S. Mechanisms by Which Glucagon-Like-Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors Reduce Cardiovascular Risk in Adults With Type 2 Diabetes Mellitus. Can J Diabetes 2019; 44:93-102. [PMID: 31882322 DOI: 10.1016/j.jcjd.2019.09.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 09/09/2019] [Indexed: 02/06/2023]
Abstract
The growing global burden of type 2 diabetes mellitus confers significant morbidity and mortality in addition to significant cost to local health-care systems. In recent years, 2 classes of therapies have shown some promise in reducing the risk of adverse cardiovascular (CV) events: 1) glucagon-like-peptide-1 (GLP-1) receptor agonists and 2) sodium-glucose cotransporter-2 (SGLT-2) inhibitors. The mechanisms whereby these therapies reduce the risk of adverse CV outcomes are emerging. Both classes of therapies have overlapping yet distinct mechanisms of action. GLP-1 receptor agonists appear to target the incretin axis, inhibit gastric mobility pathways, modify CV risk factors through weight reduction, induce protection of ischemia/reperfusion injury and improve endothelial dysfunction. In comparison, SGLT-2 inhibitors appear to improve ventricular loading conditions, reduce sympathetic nervous system activation, reduce cardiac fibrosis, reduce renal hypoxia and renal-cardiac signalling, reduce left ventricular mass and improve cardiac energetics. In this review, we summarize the potential mechanisms whereby GLP-1 receptor agonists and SGLT-2 inhibitors improve CV outcomes in patients with type 2 diabetes and highlight evidence for their use in populations without diabetes.
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Affiliation(s)
- Abhinav Sharma
- Division of Cardiology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Subodh Verma
- Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
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19
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Knudsen LB. Inventing Liraglutide, a Glucagon-Like Peptide-1 Analogue, for the Treatment of Diabetes and Obesity. ACS Pharmacol Transl Sci 2019; 2:468-484. [PMID: 32259078 DOI: 10.1021/acsptsci.9b00048] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Indexed: 01/08/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) has been in focus since the early 1980s as a long looked for incretin hormone, released from the gastrointestinal tract and with an important effect on glucose-dependent insulin secretion, providing efficient glucose lowering, with little risk for hypoglycemia. The enzyme dipeptidyl peptidase-4 (DPP-4) degrades GLP-1 very fast, and the remaining metabolite is cleared rapidly by the kidneys. Liraglutide is a fatty acid acylated analogue of GLP-1 that provides efficacy for 24 h/day. The mechanism of action for liraglutide is reviewed in detail with focus on pancreatic efficacy and safety, thyroid safety, and weight loss mechanism. Evolving science hypothesizes that GLP-1 has important effects on atherosclerosis, relevant for the cardiovascular benefit seen in the treatment of diabetes and obesity. Also, GLP-1 may be relevant in neurodegenerative diseases.
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Affiliation(s)
- Lotte Bjerre Knudsen
- Global Drug Discovery, Novo Nordisk, Novo Nordisk Park, DK-2760 Maaloev, Denmark
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20
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Khodeer DM, Bilasy SE, Farag NE, Mehana AE, Elbaz AA. Sitagliptin protects diabetic rats with acute myocardial infarction through induction of angiogenesis: role of IGF-1 and VEGF. Can J Physiol Pharmacol 2019; 97:1053-1063. [PMID: 31116952 DOI: 10.1139/cjpp-2018-0670] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Angiogenesis is regulated in a tissue-specific manner in all patients, especially those with diabetes. In this study, we describe a novel molecular pathway of angiogenesis regulation in diabetic rats with myocardial infarction (MI) and examine the cardioprotective effects of different doses of sitagliptin. Male rats were divided into 5 groups: normal vehicle group, diabetic group, diabetic + MI, diabetic + MI + 5 mg/kg sitagliptin, and diabetic + MI + 10 mg/kg sitagliptin. Isoproterenol in diabetic rats resulted in significant (p < 0.05) disturbance to the electrocardiogram, cardiac histopathological manifestations, and an increase in inflammatory markers compared with the vehicle and diabetic groups. Treatment with sitagliptin improved the electrocardiogram and histopathological sections, upregulated vascular endothelial growth factor (VEGF) and transmembrane phosphoglycoprotein protein (CD34) in cardiac tissues, and increased serum insulin-like growth factor 1 (IGF-1) and decreased cardiac tissue homogenate for interleukin 6 (IL-6) and cyclooxygenase 2 (COX-2). A relationship was found between serum IGF-1 and cardiac VEGF and CD34 accompanied by an improvement in cardiac function of diabetic rats with MI. Therefore, the observed effects of sitagliptin occurred at least partly through an improvement in angiogenesis and the mitigation of inflammation. Consequently, these data suggest that sitagliptin may contribute, in a dose-dependent manner, to protection against acute MI in diabetic individuals.
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Affiliation(s)
- Dina M Khodeer
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Shymaa E Bilasy
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Noha E Farag
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Amir E Mehana
- Department of Zoology, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Amani A Elbaz
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
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21
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Alexiadou K, Anyiam O, Tan T. Cracking the combination: Gut hormones for the treatment of obesity and diabetes. J Neuroendocrinol 2019; 31:e12664. [PMID: 30466162 PMCID: PMC6563152 DOI: 10.1111/jne.12664] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 11/11/2018] [Accepted: 11/17/2018] [Indexed: 12/21/2022]
Abstract
Obesity and type 2 diabetes are a veritable global pandemic. There is an imperative to develop new therapies for these conditions that can be delivered at scale to patients, which deliver effective and titratable weight loss, amelioration of diabetes, prevention of diabetic complications and improvements in cardiovascular health. Although agents based on glucagon-like peptide-1 (GLP-1) are now in routine use for diabetes and obesity, the limited efficacy of such drugs means that newer agents are required. By combining the effects of GLP-1 with other gut and metabolic hormones such as glucagon (GCG), oxyntomodulin, glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY), we may obtain improved weight loss, increased energy expenditure and improved metabolic profiles. Drugs based on dual agonism of GLP1R/GCGR and GLP1R/GIPR are being actively developed in clinical trials. Triple agonism, for example with GLPR1/GCGR/GIPR unimolecular agonists or using GLP-1/oxyntomodulin/PYY, is also being explored. Multi-agonist drugs seem set to deliver the next generation of therapies for diabetes and obesity soon.
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Affiliation(s)
| | - Oluwaseun Anyiam
- Section of Investigative MedicineImperial College LondonLondonUK
| | - Tricia Tan
- Section of Investigative MedicineImperial College LondonLondonUK
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Bahtiyar G, Pujals-Kury J, Sacerdote A. Cardiovascular Effects of Different GLP-1 Receptor Agonists in Patients with Type 2 Diabetes. Curr Diab Rep 2018; 18:92. [PMID: 30171481 DOI: 10.1007/s11892-018-1043-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have positive effects on weight loss, blood pressure, hyperlipidemia, and glycemic control. They exhibit a broad range of effects on the cardiovascular system that are independent of changes in blood glucose. Cardiovascular outcome trials have demonstrated safety of GLP-1 RAs but results for cardiovascular efficacy were varied. The aim of the present review is the assessment of the effects of GLP-1 RAs on cardiovascular risk factors, and major cardiovascular events. RECENT FINDINGS Use of GLP-1 RAs was associated with relative risk reduction in cardiovascular mortality and all-cause mortality with no significant differences for the incidence of severe hypoglycemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer when compared to placebo. Although there are differences between individual medications with respect to their effects on cardiovascular events, GLP-1 RAs offer a favorable risk-benefit profile. The present review confirms the cardiovascular safety and efficacy vs placebo of GLP-1 RAs in patients with type 2 diabetes at moderate-to-high atherosclerotic cardiovascular risk without significant side effects. Although professional guidelines recommend metformin as the sole first-line agent, GLP-1 RAs can be used as first-line therapy in individuals with type 2 diabetes who either are intolerant to metformin or have high cardiovascular risk factors.
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Affiliation(s)
- Gül Bahtiyar
- Division of Endocrinology, State University of New York Health Science Center, Brooklyn, NY, USA
- Department of Medicine, Woodhull Medical & Mental Health Center, Brooklyn, NY, USA
- Department of Internal Medicine, Division of Endocrinology, Woodhull Medical & Mental Health Center, New York University School of Medicine, 760 Broadway, Brooklyn, NY, 11206, USA
| | - Jean Pujals-Kury
- Division of Endocrinology, State University of New York Health Science Center, Brooklyn, NY, USA
| | - Alan Sacerdote
- Division of Endocrinology, State University of New York Health Science Center, Brooklyn, NY, USA.
- Department of Medicine, Woodhull Medical & Mental Health Center, Brooklyn, NY, USA.
- Department of Internal Medicine, Division of Endocrinology, Woodhull Medical & Mental Health Center, New York University School of Medicine, 760 Broadway, Brooklyn, NY, 11206, USA.
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23
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After the LEADER trial and SUSTAIN-6, how do we explain the cardiovascular benefits of some GLP-1 receptor agonists? DIABETES & METABOLISM 2018; 43 Suppl 1:2S3-2S12. [PMID: 28431669 DOI: 10.1016/s1262-3636(17)30067-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Recent cardiovascular outcome trials - the LEADER with liragutide and SUSTAIN-6 with semaglutide - have shown significant reductions of major cardiovascular (CV) events with these glucagon-like peptide (GLP)-1 receptor agonists. Progressive separation of the treatment and placebo curves, starting clearly between 12 and 18 months of the trial period, and significant reductions in the risk of myocardial infarction and stroke, indicate that the beneficial CV effects observed with GLP-1 receptor agonists could be due to an antiatherogenic effect. So far, the reasons for such an effect of GLP-1 receptor agonists have not been entirely clear, although several hypotheses may be proposed. As the reductions in glycated haemoglobin and systolic blood pressure (SBP) in these trials were modest, and both trials lasted only a short period of time, reductions in hyperglycaemia and SBP are unlikely to be involved in the beneficial CV effects of GLP-1 receptor agonists. On the other hand, their effect on lipids and, in particular, the dramatic decrease in postprandial hypertriglyceridaemia may explain their beneficial CV actions. Reduction of body weight, including a significant decrease in visceral fat in patients using GLP-1 receptor agonists, may also have beneficial CV effects by reducing chronic proatherogenic inflammation. In addition, there are in-vitro data showing a direct anti-inflammatory effect with these agents that could also be involved in their beneficial CV effects. Moreover, studies in humans have shown significant beneficial effects on ischaemic myocardium after a very short treatment period, suggesting a direct effect of GLP-1 receptor agonists on myocardium, although the precise mechanism remains unclear. Finally, as a reduction in insulin resistance has been associated with a decrease in CV risk, it cannot be ruled out that the lowering of insulin resistance induced by GLP-1 receptor agonists might also be involved in their beneficial CV actions.
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24
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Orabi B, Kaddoura R, Omar AS, Carr C, Alkhulaifi A. Molecular and clinical roles of incretin-based drugs in patients with heart failure. Heart Fail Rev 2018; 23:363-376. [PMID: 29682682 DOI: 10.1007/s10741-018-9702-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors produce some beneficial and deleterious effects in diabetic patients not mediated by their glycemic lowering effects, and there is a need for better understanding of the molecular basis of these effects. They possess antioxidant and anti-inflammatory effects with some direct vasodilatory action (animal and human trial data) that may indirectly influence heart failure (HF). Unlike GLP-1R agonists, signaling for HF adverse effects was observed with two DPP-4 inhibitors, saxagliptin and alogliptin. Accordingly, these drugs should be used with caution in heart failure patients.
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Affiliation(s)
- Bassant Orabi
- Department of Clinical pharmacy, Heart Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Rasha Kaddoura
- Department of Clinical pharmacy, Heart Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Amr S Omar
- Department of Cardiothoracic Surgery/Cardiac Anaesthesia & ICU, Heart Hospital, Hamad Medical Corporation, (PO: 3050), Doha, Qatar.
- Department of Critical Care Medicine, Beni Suef University, Beni Suef, Egypt.
- Weill Cornell Medical College in Qatar, Doha, Qatar.
| | - Cornelia Carr
- Department of Cardiothoracic Surgery/Cardiac Anaesthesia & ICU, Heart Hospital, Hamad Medical Corporation, (PO: 3050), Doha, Qatar
| | - Abdulaziz Alkhulaifi
- Department of Cardiothoracic Surgery/Cardiac Anaesthesia & ICU, Heart Hospital, Hamad Medical Corporation, (PO: 3050), Doha, Qatar
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25
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Packer M. Augmentation of glucagon-like peptide-1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure. Eur J Heart Fail 2018; 20:973-977. [PMID: 29603541 DOI: 10.1002/ejhf.1185] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 01/23/2018] [Accepted: 02/26/2018] [Indexed: 01/18/2023] Open
Abstract
Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP-1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA
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26
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Cardiac-specific inducible overexpression of human plasma membrane Ca 2+ ATPase 4b is cardioprotective and improves survival in mice following ischemic injury. Clin Sci (Lond) 2018; 132:641-654. [PMID: 29487197 DOI: 10.1042/cs20171337] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 02/26/2018] [Accepted: 02/27/2018] [Indexed: 01/09/2023]
Abstract
Background: Heart failure (HF) is associated with reduced expression of plasma membrane Ca2+-ATPase 4 (PMCA4). Cardiac-specific overexpression of human PMCA4b in mice inhibited nNOS activity and reduced cardiac hypertrophy by inhibiting calcineurin. Here we examine temporally regulated cardiac-specific overexpression of hPMCA4b in mouse models of myocardial ischemia reperfusion injury (IRI) ex vivo, and HF following experimental myocardial infarction (MI) in vivoMethods and results: Doxycycline-regulated cardiomyocyte-specific overexpression and activity of hPMCA4b produced adaptive changes in expression levels of Ca2+-regulatory genes, and induced hypertrophy without significant differences in Ca2+ transients or diastolic Ca2+ concentrations. Total cardiac NOS and nNOS-specific activities were reduced in mice with cardiac overexpression of hPMCA4b while nNOS, eNOS and iNOS protein levels did not differ. hMPCA4b-overexpressing mice also exhibited elevated systolic blood pressure vs. controls, with increased contractility and lusitropy in vivo In isolated hearts undergoing IRI, hPMCA4b overexpression was cardioprotective. NO donor-treated hearts overexpressing hPMCA4b showed reduced LVDP and larger infarct size versus vehicle-treated hearts undergoing IRI, demonstrating that the cardioprotective benefits of hPMCA4b-repressed nNOS are lost by restoring NO availability. Finally, both pre-existing and post-MI induction of hPMCA4b overexpression reduced infarct expansion and improved survival from HF.Conclusions: Cardiac PMCA4b regulates nNOS activity, cardiac mass and contractility, such that PMCA4b overexpression preserves cardiac function following IRI, heightens cardiac performance and limits infarct progression, cardiac hypertrophy and HF, even when induced late post-MI. These data identify PMCA4b as a novel therapeutic target for IRI and HF.
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27
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Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab 2018; 20 Suppl 1:5-21. [PMID: 29364588 DOI: 10.1111/dom.13129] [Citation(s) in RCA: 509] [Impact Index Per Article: 72.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 10/12/2017] [Indexed: 12/17/2022]
Abstract
Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose-dependent insulinotropic polypeptide) und GLP-1 (glucagon-like peptide-1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP-1, L cells) gut. Together, they are responsible for the incretin effect: a two- to three-fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present. This is the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP-1 in mediating the incretin effect even in healthy subjects. However, the insulinotropic and glucagonostatic effects of GLP-1 are preserved in subjects with type 2 diabetes to the degree that pharmacological stimulation of GLP-1 receptors significantly reduces plasma glucose and improves glycaemic control. Thus, it has become a parent compound of incretin-based glucose-lowering medications (GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 or DPP-4). GLP-1, in addition, has multiple effects on various organ systems. Most relevant are a reduction in appetite and food intake, leading to weight loss in the long term. Since GLP-1 secretion from the gut seems to be impaired in obese subjects, this may even indicate a role in the pathophysiology of obesity. Along these lines, an increased secretion of GLP-1 induced by delivering nutrients to lower parts of the small intestines (rich in L cells) may be one factor (among others like peptide YY) explaining weight loss and improvements in glycaemic control after bariatric surgery (e.g., Roux-en-Y gastric bypass). GIP and GLP-1, originally characterized as incretin hormones, have additional effects in adipose cells, bone, and the cardiovascular system. Especially, the latter have received attention based on recent findings that GLP-1 receptor agonists such as liraglutide reduce cardiovascular events and prolong life in high-risk patients with type 2 diabetes. Thus, incretin hormones have an important role physiologically, namely they are involved in the pathophysiology of obesity and type 2 diabetes, and they have therapeutic potential that can be traced to well-characterized physiological effects.
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Affiliation(s)
- Michael A Nauck
- Diabetes Center Bochum-Hattingen, Medical Department I, St. Josef-Hospital, Ruhr-University, Bochum, Germany
| | - Juris J Meier
- Diabetes Center Bochum-Hattingen, Medical Department I, St. Josef-Hospital, Ruhr-University, Bochum, Germany
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28
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Shah HS, Morieri ML, Marcovina SM, Sigal RJ, Gerstein HC, Wagner MJ, Motsinger-Reif AA, Buse JB, Kraft P, Mychaleckyj JC, Doria A. Modulation of GLP-1 Levels by a Genetic Variant That Regulates the Cardiovascular Effects of Intensive Glycemic Control in ACCORD. Diabetes Care 2018; 41:348-355. [PMID: 29183908 PMCID: PMC5780047 DOI: 10.2337/dc17-1638] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 10/22/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE A genome-wide association study in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial identified two markers (rs57922 and rs9299870) that were significantly associated with cardiovascular mortality during intensive glycemic control and could potentially be used, when combined into a genetic risk score (GRS), to identify patients with diabetes likely to derive benefit from intensive control rather than harm. The aim of this study was to gain insights into the pathways involved in the modulatory effect of these variants. RESEARCH DESIGN AND METHODS Fasting levels of 65 biomarkers were measured at baseline and at 12 months of follow-up in the ACCORD-Memory in Diabetes (ACCORD-MIND) MRI substudy (n = 562). Using linear regression models, we tested the association of the GRS with baseline and 12-month biomarker levels, and with their difference (Δ), among white subjects, with genotype data (n = 351) stratified by intervention arm. RESULTS A significant association was observed between GRS and ΔGLP-1 (glucagon-like peptide 1, active) in the intensive arm (P = 3 × 10-4). This effect was driven by rs57922 (P = 5 × 10-4). C/C homozygotes, who had been found to derive cardiovascular benefits from intensive treatment, showed a 22% increase in GLP-1 levels during follow-up. By contrast, T/T homozygotes, who had been found to experience increased cardiac mortality with intensive treatment, showed a 28% reduction in GLP-1 levels. No association between ΔGLP-1 and GRS or rs57922 was observed in the standard treatment arm. CONCLUSIONS Differences in GLP-1 axis activation may mediate the modulatory effect of variant rs57922 on the cardiovascular response to intensive glycemic control. These findings highlight the importance of GLP-1 as a cardioprotective factor.
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Affiliation(s)
- Hetal S Shah
- Research Division, Joslin Diabetes Center, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Mario Luca Morieri
- Research Division, Joslin Diabetes Center, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Santica M Marcovina
- Department of Medicine, University of Washington, and Northwest Lipid Metabolism and Diabetes Research Laboratories, Seattle, WA
| | - Ronald J Sigal
- Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Faculties of Medicine and Kinesiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Hertzel C Gerstein
- Department of Medicine and the Population Health Research Institute, McMaster University, and Hamilton Health Sciences, Ontario, Hamilton, Canada
| | - Michael J Wagner
- Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Alison A Motsinger-Reif
- Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC
| | - John B Buse
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Peter Kraft
- Department of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Josyf C Mychaleckyj
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA
| | - Alessandro Doria
- Research Division, Joslin Diabetes Center, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
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Wahl MP, Scalzo RL, Regensteiner JG, Reusch JEB. Mechanisms of Aerobic Exercise Impairment in Diabetes: A Narrative Review. Front Endocrinol (Lausanne) 2018; 9:181. [PMID: 29720965 PMCID: PMC5915473 DOI: 10.3389/fendo.2018.00181] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 04/04/2018] [Indexed: 12/21/2022] Open
Abstract
The prevalence of diabetes in the United States and globally has been rapidly increasing over the last several decades. There are now estimated to be 30.3 million people in the United States and 422 million people worldwide with diabetes. Diabetes is associated with a greatly increased risk of cardiovascular mortality, which is the leading cause of death in adults with diabetes. While exercise training is a cornerstone of diabetes treatment, people with diabetes have well-described aerobic exercise impairments that may create an additional diabetes-specific barrier to adding regular exercise to their lifestyle. Physiologic mechanisms linked to exercise impairment in diabetes include insulin resistance, cardiac abnormalities, mitochondrial function, and the ability of the body to supply oxygen. In this paper, we highlight the abnormalities of exercise in type 2 diabetes as well as potential therapeutic approaches.
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Affiliation(s)
- Matthew P. Wahl
- Division of Endocrinology, University of Colorado School of Medicine, Aurora, CO, United States
- Veterans Administration Eastern Colorado Health Care System, Denver, CO, United States
| | - Rebecca L. Scalzo
- Division of Endocrinology, University of Colorado School of Medicine, Aurora, CO, United States
- Center for Women’s Health Research, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
| | - Judith G. Regensteiner
- Center for Women’s Health Research, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
- Division of General Internal Medicine, University of Colorado School of Medicine, Aurora, CO, United States
| | - Jane E. B. Reusch
- Division of Endocrinology, University of Colorado School of Medicine, Aurora, CO, United States
- Veterans Administration Eastern Colorado Health Care System, Denver, CO, United States
- Center for Women’s Health Research, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
- *Correspondence: Jane E. B. Reusch,
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30
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Nakatani Y, Maeda M, Matsumura M, Shimizu R, Banba N, Aso Y, Yasu T, Harasawa H. Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy. DIABETES & METABOLISM 2017. [PMID: 28648835 DOI: 10.1016/j.diabet.2017.05.009] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
AIM This study evaluated the effects of a glucagon-like peptide-1 receptor agonist on gastrointestinal (GI) tract motility and residue rates by examining GI transit time and lumen using capsule endoscopy. MATERIAL AND METHODS GI motility and lumen were assessed by capsule endoscopy before and after liraglutide administration in 14 patients with type 2 diabetes mellitus (T2DM). RESULTS Gastric transit time in the group with diabetic neuropathy (DN) was 1:12:36±1:04:30h before liraglutide administration and 0:48:40±0:32:52h after administration (nonsignificant difference, P=0.19). Gastric transit time in the non-DN group was 1:01:30±0:52:59h before administration and 2:33:29±1:37:24h after administration (significant increase, P=0.03). Duodenal and small intestine transit time in the DN group was 4:10:34±0:25:54h before and 6:38:42±3:52:42h after administration (not significant, P=0.09) and, in the non-DN group, 3:51:03±0:53:47h before and 6:45:31±2:41:36h after administration (significant increase, P=0.03). The GI residue rate in the DN group was 32.1±24% before administration and 90.0±9.1% after administration (significant increase, P<0.001), and increased in all patients; in the non-DN group, it was 32.1±35.3% before and 78.3±23.9% after administration (significant increase, P<0.001), and also increased in all patients. CONCLUSION Liraglutide causes delayed gastric emptying and inhibits duodenal and small intestine motility. However, these GI movement-inhibiting effects may be decreased or absent in patients with DN-associated dysautonomia.
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Affiliation(s)
- Y Nakatani
- Department of Diabetes and Endocrinology, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan.
| | - M Maeda
- Department of Gastroenterology, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan
| | - M Matsumura
- Department of Endocrinology and Metabolism, Dokkyo Medical University, 880, Kitakobayashi Shimotsugagun Mibumachi, 321-0293 Tochigi, Japan
| | - R Shimizu
- Department of Cardiovascular Medicine, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan
| | - N Banba
- Department of Diabetes and Endocrinology, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan
| | - Y Aso
- Department of Endocrinology and Metabolism, Dokkyo Medical University, 880, Kitakobayashi Shimotsugagun Mibumachi, 321-0293 Tochigi, Japan
| | - T Yasu
- Department of Cardiovascular Medicine, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan
| | - H Harasawa
- Department of Pulmonary Medicine, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan
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31
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Li J, Zheng J, Wang S, Lau HK, Fathi A, Wang Q. Cardiovascular Benefits of Native GLP-1 and its Metabolites: An Indicator for GLP-1-Therapy Strategies. Front Physiol 2017; 8:15. [PMID: 28194113 PMCID: PMC5276855 DOI: 10.3389/fphys.2017.00015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Accepted: 01/09/2017] [Indexed: 12/23/2022] Open
Abstract
Cardiovascular disease is a common co-morbidity and leading cause of death in patients with type 2 diabetes mellitus (T2DM). Glucagon-like peptide 1 (GLP-1) is a peptide hormone produced by intestinal L cells in response to feeding. Native GLP-1 (7-36) amide is rapidly degraded by diaminopeptidyl peptidase-4 (DPP4) to GLP-1 (9-36) amide, making 9-36a the major circulating form. While it is 7-36a, and not its metabolites, which exerts trophic effects on islet β-cells, recent studies suggest that both 7-36a and its metabolites have direct cardiovascular effects, including preserving cardiomyocyte viability, ameliorating cardiac function, and vasodilation. In particular, the difference in cardiovascular effects between 7-36a and 9-36a is attracting attention. Growing evidence has strengthened the presumption that their cardiovascular effects are overlapping, but distinct and complementary to each other; 7-36a exerts cardiovascular effects in a GLP-1 receptor (GLP-1R) dependent pathway, whereas 9-36a does so in a GLP-1R independent pathway. GLP-1 therapies have been developed using two main strategies: DPP4-resistant GLP-1 analogs/GLP-1R agonists and DPP4 inhibitors, which both aim to prolong the life-time of circulating 7-36a. One prominent concern that should be addressed is that the cardiovascular benefits of 9-36a are lacking in these strategies. This review attempts to differentiate the cardiovascular effects between 7-36a and 9-36a in order to provide new insights into GLP-1 physiology, and facilitate our efforts to develop a superior GLP-1-therapy strategy for T2DM and cardiovascular diseases.
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Affiliation(s)
- Junfeng Li
- Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Fudan UniversityShanghai, China; Department of Endocrinology, Renmin Hospital of Wuhan UniversityWuhan, China
| | - Juan Zheng
- Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's HospitalToronto, ON, Canada; Department of Physiology, Faculty of Medicine, University of TorontoToronto, ON, Canada
| | - Susanne Wang
- Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's HospitalToronto, ON, Canada; Department of Physiology, Faculty of Medicine, University of TorontoToronto, ON, Canada
| | - Harry K Lau
- Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's HospitalToronto, ON, Canada; Department of Physiology, Faculty of Medicine, University of TorontoToronto, ON, Canada
| | - Ali Fathi
- Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital Toronto, ON, Canada
| | - Qinghua Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Fudan UniversityShanghai, China; Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's HospitalToronto, ON, Canada; Department of Physiology, Faculty of Medicine, University of TorontoToronto, ON, Canada
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Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics. Sci Rep 2017; 7:39276. [PMID: 28098235 PMCID: PMC5241776 DOI: 10.1038/srep39276] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 11/21/2016] [Indexed: 12/14/2022] Open
Abstract
Pediatric restrictive cardiomyopathy (RCM) is a genetically heterogeneous heart disease with limited therapeutic options. RCM cases are largely idiopathic; however, even within families with a known genetic cause for cardiomyopathy, there is striking variability in disease severity. Although accumulating evidence implicates both gene expression and alternative splicing in development of dilated cardiomyopathy (DCM), there have been no detailed molecular characterizations of underlying pathways dysregulated in RCM. RNA-Seq on a cohort of pediatric RCM patients compared to other forms of adult cardiomyopathy and controls identified transcriptional differences highly common to the cardiomyopathies, as well as those unique to RCM. Transcripts selectively induced in RCM include many known and novel G-protein coupled receptors linked to calcium handling and contractile regulation. In-depth comparisons of alternative splicing revealed splicing events shared among cardiomyopathy subtypes, as well as those linked solely to RCM. Genes identified with altered alternative splicing implicate RBM20, a DCM splicing factor, as a potential mediator of alternative splicing in RCM. We present the first comprehensive report on molecular pathways dysregulated in pediatric RCM including unique/shared pathways identified compared to other cardiomyopathy subtypes and demonstrate that disruption of alternative splicing patterns in pediatric RCM occurs in the inverse direction as DCM.
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Cariou B. Pleiotropic effects of insulin and GLP-1 receptor agonists: Potential benefits of the association. DIABETES & METABOLISM 2016; 41:6S28-6S35. [PMID: 26774017 DOI: 10.1016/s1262-3636(16)30006-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The combination of basal insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is an emerging option for patients with type 2 diabetes (T2D). GLP-1RAs have been shown to improve glycaemic control with a low risk of hypoglycaemia and to promote body weight loss. However, GLP-1 receptors (GLP-1Rs) are widely expressed in extrapancreatic tissues and could sustain pleiotropic actions of GLP-1RAs beyond glycaemic control. The underlying molecular mechanisms maintaining these extrapancreatic actions of GLP-1 are complex, and involve GLP-1R signalling in both the brain and several peripheral tissues. The present review focuses specifically on the role of GLP-1RAs in the cardiovascular system and liver. Preclinical data in rodents and pilot studies in humans suggest that GLP-1RAs may have potential beneficial effects on heart function, blood pressure, postprandial lipaemia, liver steatosis and non-alcoholic steatohepatitis (NASH). Long-term studies are now warranted to determine the safety and clinical relevance of the association between insulin and GLP-1RAs in T2D.
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Affiliation(s)
- B Cariou
- Clinique d'Endocrinologie, l'institut du thorax, CHU de Nantes, Nantes, F-44000 France; INSERM, UMR1087, l'institut du thorax, Nantes, F-44000 France; Faculté de Médecine, Université de Nantes, Nantes, F-44000 France.
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Htike ZZ, Yates T, Brady EM, Webb D, Gray LJ, Swarbrick D, McCann GP, Khunti K, Davies MJ. Rationale and design of the randomised controlled trial to assess the impact of liraglutide on cardiac function and structure in young adults with type 2 diabetes (the LYDIA study). Cardiovasc Diabetol 2016; 15:102. [PMID: 27440110 PMCID: PMC4955217 DOI: 10.1186/s12933-016-0421-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Accepted: 07/06/2016] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The prevalence of type 2 diabetes (T2DM) in younger adults is growing. Compared to the late onset T2DM, it is well recognized that the disease tends to behave more aggressively in the younger age group with evidence of premature micro and macrovasular diseases and shorter life span. This increased mortality is largely attributed to cardiovascular complications. In a recent pilot study, young adults with T2DM were found to have significantly lower peak diastolic strain rate (PEDSR) on cardiac MRI (CMR), a forerunner of diabetic cardiomyopathy. Liraglutide, a glucagon like peptide-1 (GLP-1) analogue, is one of the new classes of glucose lowering therapies licensed to be used in management of T2DM. In randomised controlled trials, liraglutide improves glycaemic control by 1-1.5 % with an added benefit of weight loss of 2-3 kg. In addition, there is emerging evidence elucidating the cardioprotective effects of GLP-1 analogues independent of glycaemic control. In a small study, liraglutide has also been shown to improve cardiac function in patients with coronary ischaemia or congestive heart failure. METHODS AND AIMS This is a prospective, randomised, open-label, blind end-point (PROBE) active-comparator trial. A total of 90 obese eligible participants with T2DM (18-50 years) will be randomised to either liraglutide 1.8 mg once daily or sitagliptin 100 mg once daily for 26 weeks. The primary aim is to assess whether liraglutide improves diastolic function compared to sitagliptin as measured by PEDSR using CMR. DISCUSSION Although newer classes of GLP-1 analogues are made available in recent years, there are very few published studies demonstrating the beneficial effect of GLP-1 analogues on cardiovascular endpoints. In a recently published LEADER study, liraglutide has shown superiority to placebo in a population of type 2 diabetes with high risk of cardiovascular disease. To the best of our knowledge, there are no published studies establishing the effect of liraglutide on cardiac function in younger patients with T2DM on a larger scale. The LYDIA study will comprehensively describe changes in various parameters of cardiac structure and function in patients treated with liraglutide aiming to provide new evidence on effect of liraglutide on diastolic function in young obese people with T2DM. Trial Registration ClinicalTrials.gov identifier: NCT02043054.
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Affiliation(s)
- Z. Z. Htike
- />NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK and Health Sciences, University of Leicester, Leicester, UK
| | - T. Yates
- />NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK and Health Sciences, University of Leicester, Leicester, UK
| | - E. M. Brady
- />NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK and Health Sciences, University of Leicester, Leicester, UK
| | - D. Webb
- />NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK and Health Sciences, University of Leicester, Leicester, UK
| | - L. J. Gray
- />NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK and Health Sciences, University of Leicester, Leicester, UK
| | - D. Swarbrick
- />Department of Cardiovascular Sciences, Glenfield Hospital, University of Leicester, Leicester, UK
- />NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
| | - G. P. McCann
- />Department of Cardiovascular Sciences, Glenfield Hospital, University of Leicester, Leicester, UK
- />NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
| | - K. Khunti
- />NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK and Health Sciences, University of Leicester, Leicester, UK
| | - M. J. Davies
- />NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK and Health Sciences, University of Leicester, Leicester, UK
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Effect of liraglutide on physical performance in type 2 diabetes (LIPER2): A randomised, double-blind, controlled trial. Contemp Clin Trials Commun 2016; 4:46-51. [PMID: 29736469 PMCID: PMC5935879 DOI: 10.1016/j.conctc.2016.06.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 05/17/2016] [Accepted: 06/22/2016] [Indexed: 12/12/2022] Open
Abstract
Preclinical studies and small clinical trials suggest that glucagon-like peptide 1 (GLP1) may have a positive effect on ventricular function. Liraglutide is a GLP1-analogue used in the treatment of type 2 diabetes. LIPER2 is a phase IV, randomised, double-blind, placebo-controlled, parallel-design trial, assessing the effect of 6 months' liraglutide 1.8 mg/d on measures of cardiac function and physical performance in patients with type 2 diabetes. A total of 30 patients with type 2 diabetes will be included, if their HbA1c is between 7 and 10% while on oral agents (including metformin if tolerated and not contraindicated), a maximum of 2 intermediate or long-acting insulin injections per day or a combination of both. After their baseline examinations, patients are randomised to receive a daily subcutaneous liraglutide or placebo injection (titrated to 1.8 mg/d if tolerated) for 6 months. The primary end-point is the maximal oxygen consumption during cycle ergometry at the end of the study period. Other end-points include distance covered during a 6-min walk test, left ventricular ejection fraction and other measures of ventricular systolic and diastolic functions assessed by echocardiography, heart rate, blood pressure, pro-brain natriuretic peptide, C-reactive protein, HbA1c, lipids, apolipoprotein B, body weight and waist girth. Safety end-points include adverse event reporting, blood count, kidney and liver function, amylase, lipase, electrolytes, calcitonin, CA19.9 and pregnancy test for fertile women. At the time of this report, recruitment is still ongoing. Results are expected to be reported in December 2016.
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Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus - Mechanisms, Management, and Clinical Considerations. Circulation 2016; 133:2459-502. [PMID: 27297342 PMCID: PMC4910510 DOI: 10.1161/circulationaha.116.022194] [Citation(s) in RCA: 733] [Impact Index Per Article: 81.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes mellitus exacerbates mechanisms underlying atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control with currently available drugs or approaches. In the setting of multifactorial risk reduction with statins and other lipid-lowering agents, antihypertensive therapies, and antihyperglycemic treatment strategies, cardiovascular complication rates are falling, yet remain higher for patients with diabetes mellitus than for those without. This review considers the mechanisms, history, controversies, new pharmacological agents, and recent evidence for current guidelines for cardiovascular management in the patient with diabetes mellitus to support evidence-based care in the patient with diabetes mellitus and heart disease outside of the acute care setting.
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Affiliation(s)
- Cecilia C Low Wang
- From Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado School of Medicine, Aurora (C.C.L.); CPC Clinical Research, Aurora, CO (C.C.L., C.N.H., W.R.H.); Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (C.N.H., W.R.H.); Joslin Diabetes Center, and Harvard Medical School, Boston, MA (A.B.G.)
| | - Connie N Hess
- From Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado School of Medicine, Aurora (C.C.L.); CPC Clinical Research, Aurora, CO (C.C.L., C.N.H., W.R.H.); Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (C.N.H., W.R.H.); Joslin Diabetes Center, and Harvard Medical School, Boston, MA (A.B.G.)
| | - William R Hiatt
- From Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado School of Medicine, Aurora (C.C.L.); CPC Clinical Research, Aurora, CO (C.C.L., C.N.H., W.R.H.); Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (C.N.H., W.R.H.); Joslin Diabetes Center, and Harvard Medical School, Boston, MA (A.B.G.)
| | - Allison B Goldfine
- From Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado School of Medicine, Aurora (C.C.L.); CPC Clinical Research, Aurora, CO (C.C.L., C.N.H., W.R.H.); Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (C.N.H., W.R.H.); Joslin Diabetes Center, and Harvard Medical School, Boston, MA (A.B.G.).
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Kang YM, Jung CH. Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists. Endocrinol Metab (Seoul) 2016; 31:258-74. [PMID: 27118277 PMCID: PMC4923410 DOI: 10.3803/enm.2016.31.2.258] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 02/29/2016] [Accepted: 03/08/2016] [Indexed: 12/13/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP-1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP-1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes.
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Affiliation(s)
- Yu Mi Kang
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang Hee Jung
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Nauck MA, Abd El Aziz MS, Meier JJ. DPP-4-Hemmer und GLP-1-Rezeptor-Agonisten. DER DIABETOLOGE 2016; 12:184-194. [DOI: 10.1007/s11428-016-0083-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Robinson E, Tate M, Lockhart S, McPeake C, O'Neill KM, Edgar KS, Calderwood D, Green BD, McDermott BJ, Grieve DJ. Metabolically-inactive glucagon-like peptide-1(9-36)amide confers selective protective actions against post-myocardial infarction remodelling. Cardiovasc Diabetol 2016; 15:65. [PMID: 27079193 PMCID: PMC4832495 DOI: 10.1186/s12933-016-0386-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 04/07/2016] [Indexed: 12/19/2022] Open
Abstract
Background Glucagon-like peptide-1 (GLP-1) therapies are routinely used for glycaemic control in diabetes and their emerging cardiovascular actions have been a major recent research focus. In addition to GLP-1 receptor activation, the metabolically-inactive breakdown product, GLP-1(9–36)amide, also appears to exert notable cardiovascular effects, including protection against acute cardiac ischaemia. Here, we specifically studied the influence of GLP-1(9–36)amide on chronic post-myocardial infarction (MI) remodelling, which is a major driver of heart failure progression. Methods Adult female C57BL/6 J mice were subjected to permanent coronary artery ligation or sham surgery prior to continuous infusion with GLP-1(9–36)amide or vehicle control for 4 weeks. Results Infarct size was similar between groups with no effect of GLP-1(9–36)amide on MI-induced cardiac hypertrophy, although modest reduction of in vitro phenylephrine-induced H9c2 cardiomyoblast hypertrophy was observed. Whilst echocardiographic systolic dysfunction post-MI remained unchanged, diastolic dysfunction (decreased mitral valve E/A ratio, increased E wave deceleration rate) was improved by GLP-1(9–36)amide treatment. This was associated with modulation of genes related to extracellular matrix turnover (MMP-2, MMP-9, TIMP-2), although interstitial fibrosis and pro-fibrotic gene expression were unaltered by GLP-1(9–36)amide. Cardiac macrophage infiltration was also reduced by GLP-1(9–36)amide together with pro-inflammatory cytokine expression (IL-1β, IL-6, MCP-1), whilst in vitro studies using RAW264.7 macrophages revealed global potentiation of basal pro-inflammatory and tissue protective cytokines (e.g. IL-1β, TNF-α, IL-10, Fizz1) in the presence of GLP-1(9–36)amide versus exendin-4. Conclusions These data suggest that GLP-1(9–36)amide confers selective protection against post-MI remodelling via preferential preservation of diastolic function, most likely due to modulation of infiltrating macrophages, indicating that this often overlooked GLP-1 breakdown product may exert significant actions in this setting which should be considered in the context of GLP-1 therapy in patients with cardiovascular disease.
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Affiliation(s)
- Emma Robinson
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Mitchel Tate
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Samuel Lockhart
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Claire McPeake
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Karla M O'Neill
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Kevin S Edgar
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Danielle Calderwood
- School of Biological Sciences, Institute for Global Food Security, Queen's University Belfast, Belfast, BT9 5HN, UK
| | - Brian D Green
- School of Biological Sciences, Institute for Global Food Security, Queen's University Belfast, Belfast, BT9 5HN, UK
| | - Barbara J McDermott
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - David J Grieve
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
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Poudyal H. Mechanisms for the cardiovascular effects of glucagon-like peptide-1. Acta Physiol (Oxf) 2016; 216:277-313. [PMID: 26384481 DOI: 10.1111/apha.12604] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 07/25/2015] [Accepted: 09/10/2015] [Indexed: 12/16/2022]
Abstract
Over the past three decades, at least 10 hormones secreted by the enteroendocrine cells have been discovered, which directly affect the cardiovascular system through their innate receptors expressed in the heart and blood vessels or through a neural mechanism. Glucagon-like peptide-1 (GLP-1), an important incretin, is perhaps best studied of these gut-derived hormones with important cardiovascular effects. In this review, I have discussed the mechanism of GLP-1 release from the enteroendocrine L-cells and its physiological effects on the cardiovascular system. Current evidence suggests that GLP-1 has positive inotropic and chronotropic effects on the heart and may be important in preserving left ventricular structure and function by direct and indirect mechanisms. The direct effects of GLP-1 in the heart may be mediated through GLP-1R expressed in atria as well as arteries and arterioles in the left ventricle and mainly involve in the activation of multiple pro-survival kinases and enhanced energy utilization. There is also good evidence to support the involvement of a second, yet to be identified, GLP-1 receptor. Further, GLP-1(9-36)amide, which was previously thought to be the inactive metabolite of the active GLP-1(7-36)amide, may also have direct cardioprotective effects. GLP-1's action on GLP-1R expressed in the central nervous system, kidney, vasculature and the pancreas may indirectly contribute to its cardioprotective effects.
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Affiliation(s)
- H. Poudyal
- Department of Diabetes, Endocrinology and Nutrition; Graduate School of Medicine and Hakubi Centre for Advanced Research; Kyoto University; Kyoto Japan
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Suman RK, Borde MK, Mohanty IR, Maheshwari U, Deshmukh YA. Myocardial Salvaging Effects of Berberine in Experimental Diabetes Co-Existing with Myocardial Infarction. J Clin Diagn Res 2016; 10:FF13-8. [PMID: 27134894 DOI: 10.7860/jcdr/2016/15794.7459] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 12/16/2015] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Berberine, an isoquinoline alkaloid isolated from the Berberis aristata, has been shown to display a wide array of pharmacological activities (hypoglycaemic and hypolipidemic). AIM The present study was designed to investigate whether these pharmacological properties translate into the cardioprotective effects of Berberine in the setting of diabetes mellitus. MATERIALS AND METHODS Necessary approval from the Institutional Animal Ethics Committee was taken for the study. Experimental diabetes was produced with single dose of Streptozotocin (STZ): 45mg/kg ip and myocardial infarction was induced by administering Isoproterenol (ISP): 85mg/kg, sc to rats on 35(th) & 36(th) day. After the confirmation of diabetes on 7(th) day (>200mg/dl), Berberine (100 mg/kg) was administered orally to experimental rats from day 8 and continued for 30 days thereafter. Various anti-diabetic (Glucose, HbA1c), cardioprotective (CPK-MB), metabolic (lipid profile), safety {liver function (SGPT, kidney function (Creatinine)} and histopathological indices of injury were evaluated in Healthy Control, Diabetic Control and Berberine treated groups. RESULTS Administration of STZ-ISP resulted in a significant decrease in body weight (p<0.001), diabetic changes (increase in blood glucose, HbA1c), cardiac injury (leakage of myocardial CPK-MB), altered lipid profile, SGPT, creatinine levels (p<0.001) in the diabetic control group rats as compared to healthy control. Berberine treatment demonstrated significant antidiabetic as well as myocardial salvaging effects as indicated by restoration of blood glucose, HbA1c and CPK-MB levels (p<0.001) compared to diabetic control group. In addition, Berberine favourably modulated the lipid parameters (total cholesterol, triglycerides, HDL, LDL). Subsequent to ISP challenge, histopathological assessment of heart, pancreas and biochemical indices of injury confirmed the cardioprotective effects of Berberine in setting of diabetes. In addition, Berberine was found to be safe to the liver and kidney. CONCLUSION Berberine treatment produced myocardial salvaging effects in the setting of diabetes challenged with ISP induced myocardial necrosis. Cardioprotection may be attributed to anti-diabetic and hypolipidemic activities.
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Affiliation(s)
- Rajesh Kumar Suman
- Tutor, Department of Pharmacology, MGM Medical College , Navi Mumbai, India
| | - Manjusha K Borde
- Tutor, Department of Pharmacology, MGM Medical College , Navi Mumbai, India
| | - Ipseeta Ray Mohanty
- Professor, Department of Pharmacology, MGM Medical College , Navi Mumbai, India
| | - Ujwala Maheshwari
- Professor, Department of Pathology, MGM Medical College , Navi Mumbai, India
| | - Y A Deshmukh
- Professor and Head, Department of Pharmacology, MGM Medical College , Navi Mumbai, India
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Zhou Y, He X, Chen Y, Huang Y, Wu L, He J. Exendin-4 attenuates cardiac hypertrophy via AMPK/mTOR signaling pathway activation. Biochem Biophys Res Commun 2015; 468:394-9. [PMID: 26519882 DOI: 10.1016/j.bbrc.2015.09.179] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 09/29/2015] [Indexed: 12/29/2022]
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Irwin N, Flatt PR. New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders. World J Diabetes 2015; 6:1285-1295. [PMID: 26557956 PMCID: PMC4635139 DOI: 10.4239/wjd.v6.i15.1285] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 09/25/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
The applicability of stable gut hormones for the treatment of obesity-related diabetes is now undisputable. This is based predominantly on prominent and sustained glucose-lowering actions, plus evidence that these peptides can augment insulin secretion and pancreatic islet function over time. This review highlights the therapeutic potential of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), oxyntomodulin (OXM) and cholecystokinin (CCK) for obesity-related diabetes. Stable GLP-1 mimetics have already been successfully adopted into the diabetic clinic, whereas GIP, CCK and OXM molecules offer promise as potential new classes of antidiabetic drugs. Moreover, recent studies have shown improved therapeutic effects following simultaneous modulation of multiple receptor signalling pathways by combination therapy or use of dual/triple agonist peptides. However, timing and composition of injections may be important to permit interludes of beta-cell rest. The review also addresses the possible perils of incretin based drugs for treatment of prediabetes. Finally, the unanticipated utility of stable gut peptides as effective treatments for complications of diabetes, bone disorders, cognitive impairment and cardiovascular dysfunction is considered.
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Takahashi A, Ihara M, Yamazaki S, Asanuma H, Asakura M, Kitakaze M. Impact of Either GLP-1 Agonists or DPP-4 Inhibitors on Pathophysiology of Heart Failure. Int Heart J 2015; 56:372-6. [PMID: 26104180 DOI: 10.1536/ihj.15-028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Since diabetes mellitus (DM) is the most common cause of heart failure (HF), it is critically important to clarify whether incretin hormones including glucagon-like peptide-1 (GLP-1), which play an important role in blood glucose control, mediate cardioprotection. There are many lines of basic research evidence indicating that GLP-1 improves the pathophysiology of HF: In murine and canine HF models, either GLP-1 analogues or DPP-IV inhibitors improved cardiac functions. The first question that arises is how either GLP-1 analogues or DPP-IV inhibitors mediate cardioprotection. Cardiovascular diseases are tightly linked to impaired glucose tolerance (IGT): IGT is not only one of the causes of cardiovascular events but also the result of HF. Indeed, the treatment of IGT improved HF, showing that one of the mechanisms attributable to DPP-IV inhibitors is related to the improvement of IGT. Intriguingly, either DPP-IV inhibitors or GLP-1 analogues mediate cardioprotection even without IGT, suggesting two possible explanations: One is that GLP-1 analogues directly activate the prosurvival kinases, such as Akt and Erk1/2, and another is that DPP-IV inhibition increases cardioprotective peptides such as BNP and SDF-1α. The next question is whether cardioprotection is translated to clinical medicine. Small scale clinical trials proved their cardioprotective effects; however, several large scale clinical trials have not proved the beneficial effects of DPP-IV inhibitors. Taken together, GLP-1 analogues or DPP-IV inhibitors can mediate cardioprotection, however, what needs to be clarified is who mainly receives their benefits among the patients with cardiovascular diseases and/or DM.
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Affiliation(s)
- Ayako Takahashi
- Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center
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Abstract
Our translational research group focuses on addressing the problem of exercise defects in diabetes with basic research efforts in cell and rodent models and clinical research efforts in subjects with diabetes mellitus. CREB (cAMP-response-element-binding protein) regulates cellular differentiation of neurons, β-cells, adipocytes and smooth muscle cells; it is also a potent survival factor and an upstream regulator of mitochondrial biogenesis. In diabetes and cardiovascular disease, CREB protein content is decreased in the vascular media, and its regulation in aberrant in β-cells, neurons and cardiomyocytes. Loss of CREB content and function leads to decreased vascular target tissue resilience when exposed to stressors such as metabolic, oxidative or sheer stress. This basic research programme set the stage for our central hypothesis that diabetes-mediated CREB dysfunction predisposes the diabetes disease progression and cardiovascular complications. Our clinical research programme revealed that diabetes mellitus leads to defects in functional exercise capacity. Our group has determined that the defects in exercise correlate with insulin resistance, endothelial dysfunction, decreased cardiac perfusion and diastolic dysfunction, slowed muscle perfusion kinetics, decreased muscle perfusion and slowed oxidative phosphorylation. Combined basic and clinical research has defined the relationship between exercise and vascular function with particular emphasis on how the signalling to CREB and eNOS [endothelial NOS (nitric oxide synthase)] regulates tissue perfusion, mitochondrial dynamics, vascular function and exercise capacity. The present review summarizes our current working hypothesis that restoration of eNOS/NOS dysfunction will restore cellular homoeostasis and permit an optimal tissue response to an exercise training intervention.
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Monami M, Mannucci E. Dipeptidyl Peptidase-4 Inhibitors and Heart Failure: Friends or Foes? CURRENT CARDIOVASCULAR RISK REPORTS 2015. [DOI: 10.1007/s12170-015-0465-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix. Basic Res Cardiol 2015; 110:20. [PMID: 25725809 PMCID: PMC4344953 DOI: 10.1007/s00395-015-0476-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 02/22/2015] [Accepted: 02/23/2015] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits in experimental/clinical heart failure. We specifically investigated the role of the GLP-1 mimetic, exendin-4, in post-myocardial infarction (MI) remodelling, which is a key contributor to heart failure. Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior to infusion with exendin-4/vehicle for 4 weeks. Metabolic parameters and infarct sizes were comparable between groups. Exendin-4 protected against cardiac dysfunction and chamber dilatation post-MI and improved survival. Furthermore, exendin-4 modestly decreased cardiomyocyte hypertrophy/apoptosis but markedly attenuated interstitial fibrosis and myocardial inflammation post-MI. This was associated with altered extracellular matrix (procollagen IαI/IIIαI, connective tissue growth factor, fibronectin, TGF-β3) and inflammatory (IL-10, IL-1β, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3β and Smad2/3 signalling. Exendin-4 also altered macrophage response gene expression in the absence of direct actions on cardiac fibroblast differentiation, suggesting cardioprotective effects occurring secondary to modulation of inflammation. Our findings indicate that exendin-4 protects against post-MI remodelling via preferential actions on inflammation and the extracellular matrix independently of its established actions on glycaemic control, thereby suggesting that selective targeting of GLP-1 signalling may be required to realise its clear therapeutic potential for post-MI heart failure.
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Myat A, Arri S, Bhatt DL, Gersh BJ, Redwood SR, Marber MS. Design and rationale for the randomised, double-blinded, placebo-controlled Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) crossover study. Cardiovasc Diabetol 2015; 14:27. [PMID: 25848859 PMCID: PMC4358711 DOI: 10.1186/s12933-015-0193-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 02/07/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Glucagon-like peptide-1 is an incretin hormone essential for normal human glucose homeostasis. Expression of the glucagon-like peptide-1 receptor in the myocardium has fuelled growing interest in the direct and indirect cardiovascular effects of native glucagon-like peptide-1, its degradation product glucagon-like peptide-1(9-36), and the synthetic glucagon-like peptide-1 receptor agonists. Preclinical studies have demonstrated cardioprotective actions of all three compounds in the setting of experimental myocardial infarction and left ventricular systolic dysfunction. This has led to Phase 2 trials of native glucagon-like peptide-1 and incretin-based therapies in humans with and without Type 2 diabetes mellitus. These studies have demonstrated the ability of glucagon-like peptide-1, independent of glycaemic control, to positively modulate the metabolic and haemodynamic parameters of individuals with coronary artery disease and left ventricular systolic dysfunction. We aim to add to this growing body of evidence by studying the effect of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation. The hypothesis being liraglutide, a subcutaneously injectable glucagon-like peptide-1 receptor agonist, is able to improve exercise haemodynamics in patients with obstructive coronary artery disease when compared with saline placebo. METHODS AND DESIGN The Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) trial is an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological study. Primary endpoints are change in rate pressure product at 0.1 mV ST-segment depression and change in degree of ST-segment depression at peak exercise during sequential exercise tolerance testing performed over a 6-week study period in which 26 patients will be randomised to either liraglutide or saline with crossover to the opposing regimen at week 3. DISCUSSION The study will be conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The local Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency have approved the study. TRIAL REGISTRATION National Institute of Health Research Clinical Research Network (NIHR CRN) Portfolio ID 11112 and ClinicalTrials.gov Identifier NCT02315001.
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Affiliation(s)
- Aung Myat
- />King’s College London British Heart Foundation Centre of Research Excellence, The Rayne Institute, Cardiovascular Division, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH UK
| | - Satpal Arri
- />King’s College London British Heart Foundation Centre of Research Excellence, The Rayne Institute, Cardiovascular Division, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH UK
| | - Deepak L Bhatt
- />Brigham and Women’s Hospital Heart & Vascular Centre and Harvard Medical School, Boston, MA 02115 USA
| | - Bernard J Gersh
- />Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905 USA
| | - Simon R Redwood
- />King’s College London British Heart Foundation Centre of Research Excellence, The Rayne Institute, Cardiovascular Division, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH UK
| | - Michael S Marber
- />King’s College London British Heart Foundation Centre of Research Excellence, The Rayne Institute, Cardiovascular Division, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH UK
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Advani A, Bugyei-Twum A, Connelly KA. Cardiovascular effects of incretins in diabetes. Can J Diabetes 2015; 37:309-14. [PMID: 24500557 DOI: 10.1016/j.jcjd.2013.06.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 06/26/2013] [Accepted: 06/27/2013] [Indexed: 12/24/2022]
Abstract
Recent years have seen an enormous increase in the number of therapeutic agents available for lowering blood glucose levels in people with type 2 diabetes. Among these agents, the incretin mimetics glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors have received particular attention for the potential of these interventions to positively impact on cardiovascular outcomes. Although the results of large-scale cardiovascular outcome trials eagerly are anticipated, an increasing body of literature from preclinical and early phase clinical studies has indicated that both GLP-1R agonists and DPP4 inhibitors may exert glucose-independent cardiovascular effects. Despite its role in glucose homeostasis, the GLP-1R is surprisingly widely distributed throughout the body, including in the heart. GLP-1 may exert its effects through both receptor-dependent and receptor-independent mechanisms and through the actions of both the intact peptide and its metabolites. In addition, DPP4 inhibition not only augments the circulating levels of incretin hormones, but it also holds the capacity to augment the activity of other biologically important substrates, most notably the small protein stromal cell-derived factor 1 alpha. Whether these collective functions will act to reduce cardiovascular events in patients remains to be determined.
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Affiliation(s)
- Andrew Advani
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital and University of Toronto, Ontario, Canada
| | - Antoinette Bugyei-Twum
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital and University of Toronto, Ontario, Canada
| | - Kim A Connelly
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital and University of Toronto, Ontario, Canada.
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Abstract
The Banting Medal for Scientific Achievement is the highest scientific award of the American Diabetes Association (ADA). Given in memory of Sir Frederick Banting, one of the key investigators in the discovery of insulin, the Banting Medal is awarded annually for scientific excellence, recognizing significant long-term contributions to the understanding, treatment, or prevention of diabetes. Daniel J. Drucker, MD, of the Department of Medicine, Mount Sinai Hospital and the Lunenfeld-Tanenbaum Research Institute in Toronto, Ontario, Canada, received the prestigious award at the ADA's 74th Scientific Sessions, 13-17 June 2014, in San Francisco, California. He presented the Banting Lecture, "Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation," on Sunday, 15 June 2014.Gut peptides convey nutrient-regulated signals to the enteric nervous system and to distal organs, acting as circulating hormones secreted in the basal and postprandial state. Here I provide an overview of the actions of glucagon-like peptide (GLP)-1 and GLP-2, the two major enteroendocrine L-cell peptides. The endogenous physiological actions of GLP-1 have been delineated using antagonists and Glp1r(-/-) mice and include the control of islet hormone secretion in a glucose-dependent manner, leading to improvement of fasting and postprandial glucose homeostasis. GLP-1 receptors (GLP-1Rs) are also widely distributed in multiple extrapancreatic organs, providing a mechanistic explanation for the nonglycemic actions attributed to GLP-1. The multiple metabolic actions of GLP-1 enable reduction of glycemia and body weight in diabetic and obese subjects, providing the opportunity to reduce glycemia in human subjects with diabetes with a low risk of hypoglycemia. GLP-2 plays a key role in the control of energy absorption and in the integrity of the intestinal mucosa, and a GLP-2R agonist, teduglutide, is now used for augmentation of energy absorption in parenteral nutrition-dependent subjects with short bowel syndrome. GLP-1 and GLP-2 are both cleaved by dipeptidyl peptidase-4 (DPP-4); hence, inhibition of DPP-4 activity enables yet another pathway for potentiation of incretin action and the therapy for type 2 diabetes. Here I review our 30-year experience with the elucidation of gut hormone action and, wherever possible, highlight therapeutic implications of our preclinical studies and future opportunities for incretin research.
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Affiliation(s)
- Daniel J Drucker
- Department of Medicine, Mount Sinai Hospital and the Lunenfeld-Tanenbaum Research Institute, University of Toronto, Toronto, Ontario, Canada
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