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Zarei M, Sahebi Vaighan N, Farjoo MH, Talebi S, Zarei M. Incretin-based therapy: a new horizon in diabetes management. J Diabetes Metab Disord 2024; 23:1665-1686. [PMID: 39610543 PMCID: PMC11599551 DOI: 10.1007/s40200-024-01479-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 07/22/2024] [Indexed: 11/30/2024]
Abstract
Diabetes mellitus, a metabolic syndrome characterized by hyperglycemia and insulin dysfunction, often leads to serious complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Incretins, gut peptide hormones released post-nutrient intake, have shown promising therapeutic effects on these complications due to their wide-ranging biological impacts on various body systems. This review focuses on the role of incretin-based therapies, particularly Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, in managing diabetes and its complications. We also discuss the potential of novel agents like semaglutide, a recently approved oral compound, and dual/triple agonists targeting GLP-1/GIP, GLP-1/glucagon, and GLP-1/GIP/glucagon receptors, which are currently under investigation. The review aims to provide a comprehensive understanding of the beneficial impacts of natural incretins and the therapeutic potential of incretin-based therapies in diabetes management.
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Affiliation(s)
- Malek Zarei
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Navideh Sahebi Vaighan
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hadi Farjoo
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soosan Talebi
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Zarei
- Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
- John B. Little Center for Radiation Sciences, Harvard T.H Chan School of Public Health, Boston, MA USA
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Jang KW, Hur J, Lee DW, Kim SR. Metabolic Syndrome, Kidney-Related Adiposity, and Kidney Microcirculation: Unraveling the Damage. Biomedicines 2024; 12:2706. [PMID: 39767613 PMCID: PMC11673429 DOI: 10.3390/biomedicines12122706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/24/2024] [Accepted: 11/25/2024] [Indexed: 01/03/2025] Open
Abstract
Metabolic syndrome (MetS) is a cluster of interrelated risk factors, including insulin resistance, hypertension, dyslipidemia, and visceral adiposity, all of which contribute to kidney microvascular injury and the progression of chronic kidney disease (CKD). However, the specific impact of each component of MetS on kidney microcirculation remains unclear. Given the increasing prevalence of obesity, understanding how visceral fat-particularly fat surrounding the kidneys-affects kidney microcirculation is critical. This review examines the consequences of visceral obesity and other components of MetS on renal microcirculation. These kidney-related fat deposits can contribute to the mechanical compression of renal vasculature, promote inflammation and oxidative stress, and induce endothelial dysfunction, all of which accelerate kidney damage. Each factor of MetS initiates a series of hemodynamic and metabolic disturbances that impair kidney microcirculation, leading to vascular remodeling and microvascular rarefaction. The review concludes by discussing therapeutic strategies targeting the individual components of MetS, which have shown promise in alleviating inflammation and oxidative stress. Integrated approaches that address both of the components of MetS and kidney-related adiposity may improve renal outcomes and slow the progression of CKD.
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Affiliation(s)
- Kyu Won Jang
- Division of Nephrology and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (K.W.J.); (J.H.); (D.W.L.)
| | - Jin Hur
- Division of Nephrology and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (K.W.J.); (J.H.); (D.W.L.)
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Dong Won Lee
- Division of Nephrology and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (K.W.J.); (J.H.); (D.W.L.)
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Seo Rin Kim
- Division of Nephrology and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (K.W.J.); (J.H.); (D.W.L.)
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
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Yanai H, Adachi H, Hakoshima M, Katsuyama H. Glucagon-Like Peptide 1 Receptor Agonists Versus Sodium-Glucose Cotransporter 2 Inhibitors for Atherosclerotic Cardiovascular Disease in Patients With Type 2 Diabetes. Cardiol Res 2023; 14:12-21. [PMID: 36896226 PMCID: PMC9990545 DOI: 10.14740/cr1459] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 02/11/2023] [Indexed: 02/27/2023] Open
Abstract
Beyond improving hemoglobin A1c (HbA1c) in adults with type 2 diabetes, glucagon-like peptide 1 receptor agonists (GLP-1RA) have been approved for reducing risk of major adverse cardiovascular events (MACE) with established cardiovascular disease (CVD) or multiple CV risk factors. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) also reduced the risk for the primary composite CV outcome in patients with type 2 diabetes at high risk for CV events. In the American Diabetes Association (ADA) and European Association of Study in Diabetes (EASD) consensus report 2022, there is the description "In people with established atherosclerotic CVD (ASCVD) or with a high risk for ASCVD, GLP-1RA were prioritized over SGLT2i"; however, the evidence supporting such statement is limited. Therefore, we studied the superiority of GLP-1RA over SGLT2i for prevention of ASCVD from various viewpoints. We could not find a meaningful difference in the risk reduction in three-point MACE (3P-MACE), mortality due to any cause, mortality due to CV cause and nonfatal myocardial infarction between GLP-1RA and SGLT2i trials. The risk of nonfatal stroke decreased in all five GLP-1RA trials; however, two of three SGLT2i trials showed an increase in risk of nonfatal stroke. The risk of hospitalization for heart failure (HHF) decreased in all three SGLT2i trials, and one GLP-1RA trial showed an increase in risk of HHF. The risk reduction of HHF in SGLT2i trials was greater than that in GLP-1RA trials. These findings were consistent with current systematic reviews and meta-analyses. The risk reduction of 3P-MACE was significantly and negatively correlated with changes in HbA1c (R = -0.861, P = 0.006) and body weight (R = -0.895, P = 0.003) in GLP-1RA and SGLT2i trials. The studies using SGLT2i failed to reduce carotid intima media thickness (cIMT), the surrogate marker for atherosclerosis; however, several studies using GLP-1RA successfully reduced cIMT in patients with type 2 diabetes. Compared with SGLT2i, GLP-1RA had a higher probability of decreasing serum triglyceride. GLP-1RA have multiple vascular biological anti-atherogenic properties.
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Affiliation(s)
- Hidekatsu Yanai
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
| | - Hiroki Adachi
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
| | - Mariko Hakoshima
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
| | - Hisayuki Katsuyama
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
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4
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Lin DSH, Yu AL, Lo HY, Lien CW, Lee JK, Chen WJ. Major adverse cardiovascular and limb events in people with diabetes treated with GLP-1 receptor agonists vs SGLT2 inhibitors. Diabetologia 2022; 65:2032-2043. [PMID: 35945333 DOI: 10.1007/s00125-022-05772-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 05/16/2022] [Indexed: 01/11/2023]
Abstract
AIMS/HYPOTHESIS This study aimed to assess the real-world outcomes of people with diabetes mellitus treated with glucagon-like peptide-1 receptor agonists (GLP1RAs) compared with those treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) in terms of major adverse cardiovascular and limb events. Peripheral artery disease is a common cause of morbidity in people with diabetes. Previous cardiovascular outcome trials have demonstrated the benefits of GLP1RAs and SGLT2is for reducing various cardiovascular events, but the safety and efficacy of these drugs on limb outcomes remain subject to debate and ambiguity. METHODS A retrospective cohort study was conducted in which data were collected from the Taiwan National Health Insurance Research Database. In total, 379,256 individuals with diabetes receiving either GLP1RA or SGLT2i with treatment initiated between 1 May 2016 and 31 December 2019 were identified. The primary outcome was major adverse limb events (MALE), defined as the composite of newly diagnosed critical limb ischaemia, percutaneous transluminal angioplasty or peripheral bypass for peripheral artery disease, and non-traumatic amputation. The secondary outcome was major adverse cardiac events, which was a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke. Other examined outcomes included death from any cause and hospitalisation for heart failure. Propensity score matching was performed at a 1:4 ratio between the GLP1RA and SGLT2i groups to mitigate possible selection bias. RESULTS A total of 287,091 patients were eligible for analysis, with 81,152 patients treated with SGLT2i and 20,288 patients treated with GLP1RA after matching. The incidence of MALE was significantly lower in the GLP1RA group than in the SGLT2i group (3.6 vs 4.5 events per 1000 person-years; subdistribution HR 0.80; 95% CI 0.67, 0.96), primarily due to a lower incidence of critical limb ischaemia. The reduced risks of MALE associated with GLP1RA use were particularly noticeable in people with diabetic peripheral neuropathy (subdistribution HR 0.66 vs 1.11; p for interaction 0.006). CONCLUSIONS/INTERPRETATION In people with diabetes, GLP1RA use was associated with significantly reduced risks of MALE compared with SGLT2i within the first 2 years after initiation, especially among people with diabetic neuropathy.
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Affiliation(s)
- Donna Shu-Han Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - An-Li Yu
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Hao-Yun Lo
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Wei Lien
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jen-Kuang Lee
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
- Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
- Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan.
- Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan.
| | - Wen-Jone Chen
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Emergency, National Taiwan University College of Medicine, Taipei, Taiwan
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Mišúth S, Uhrinová M, Klimas J, Vavrincová-Yaghi D, Vavrinec P. Vildagliptin improves vascular smooth muscle relaxation and decreases cellular senescence in the aorta of doxorubicin-treated rats. Vascul Pharmacol 2021; 138:106855. [PMID: 33744414 DOI: 10.1016/j.vph.2021.106855] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/24/2021] [Accepted: 03/14/2021] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Doxorubicin (DOX) is a chemotherapeutic agent used in cancer treatment. Its use is limited by later toxicity to the cardiovascular system (CVS). Cellular senescence has been proposed as one mechanism of DOX toxicity. It has also been suggested that senescence reduction can improve the condition in many pathologies. We hypothesised that vildagliptin treatment can reduce senescence and thus improve the relaxation of vascular smooth muscle (VSM) in the aorta of a rat DOX model. METHODS The rats received DOX and were treated with vildagliptin for 6 weeks. Thereafter, the rats were sacrificed, and the aorta prepared for measurements of VSM relaxation and RNA isolation to detect the level of senescence markers. To further prove the antisenescence effect of the main vildagliptin effector glucagon-like peptide 1(GLP-1), VSM cells (VSMCs) were incubated with DOX and treated with GLP-1. Subsequently, senescence was detected by senescence-associated beta-galactosidase (SA-β-gal) and by the presence of senescence markers. RESULTS DOX in rats caused diminished relaxation of VSM to sodium nitrate and caused an increase in the senescence mRNA markers p16Ink4a and p27Kip1 and the senescence-associated secretory phenotype (SASP) IL-6 and IL-8. Vildagliptin treatment led to improved relaxation and a reduction in senescence and SASP markers. Furthermore, in VSMCs DOX increased SA-β-gal activity, p16Ink4a, p27Kip1, IL-6 and IL-8, and GLP1 treatment led to a decrease of both senescence and SASP markers. CONCLUSION In summary we conclude that vildagliptin can reduce senescence and improve relaxation of vascular smooth muscle in the aorta of DOX-treated rats, and GLP-1 can reduce senescence of DOX-treated VSMCs. These data suggest that incretin-based drugs are promising candidates for patients suffering from late doxorubicin cardiovascular toxicity.
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MESH Headings
- Animals
- Antibiotics, Antineoplastic/toxicity
- Aorta/drug effects
- Aorta/metabolism
- Aorta/pathology
- Aorta/physiopathology
- Cell Proliferation/drug effects
- Cells, Cultured
- Cellular Senescence/drug effects
- Cyclin-Dependent Kinase Inhibitor p16/metabolism
- Cyclin-Dependent Kinase Inhibitor p27/metabolism
- Doxorubicin/toxicity
- Glucagon-Like Peptide 1/pharmacology
- Incretins/pharmacology
- Interleukin-6/metabolism
- Interleukin-8/metabolism
- Male
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/physiopathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Rats, Wistar
- Signal Transduction
- Vascular Remodeling/drug effects
- Vasodilation/drug effects
- Vildagliptin/pharmacology
- Rats
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Affiliation(s)
- Svetozár Mišúth
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Marína Uhrinová
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Ján Klimas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Diana Vavrincová-Yaghi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Peter Vavrinec
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia.
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Bjørnholm KD, Skovsted GF, Mitgaard-Thomsen A, Rakipovski G, Tveden-Nyborg P, Lykkesfeldt J, Povlsen GK. Liraglutide treatment improves endothelial function in the Ldlr-/- mouse model of atherosclerosis and affects genes involved in vascular remodelling and inflammation. Basic Clin Pharmacol Toxicol 2021; 128:103-114. [PMID: 32896073 DOI: 10.1111/bcpt.13486] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 08/12/2020] [Accepted: 08/31/2020] [Indexed: 12/29/2022]
Abstract
Recent clinical intervention studies have shown that the GLP1 analogue liraglutide lowers cardiovascular risk, but the underlying mechanism has not yet been fully elucidated. This study investigated the effects of liraglutide on endothelial function in the Ldlr-/- mouse model. Mice (n = 12/group) were fed Western diet (WD) or chow for 12 weeks followed by 4 weeks of treatment with liraglutide (1 mg/kg/day) or vehicle subcutaneously. Weight loss, blood lipid content, plaque burden, vasomotor function of the aorta and gene expression pattern in aorta and brachiocephalic artery were monitored. Liraglutide treatment significantly induced weight loss (P < .0001), decreased blood triglycerides (P < .0001) and total cholesterol (P < .0001) in WD-fed mice but did not decrease plaque burden. Liraglutide also improved endothelium-mediated dilation of the distal thoracis aorta (P = .0067), but it did not affect phenylephrine or sodium nitroprusside responses. Fluidigm analyses of 96 genes showed significantly altered expression of seven genes related to inflammation, vascular smooth muscle cells and extracellular matrix composition in liraglutide-treated animals. We conclude that treatment with liraglutide decreased endothelial dysfunction and that this could be linked to decreased inflammation or regulation of vascular remodelling.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Aorta, Thoracic/drug effects
- Aorta, Thoracic/metabolism
- Aorta, Thoracic/pathology
- Aorta, Thoracic/physiopathology
- Atherosclerosis/drug therapy
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Atherosclerosis/physiopathology
- Disease Models, Animal
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Endothelium, Vascular/physiopathology
- Gene Expression Regulation
- Inflammation/metabolism
- Inflammation/pathology
- Inflammation/physiopathology
- Inflammation/prevention & control
- Liraglutide/pharmacology
- Male
- Mice, Knockout
- Plaque, Atherosclerotic
- Receptors, LDL/genetics
- Receptors, LDL/metabolism
- Signal Transduction
- Vascular Remodeling/drug effects
- Vasodilation/drug effects
- Mice
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Affiliation(s)
- Katrine Dahl Bjørnholm
- Department of Experimental Animal Models, University of Copenhagen, Frederiksberg, Denmark
- Department of Cardiovascular Disease Research, Novo Nordisk, Måløv, Denmark
| | - Gry Freja Skovsted
- Department of Experimental Animal Models, University of Copenhagen, Frederiksberg, Denmark
| | | | - Günaj Rakipovski
- Department of Cardiovascular Disease Research, Novo Nordisk, Måløv, Denmark
| | - Pernille Tveden-Nyborg
- Department of Experimental Animal Models, University of Copenhagen, Frederiksberg, Denmark
| | - Jens Lykkesfeldt
- Department of Experimental Animal Models, University of Copenhagen, Frederiksberg, Denmark
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Huang L, Lin T, Shi M, Chen X, Wu P. Liraglutide suppresses production of extracellular matrix proteins and ameliorates renal injury of diabetic nephropathy by enhancing Wnt/β-catenin signaling. Am J Physiol Renal Physiol 2020; 319:F458-F468. [PMID: 32715762 DOI: 10.1152/ajprenal.00128.2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The Wnt/β-catenin signaling pathway is involved in production of the extracellular matrix (ECM) by mesangial cells (MCs). Recent studies by us and others have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have protective effects against diabetic nephropathy. The purpose of the present study was to investigate whether the Wnt/β-catenin signaling in MCs contributes to GLP-1RA-induced inhibition of ECM accumulation and mitigation of glomerular injury in diabetic nephropathy. In cultured human mesangial cells, liraglutide (a GLP-1RA) treatment significantly reduced high glucose (HG)-stimulated production of fibronectin, collagen type IV, and α-smooth muscle actin, and the liraglutide effects were significantly attenuated by XAV-939, a selective inhibitor of Wnt/β-catenin signaling. Furthermore, HG treatment significantly decreased protein abundance of Wnt4, Wnt5a, phospho-glycogen synthase kinase-3β, and β-catenin. These HG effects on Wnt/β-catenin signaling proteins were significantly blunted by liraglutide treatment. For in vivo experiments, we administered liraglutide (200 μg·kg-1·12 h-1) by subcutaneous injection to streptozocin-induced type 1 diabetic rats for 8 wk. Administration of liraglutide significantly improved elevated blood urine nitrogen, serum creatinine, and urinary albumin excretion rate and alleviated renal hypertrophy, mesangial expansion, and glomerular fibrosis in type 1 diabetic rats, whereas blood glucose level and body weight did not have significant changes. Consistent with the in vitro experiments, liraglutide treatment significantly reduced the diabetes-induced increases in glomerular fibronectin, collagen type IV, and α-smooth muscle actin and decreases in glomerular Wnt/β-catenin signaling proteins. These results suggest that liraglutide alleviated glomerular ECM accumulation and renal injury in diabetic nephropathy by enhancing Wnt/β-catenin signaling.
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Affiliation(s)
- Linjing Huang
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Diabetes Research Institute of Fujian Province, Fuzhou, Fujian, China
| | - Tingting Lin
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Diabetes Research Institute of Fujian Province, Fuzhou, Fujian, China
| | - Meizhen Shi
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Diabetes Research Institute of Fujian Province, Fuzhou, Fujian, China
| | - Xiuqing Chen
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Diabetes Research Institute of Fujian Province, Fuzhou, Fujian, China
| | - Peiwen Wu
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Diabetes Research Institute of Fujian Province, Fuzhou, Fujian, China
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Tentolouris A, Eleftheriadou I, Tzeravini E, Tsilingiris D, Paschou SA, Siasos G, Tentolouris N. Endothelium as a Therapeutic Target in Diabetes Mellitus: From Basic Mechanisms to Clinical Practice. Curr Med Chem 2020; 27:1089-1131. [PMID: 30663560 DOI: 10.2174/0929867326666190119154152] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/28/2018] [Accepted: 01/09/2019] [Indexed: 12/12/2022]
Abstract
Endothelium plays an essential role in human homeostasis by regulating arterial blood pressure, distributing nutrients and hormones as well as providing a smooth surface that modulates coagulation, fibrinolysis and inflammation. Endothelial dysfunction is present in Diabetes Mellitus (DM) and contributes to the development and progression of macrovascular disease, while it is also associated with most of the microvascular complications such as diabetic retinopathy, nephropathy and neuropathy. Hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia are the main factors involved in the pathogenesis of endothelial dysfunction. Regarding antidiabetic medication, metformin, gliclazide, pioglitazone, exenatide and dapagliflozin exert a beneficial effect on Endothelial Function (EF); glimepiride and glibenclamide, dipeptidyl peptidase-4 inhibitors and liraglutide have a neutral effect, while studies examining the effect of insulin analogues, empagliflozin and canagliflozin on EF are limited. In terms of lipid-lowering medication, statins improve EF in subjects with DM, while data from short-term trials suggest that fenofibrate improves EF; ezetimibe also improves EF but further studies are required in people with DM. The effect of acetylsalicylic acid on EF is dose-dependent and lower doses improve EF while higher ones do not. Clopidogrel improves EF, but more studies in subjects with DM are required. Furthermore, angiotensin- converting-enzyme inhibitors /angiotensin II receptor blockers improve EF. Phosphodiesterase type 5 inhibitors improve EF locally in the corpus cavernosum. Finally, cilostazol exerts favorable effect on EF, nevertheless, more data in people with DM are required.
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Affiliation(s)
- Anastasios Tentolouris
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Ioanna Eleftheriadou
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Evangelia Tzeravini
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Dimitrios Tsilingiris
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Stavroula A Paschou
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Gerasimos Siasos
- First Department of Cardiology, Hippokration Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Nikolaos Tentolouris
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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9
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Triggle CR, Ding H, Marei I, Anderson TJ, Hollenberg MD. Why the endothelium? The endothelium as a target to reduce diabetes-associated vascular disease. Can J Physiol Pharmacol 2020; 98:415-430. [PMID: 32150686 DOI: 10.1139/cjpp-2019-0677] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Over the past 66 years, our knowledge of the role of the endothelium in the regulation of cardiovascular function and dysfunction has advanced from the assumption that it is a single layer of cells that serves as a barrier between the blood stream and vascular smooth muscle to an understanding of its role as an essential endocrine-like organ. In terms of historical contributions, we pay particular credit to (1) the Canadian scientist Dr. Rudolf Altschul who, based on pathological changes in the appearance of the endothelium, advanced the argument in 1954 that "one is only as old as one's endothelium" and (2) the American scientist Dr. Robert Furchgott, a 1998 Nobel Prize winner in Physiology or Medicine, who identified the importance of the endothelium in the regulation of blood flow. This review provides a brief history of how our knowledge of endothelial function has advanced and now recognize that the endothelium produces a plethora of signaling molecules possessing paracrine, autocrine, and, arguably, systemic hormone functions. In addition, the endothelium is a therapeutic target for the anti-diabetic drugs metformin, glucagon-like peptide I (GLP-1) receptor agonists, and inhibitors of the sodium-glucose cotransporter 2 (SGLT2) that offset the vascular disease associated with diabetes.
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Affiliation(s)
- Chris R Triggle
- Departments of Pharmacology and Medical Education, Weill Cornell Medical College, Doha, Qatar
| | - Hong Ding
- Departments of Pharmacology and Medical Education, Weill Cornell Medical College, Doha, Qatar
| | - Isra Marei
- Departments of Pharmacology and Medical Education, Weill Cornell Medical College, Doha, Qatar
| | - Todd J Anderson
- Department of Cardiac Sciences and Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada
| | - Morley D Hollenberg
- Inflammation Research Network, Snyder Institute for Chronic Disease, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada.,Department of Physiology and Pharmacology, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada.,Department of Medicine, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada
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Incretin Hormones: The Link between Glycemic Index and Cardiometabolic Diseases. Nutrients 2019; 11:nu11081878. [PMID: 31412576 PMCID: PMC6724226 DOI: 10.3390/nu11081878] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 08/07/2019] [Accepted: 08/08/2019] [Indexed: 01/01/2023] Open
Abstract
This review aimed to describe the potential mechanisms by which incretin hormones could mediate the relationship between glycemic index and cardiometabolic diseases. A body of evidence from many studies suggests that low glycemic index (GI) diets reduces the risk for type 2 diabetes and coronary heart disease. In fact, despite the extensive literature on this topic, the mechanisms underlying unfavorable effects of high GI foods on health remain not well defined. The postprandial and hormonal milieu could play a key role in the relationship between GI and cardiovascular risk. Incretin hormones, glucagon-like peptide1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important regulators of postprandial homeostasis by amplifying insulin secretory responses. Response of GIP and GLP-1 to GI have been studied more in depth, also by several studies on isomaltulose, which have been taken as an ideal model to investigate the kinetics of incretin secretion in response to foods’ GI. In addition, extrapancreatic effects of these incretin hormones were also recently observed. Emerging from this have been exciting effects on several targets, such as body weight regulation, lipid metabolism, white adipose tissue, cardiovascular system, kidney, and liver, which may importantly affect the health status.
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11
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Garczorz W, Gallego-Colon E, Kosowska A, Kłych-Ratuszny A, Woźniak M, Marcol W, Niesner KJ, Francuz T. Exenatide exhibits anti-inflammatory properties and modulates endothelial response to tumor necrosis factor α-mediated activation. Cardiovasc Ther 2018; 36. [PMID: 29283509 DOI: 10.1111/1755-5922.12317] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 11/30/2017] [Accepted: 12/20/2017] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Cardiovascular disease is the main cause of mortality and morbidity in the industrialized world. Incretin-mimetic compounds such as exenatide are currently used in the treatment of type 2 diabetes. AIMS We investigated the effects of incretin drugs on apoptosis, adhesion molecule expression, and concentration of extracellular matrix (ECM) metalloproteinases under inflammatory conditions within the context of atherosclerotic plaque formation of both human coronary artery endothelial cells (hCAECs) and human aortic endothelial cells (hAoECs). TNF-α-stimulated hCAEC and hAoEC were treated with exenatide (1 and 10 nmol/L) and GLP-1 (10 and 100 nmol/L) then evaluated for caspase 3/7 activity and assayed for protein levels of adhesion molecules sICAM-1, sVCAM-1, and P-selectin. Concentrations of matrix metalloproteinases (MMPs) MMP-1, MMP-2, MMP-9, and their inhibitors-tissue inhibitor of metalloproteinases (TIMPs), TIMP-1, TIMP-2 were also measured to evaluate the effects on extracellular matrix turnover within an inflammatory environment. Intracellular signaling pathways were evaluated via transfection of endothelial cells with a GFP vector under the NF-κB promoter. RESULTS Our experimental data suggest that GLP-1 receptor (GLP-1R) agonists downregulate activation of NF-κB and adhesion molecules ICAM and VCAM, but not P-selectin, in both endothelial cell lines. Exendin-4 and GLP-1 modulate the expression of MMPs and TIMPs, with statistically significant effects observed at high concentrations of both incretins. Expressive modulation may be mediated by NF-κB as observed by activation of the vector when stimulated under inflammatory conditions. CONCLUSION These findings indicate that GLP-1 analogs have anti-inflammatory properties in endothelial cells that may play an important role in preventing atherosclerosis.
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Affiliation(s)
- Wojciech Garczorz
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Enrique Gallego-Colon
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Agnieszka Kosowska
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Agnieszka Kłych-Ratuszny
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Michał Woźniak
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Wiesław Marcol
- Department of Physiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - K J Niesner
- College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Tomasz Francuz
- Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
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Nomoto H, Kimachi K, Miyoshi H, Kameda H, Cho KY, Nakamura A, Nagai S, Kondo T, Atsumi T. Effects of 50 mg vildagliptin twice daily vs. 50 mg sitagliptin once daily on blood glucose fluctuations evaluated by long-term self-monitoring of blood glucose. Endocr J 2017; 64:417-424. [PMID: 28260702 DOI: 10.1507/endocrj.ej16-0546] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
To date, several clinical trials have compared differences in glucose fluctuation observed with dipeptidyl peptidase-4 inhibitor treatment in patients with type 2 diabetes mellitus. However, most patients were assessed for limited periods or during hospitalization. The aim of the present study was to evaluate the effects of switching from sitagliptin to vildagliptin, or vice versa, on 12-week glucose fluctuations using self-monitoring of blood glucose in the standard care setting. We conducted a multicenter, prospective, open-label controlled trial in Japanese patients with type 2 diabetes. Thirty-two patients were treated with vildagliptin (50 mg) twice daily or sitagliptin (50 mg) once daily and were allocated to one of two groups: vildagliptin treatment for 12 weeks before switching to sitagliptin for 12 weeks, or vice versa. Daily profiles of blood glucose were assessed several times during each treatment period, and the mean amplitude of glycemic excursions and M-value were calculated. Metabolic biomarkers such as hemoglobin A1c (HbA1c), glycated albumin, and 1,5-anhydroglucitol were also assessed. With vildagliptin treatment, mean amplitude of glycemic excursions was significantly improved compared with sitagliptin treatment (57.9 ± 22.2 vs. 68.9 ± 33.0 mg/dL; p=0.0045). M-value (p=0.019) and mean blood glucose (p=0.0021) were also lower with vildagliptin, as were HbA1c, glycated albumin, and 1,5-anhydroglucitol. There were no significant differences in other metabolic parameters evaluated. Reduction of daily blood glucose profile fluctuations by vildagliptin was superior to that of sitagliptin in Japanese patients with type 2 diabetes.
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Affiliation(s)
- Hiroshi Nomoto
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Kimihiko Kimachi
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Hideaki Miyoshi
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Hiraku Kameda
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Kyu Yong Cho
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Akinobu Nakamura
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - So Nagai
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Takuma Kondo
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Tatsuya Atsumi
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
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A Randomized Controlled Trial Comparing the Effects of Sitagliptin and Glimepiride on Endothelial Function and Metabolic Parameters: Sapporo Athero-Incretin Study 1 (SAIS1). PLoS One 2016; 11:e0164255. [PMID: 27711199 PMCID: PMC5053511 DOI: 10.1371/journal.pone.0164255] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 09/19/2016] [Indexed: 12/14/2022] Open
Abstract
Objectives The DPP-4 inhibitors are incretin-related drugs that improve hyperglycemia in a glucose-dependent manner and have been reported to exert favorable effects on atherosclerosis. However, it has not been fully elucidated whether DPP-4 inhibitors are able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of sitagliptin, a DPP-4 inhibitor, on endothelial function and glycemic metabolism compared with that of the sulfonylurea glimepiride. Materials and Methods In this multicenter, prospective, randomized parallel-group comparison study, 103 outpatients with type 2 diabetes (aged 59.9 ± 9.9 years with HbA1c levels of 7.5 ± 0.4%) with dietary cure only and/or current metformin treatment were enrolled and randomly assigned to receive sitagliptin or glimepiride therapy once daily for 26 weeks. Flow-mediated dilation (FMD), a comprehensive panel of hemodynamic parameters (Task Force® Monitor), and serum metabolic markers were assessed before and after the treatment. Results During the study period, no statistically significant change in %FMD was seen in both groups (sitagliptin, 5.6 to 5.6%; glimepiride, 5.6 to 6.0%). Secretory units of islets in transplantation, TNF-α, adiponectin and biological antioxidant potential significantly improved in the sitagliptin group, and superoxide dismutase also tended to improve in the sitagliptin group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different. Conclusions Regardless of glycemic improvement, early sitagliptin therapy did not affect endothelial function but may provide favorable effects on beta-cell function and on inflammatory and oxidative stress in patients with type 2 diabetes without advanced atherosclerosis. Trial Registration UMIN Clinical Trials Registry System UMIN 000004955
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14
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KIMURA K, NAKAMURA Y, HASEGAWA H, TSUJI M, OGUCHI T, TSUCHIYA H, GOTOH H, GOTO Y, INAGAKI M, OGUCHI K. Pleiotropic Effects of Linagliptin Monotherapy on Levels of Nitric Oxide, Nitric Oxide Synthase, and Superoxide Dismutase in Hemodialysis Patients with Diabetes. ACTA ACUST UNITED AC 2016. [DOI: 10.15369/sujms.28.9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Kengo KIMURA
- Department of Pharmacology, Showa University School of Medicine
| | - Yuya NAKAMURA
- Department of Pharmacology, Showa University School of Medicine
- Saiyu Soka Hospital
| | - Hitomi HASEGAWA
- Department of Pharmacology, Showa University School of Medicine
| | - Mayumi TSUJI
- Department of Pharmacology, Showa University School of Medicine
| | | | | | | | | | - Masahiro INAGAKI
- Department of Chemistry, College of Arts and Sciences, Showa University
| | - Katsuji OGUCHI
- Department of Pharmacology, Showa University School of Medicine
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15
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Gaspari T, Brdar M, Lee HW, Spizzo I, Hu Y, Widdop RE, Simpson RW, Dear AE. Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis. Diab Vasc Dis Res 2016; 13:56-68. [PMID: 26408644 DOI: 10.1177/1479164115605000] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists may have a role in modulation of cardiac fibrosis. Our study aimed to determine the effect of the glucagon-like peptide-1 receptor agonist liraglutide in obesity, hypertension and age-induced murine models of cardiac fibrosis and identify associated molecular mechanisms. METHODS C57Bl/6J mice on a high-fat diet and C57Bl/6J mice on a normal chow diet treated with angiotensin II were used to induce obesity and hypertension-mediated cardiac fibrosis, respectively. C57Bl/6J mice 20 months old were used to study age-induced cardiac fibrosis. Liraglutide treatment of 30 µg/kg/day-300 µg/kg s.c. twice daily was administered for 4 weeks. RESULTS Liraglutide treatment attenuated obesity, hypertension and age-induced increases in interstitial cardiac fibrosis and expression of inflammatory and oxidative stress markers. CONCLUSIONS These observations identify a potential role for liraglutide in the prevention of cardiac fibrosis and identify molecular mechanisms associated with these effects.
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Affiliation(s)
- Tracey Gaspari
- Department of Pharmacology, Monash University, Melbourne, VIC, Australia
| | - Melita Brdar
- Department of Pharmacology, Monash University, Melbourne, VIC, Australia
| | - Huey Wen Lee
- Department of Pharmacology, Monash University, Melbourne, VIC, Australia
| | - Iresha Spizzo
- Department of Pharmacology, Monash University, Melbourne, VIC, Australia
| | - Yunshan Hu
- Department of Medicine, Monash University, Melbourne, VIC, Australia
| | - Robert E Widdop
- Department of Pharmacology, Monash University, Melbourne, VIC, Australia
| | - Richard W Simpson
- Department of Medicine, Monash University, Melbourne, VIC, Australia
| | - Anthony E Dear
- Department of Medicine, Monash University, Melbourne, VIC, Australia
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16
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Saad MI, Abdelkhalek TM, Saleh MM, Kamel MA, Youssef M, Tawfik SH, Dominguez H. Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells. Endocrine 2015; 50:537-67. [PMID: 26271514 DOI: 10.1007/s12020-015-0709-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 07/25/2015] [Indexed: 12/13/2022]
Abstract
Diabetes mellitus is a heterogeneous, multifactorial, chronic disease characterized by hyperglycemia owing to insulin insufficiency and insulin resistance (IR). Recent epidemiological studies showed that the diabetes epidemic affects 382 million people worldwide in 2013, and this figure is expected to be 600 million people by 2035. Diabetes is associated with microvascular and macrovascular complications resulting in accelerated endothelial dysfunction (ED), atherosclerosis, and cardiovascular disease (CVD). Unfortunately, the complex pathophysiology of diabetic cardiovascular damage is not fully understood. Therefore, there is a clear need to better understand the molecular pathophysiology of ED in diabetes, and consequently, better treatment options and novel efficacious therapies could be identified. In the light of recent extensive research, we re-investigate the association between diabetes-associated metabolic disturbances (IR, subclinical inflammation, dyslipidemia, hyperglycemia, dysregulated production of adipokines, defective incretin and gut hormones production/action, and oxidative stress) and ED, focusing on oxidative stress and endothelial progenitor cells (EPCs). In addition, we re-emphasize that oxidative stress is the final common pathway that transduces signals from other conditions-either directly or indirectly-leading to ED and CVD.
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Affiliation(s)
- Mohamed I Saad
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.
- Hudson Institute of Medical Research, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.
| | - Taha M Abdelkhalek
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Moustafa M Saleh
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Maher A Kamel
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Mina Youssef
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Shady H Tawfik
- Department of Molecular Medicine, University of Padova, Padua, Italy
| | - Helena Dominguez
- Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark
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17
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Nakamura Y, Hasegawa H, Tsuji M, Udaka Y, Mihara M, Shimizu T, Inoue M, Goto Y, Gotoh H, Inagaki M, Oguchi K. Diabetes therapies in hemodialysis patients: Dipeptidase-4 inhibitors. World J Diabetes 2015; 6:840-9. [PMID: 26131325 PMCID: PMC4478579 DOI: 10.4239/wjd.v6.i6.840] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 03/16/2015] [Accepted: 04/01/2015] [Indexed: 02/05/2023] Open
Abstract
Although several previous studies have been published on the effects of dipeptidase-4 (DPP-4) inhibitors in diabetic hemodialysis (HD) patients, the findings have yet to be reviewed comprehensively. Eyesight failure caused by diabetic retinopathy and aging-related dementia make multiple daily insulin injections difficult for HD patients. Therefore, we reviewed the effects of DPP-4 inhibitors with a focus on oral antidiabetic drugs as a new treatment strategy in HD patients with diabetes. The following 7 DPP-4 inhibitors are available worldwide: sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and saxagliptin. All of these are administered once daily with dose adjustments in HD patients. Four types of oral antidiabetic drugs can be administered for combination oral therapy with DPP-4 inhibitors, including sulfonylureas, meglitinide, thiazolidinediones, and alpha-glucosidase inhibitor. Nine studies examined the antidiabetic effects in HD patients. Treatments decreased hemoglobin A1c and glycated albumin levels by 0.3% to 1.3% and 1.7% to 4.9%, respectively. The efficacy of DPP-4 inhibitor treatment is high among HD patients, and no patients exhibited significant severe adverse effects such as hypoglycemia and liver dysfunction. DPP-4 inhibitors are key drugs in new treatment strategies for HD patients with diabetes and with limited choices for diabetes treatment.
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18
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Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J 2015; 36:2288-96. [PMID: 26063450 DOI: 10.1093/eurheartj/ehv239] [Citation(s) in RCA: 192] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 05/16/2015] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by multiple pathophysiologic abnormalities. With time, multiple glucose-lowering medications are commonly required to reduce and maintain plasma glucose concentrations within the normal range. Type 2 diabetes mellitus individuals also are at a very high risk for microvascular complications and the incidence of heart attack and stroke is increased two- to three-fold compared with non-diabetic individuals. Therefore, when selecting medications to normalize glucose levels in T2DM patients, it is important that the agent not aggravate, and ideally even improve, cardiovascular risk factors (CVRFs) and reduce cardiovascular morbidity and mortality. In this review, we examine the effect of oral (metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP4 inhibitors, SGLT2 inhibitors, and α-glucosidase inhibitors) and injectable (glucagon-like peptide-1 receptor agonists and insulin) glucose-lowering drugs on established CVRFs and long-term studies of cardiovascular outcomes. Firm evidence that in T2DM cardiovascular disease can be reversed or prevented by improving glycaemic control is still incomplete and must await large, long-term clinical trials in patients at low risk using modern treatment strategies, i.e., drug combinations designed to maximize HbA1c reduction while minimizing hypoglycaemia and excessive weight gain.
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Affiliation(s)
- Ele Ferrannini
- Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy
| | - Ralph A DeFronzo
- Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA
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Gurkan E, Tarkun I, Sahin T, Cetinarslan B, Canturk Z. Evaluation of exenatide versus insulin glargine for the impact on endothelial functions and cardiovascular risk markers. Diabetes Res Clin Pract 2014; 106:567-75. [PMID: 25458329 DOI: 10.1016/j.diabres.2014.09.046] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 07/17/2014] [Accepted: 09/14/2014] [Indexed: 12/11/2022]
Abstract
AIMS To demonstrate the efficacy of exenatide versus insulin glargine on endothelial functions and cardiovascular risk markers. METHODS Thirty-four insulin and incretin-naive patients with type 2 diabetes mellitus (body mass index 25-45 kg/m(2)) who received metformin for at least two months were randomized to exenatide or insulin glargine treatment arms and followed-up for 26 weeks. Measurements of endothelial functions were done by ultrasonography, cardiovascular risk markers by serum enzyme-linked immunosorbent assay, and total body fat mass by bioimpedance. RESULTS Levels of high sensitivity-C-reactive protein and endothelin-1 decreased (27.5% and 18.75%, respectively) in the exenatide arm. However, in the insulin glargine arm, fibrinogen, monocyte chemoattractant protein-1, leptin and endothelin-1 levels (13.4, 30.2, 47.5, and 80%, respectively) increased. Post-treatment flow mediated dilatation and endothelium independent vascular responses were significantly higher in both arms (p=0.0001, p=0.0001). Positive correlation was observed between the changes in body weight and endothelium-independent vasodilatation, leptin, plasminogen activator inhibitor type 1 and endothelin-1 in both arms (r=0.376, r=0.507, r=0.490, r=0.362, respectively). CONCLUSIONS Insulin glargine improved endothelial functions, without leading to positive changes in cardiovascular risk markers. Exenatide treatment of 26 weeks resulted in reduced body weight and improvement in certain cardiovascular risk markers and endothelial functions.
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Affiliation(s)
- Eren Gurkan
- Department of Endocrinology and Metabolism, Kocaeli University Faculty of Medicine, Kocaeli, Turkey.
| | - Ilhan Tarkun
- Department of Endocrinology and Metabolism, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Tayfun Sahin
- Department of Cardiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Berrin Cetinarslan
- Department of Endocrinology and Metabolism, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Zeynep Canturk
- Department of Endocrinology and Metabolism, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
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Tremblay AJ, Lamarche B, Deacon CF, Weisnagel SJ, Couture P. Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Metabolism 2014; 63:1141-8. [PMID: 25034387 DOI: 10.1016/j.metabol.2014.06.004] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 05/22/2014] [Accepted: 06/09/2014] [Indexed: 12/20/2022]
Abstract
UNLABELLED Inflammation and endothelial dysfunction are increasingly being recognized as key etiological factors in the development of atherosclerosis and subsequent cardiovascular disease. These pro-atherogenic factors are strongly correlated and are often found to co-segregate in patients with type 2 diabetes. The impact of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4, on inflammation and markers of endothelial function remains to be fully characterized. OBJECTIVE The objective of the present study was to examine the effects of treatment with sitagliptin on the plasma levels of various markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. METHODS AND RESULTS Thirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1 ± 6.4 years and a body mass index of 30.7 ± 4.9 kg/m²) were recruited into this double-blind, cross-over study using sitagliptin (100mg/d) or placebo, each for a 6-week period, including a 4-week washout period between the two phases. Blood samples were taken at the end of each phase of treatment. Compared with placebo, treatment with sitagliptin significantly reduced the plasma levels of C-reactive protein (CRP) (44.9%, P=0.006), interleukin (IL)-6 (24.7%, P=0.04), IL-18 (7.3%, P=0.004), secreted phospholipase-A₂ (sPLA₂) (12.9%, P=0.04), soluble intercellular adhesion molecule-1 (5.3%, P=0.002), and E-selectin (5.9%, P=0.005). A significant inverse correlation was found between changes in glucagon-like peptide-1 (GLP-1) and changes in CRP levels (r=0.41, P=0.01) following sitagliptin therapy. Sitagliptin therapy had more pronounced effects in subjects with higher levels of inflammatory markers and cell adhesion molecules compared with subjects with lower levels. CONCLUSIONS Treatment with sitagliptin for 6 weeks reduced plasma markers of low-grade inflammation and cell adhesion molecules, most likely by increasing plasma GLP-1 levels and improving glucose-insulin homeostasis. These beneficial effects of sitagliptin might represent a further advantage in the management of diabetes and its proatherogenic comorbidities.
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Affiliation(s)
- André J Tremblay
- Institute of Nutrition and Functional Foods, Laval University, Quebec City, Quebec, Canada; Lipid Research Centre, CHUL Research Centre, Quebec City, Quebec, Canada
| | - Benoît Lamarche
- Institute of Nutrition and Functional Foods, Laval University, Quebec City, Quebec, Canada
| | - Carolyn F Deacon
- Department of Biomedical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark
| | - S John Weisnagel
- Diabetes Research Unit, CHUL Research Centre, Quebec City, Quebec, Canada
| | - Patrick Couture
- Institute of Nutrition and Functional Foods, Laval University, Quebec City, Quebec, Canada; Lipid Research Centre, CHUL Research Centre, Quebec City, Quebec, Canada.
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Zhao S, Nishimura T, Chen Y, Azeloglu EU, Gottesman O, Giannarelli C, Zafar MU, Benard L, Badimon JJ, Hajjar RJ, Goldfarb J, Iyengar R. Systems pharmacology of adverse event mitigation by drug combinations. Sci Transl Med 2014; 5:206ra140. [PMID: 24107779 DOI: 10.1126/scitranslmed.3006548] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Drugs are designed for therapy, but medication-related adverse events are common, and risk/benefit analysis is critical for determining clinical use. Rosiglitazone, an efficacious antidiabetic drug, is associated with increased myocardial infarctions (MIs), thus limiting its usage. Because diabetic patients are often prescribed multiple drugs, we searched for usage of a second drug ("drug B") in the Food and Drug Administration's Adverse Event Reporting System (FAERS) that could mitigate the risk of rosiglitazone ("drug A")-associated MI. In FAERS, rosiglitazone usage is associated with increased occurrence of MI, but its combination with exenatide significantly reduces rosiglitazone-associated MI. Clinical data from the Mount Sinai Data Warehouse support the observations from FAERS. Analysis for confounding factors using logistic regression showed that they were not responsible for the observed effect. Using cell biological networks, we predicted that the mitigating effect of exenatide on rosiglitazone-associated MI could occur through clotting regulation. Data we obtained from the db/db mouse model agreed with the network prediction. To determine whether polypharmacology could generally be a basis for adverse event mitigation, we analyzed the FAERS database for other drug combinations wherein drug B reduced serious adverse events reported with drug A usage such as anaphylactic shock and suicidality. This analysis revealed 19,133 combinations that could be further studied. We conclude that this type of crowdsourced approach of using databases like FAERS can help to identify drugs that could potentially be repurposed for mitigation of serious adverse events.
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Affiliation(s)
- Shan Zhao
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS One 2014; 9:e97554. [PMID: 24835252 PMCID: PMC4023984 DOI: 10.1371/journal.pone.0097554] [Citation(s) in RCA: 139] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 04/21/2014] [Indexed: 12/18/2022] Open
Abstract
Liraglutide is a glucagon-like peptide-1 (GLP-1) mimetic used for the treatment of Type 2 diabetes. Similar to the actions of endogenous GLP-1, liraglutide potentiates the post-prandial release of insulin, inhibits glucagon release and increases satiety. Recent epidemiological studies and clinical trials have suggested that treatment with GLP-1 mimetics may also diminish the risk of cardiovascular disease in diabetic patients. The mechanism responsible for this effect has yet to be determined; however, one possibility is that they might do so by a direct effect on vascular endothelium. Since low grade inflammation of the endothelium is an early event in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), we determined the effects of liraglutide on inflammation in cultured human aortic endothelial cells (HAECs). Liraglutide reduced the inflammatory responses to TNFα and LPS stimulation, as evidenced by both reduced protein expression of the adhesion molecules VCAM-1 and E-Selectin, and THP-1 monocyte adhesion. This was found to result from increased cell Ca2+ and several molecules sensitive to Ca2+ with known anti inflammatory actions in endothelial cells, including CaMKKβ, CaMKI, AMPK, eNOS and CREB. Treatment of the cells with STO-609, a CaMKK inhibitor, diminished both the activation of AMPK, CaMKI and the inhibition of TNFα and LPS-induced monocyte adhesion by liraglutide. Likewise, expression of an shRNA against AMPK nullified the anti-inflammatory effects of liraglutide. The results indicate that liraglutide exerts a strong anti-inflammatory effect on HAECs. They also demonstrate that this is due to its ability to increase intracellular Ca2+ and activate CAMKKβ, which in turn activates AMPK.
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Oyama JI, Higashi Y, Node K. Do incretins improve endothelial function? Cardiovasc Diabetol 2014; 13:21. [PMID: 24428883 PMCID: PMC3898564 DOI: 10.1186/1475-2840-13-21] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Accepted: 01/10/2014] [Indexed: 12/11/2022] Open
Abstract
An impaired endothelial function has been recognized in the early stage of atherosclerosis, and is a major factor affecting the future development of cardiovascular events. Type 2 diabetes mellitus (T2DM) is widely prevalent, and is one of the most important risk factors for cardiovascular disease. T2DM is associated with increases in both morbidity and mortality, particularly from cardiovascular disease.New therapies based on the incretin hormone and its actions are now becoming widely used, and appear to offer advantages over conventional therapies by keeping the body weight steady and limiting hypoglycemia, while also achieving attractive glycemic control. However, there is little data available about the effects of incretins on the cardiovascular system.This review will focus on the effects of incretin therapies, including glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase (DPP)-4 inhibitors, on the endothelial function, and will discuss the potential mechanisms underlying these effects.
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Affiliation(s)
- Jun-Ichi Oyama
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
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Miller AL, Lumeng CN, Delproposto J, Florek B, Wendorf K, Lumeng JC. Obesity-Related Hormones in Low-Income Preschool-Age Children: Implications for School Readiness. MIND, BRAIN AND EDUCATION : THE OFFICIAL JOURNAL OF THE INTERNATIONAL MIND, BRAIN, AND EDUCATION SOCIETY 2013; 7:246-255. [PMID: 25302075 PMCID: PMC4185397 DOI: 10.1111/mbe.12034] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Mechanisms underlying socioeconomic disparities in school readiness and health outcomes, particularly obesity, among preschool-aged children are complex and poorly understood. Obesity can induce changes in proteins in the circulation that contribute to the negative impact of obesity on health; such changes may relate to cognitive and emotion regulation skills important for school readiness. We investigated obesity-related hormones, body mass index (BMI), and school readiness in a pilot study of low-income preschoolers attending Head Start (participating in a larger parent study). We found that the adipokine leptin was related to preschoolers' BMI z-score, the appetite-regulating hormones ghrelin and glucagon-like peptide 1 (GLP-1), and pro-inflammatory cytokines typically associated with early life stress; and that some of these obesity-related biomarkers were in turn related to emotion regulation. Future work should evaluate how obesity may affect multiple domains of development, and consider modeling common physiological pathways related to stress, health, and school readiness.
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Affiliation(s)
- Alison L. Miller
- Department of Health Behavior and Health Education, School of Public Health, University of Michigan
- Center for Human Growth and Development, University of Michigan
| | - Carey N. Lumeng
- Department of Pediatrics and Communicable Diseases, University of Michigan
- Department of Molecular and Integrative Physiology, University of Michigan
| | | | - Brian Florek
- Center for Human Growth and Development, University of Michigan
| | - Kristin Wendorf
- Center for Human Growth and Development, University of Michigan
| | - Julie C. Lumeng
- Center for Human Growth and Development, University of Michigan
- Department of Pediatrics and Communicable Diseases, University of Michigan
- Human Nutrition Program, Department of Environmental Health Sciences, School of Public Health, University of Michigan
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Chai JT, Choudhury RP. Cardiometabolic interventions - focus on transcriptional regulators. THE EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE 2013; 2:212-218. [PMID: 24040490 PMCID: PMC3769682 DOI: 10.5083/ejcm.20424884.102] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cardiovascular disease (CVD) remains the largest healthcare burden in the Western world; and the increasing prevalence of type II diabetes mellitus, at least partially driven by a trend in lifestyle changes associated with global economic development, is likely to fuel this CVD burden worldwide. Over the past two decades, there has been an increased awareness of the convergence of risk factors contributing to both cardiovascular disease and diabetes leading to the concept of the metabolic syndrome, and the realisation of the opportunity to intervene at this intersection to simultaneously target CVD and metabolic dysfunction. This brings together the fields of cardiovascular medicine, diabetology, and increasingly clinical immunology for a unified and concerted effort to reduce risk for both conditions simultaneously. The discovery of the targeted pathways of drugs already in clinical use such as fibrates and thiazolidinediones (TZD) has led to accelerated basic and clinical research into selective and dual PPAR-α and PPAR-γ agonists, which can theoretically target glucose, lipid and lipoprotein metabolism, as well as potentially exerting inhibitoryeffects in vascular inflammation, all of which might be predicted to reduce atherosclerosis. In this article, we will discuss the basic science as well as recent clinical development in the pursuit of optimal cardiometabolic intervention along with insight into strategies for future drug development.
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Affiliation(s)
- Joshua T Chai
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine University of Oxford, United Kingdom
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Gaspari T, Welungoda I, Widdop RE, Simpson RW, Dear AE. The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE(-/-) mouse model. Diab Vasc Dis Res 2013; 10:353-60. [PMID: 23673376 DOI: 10.1177/1479164113481817] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Liraglutide, a once-daily glucagon-like peptide-1 receptor (GLP-1R) agonist, has been approved as a new treatment for type 2 diabetes and is the subject of a clinical trial programme to evaluate the effects on cardiovascular disease and safety. The current study aimed to determine the in vivo effect of liraglutide on progression of atherosclerotic vascular disease in the apolipoprotein E-deficient (ApoE(-/-)) mouse model and identify underlying mechanisms responsible. Liraglutide treatment inhibited progression of early onset, low-burden atherosclerotic disease in a partially GLP-1R-dependent manner in the ApoE(-/-) mouse model. In addition, liraglutide treatment inhibited progression of atherosclerotic plaque formation and enhanced plaque stability, again in a partially GLP-1R-dependent manner. No significant effect of liraglutide on progression of late onset, high-burden atherosclerotic disease was observed. In addition, no significant endothelial cell dysfunction was identified in ApoE(-/-) mice with early onset, low-burden atherosclerotic disease, although significant prevention of weight gain was observed in liraglutide-treated mice using this dietary protocol. Taken together, these results suggest a potential role for liraglutide in the prevention and stabilisation of atherosclerotic vascular disease together with possible protection against major cardiovascular events.
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Affiliation(s)
- Tracey Gaspari
- Department of Pharmacology, Monash University, Melbourne, VIC, Australia
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Incretin based therapeutics: connections to vascular biology and implications for potential cardiovascular disease prevention: Editorial to: "Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 in endothelial cell by repressing nuclear factor-kappa B activation" by Dai et al. Cardiovasc Drugs Ther 2013; 27:363-4. [PMID: 23722420 DOI: 10.1007/s10557-013-6465-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Herzlinger S, Horton ES. Extraglycemic effects of glp-1-based therapeutics: addressing metabolic and cardiovascular risks associated with type 2 diabetes. Diabetes Res Clin Pract 2013; 100:1-10. [PMID: 23332049 DOI: 10.1016/j.diabres.2012.11.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Accepted: 11/14/2012] [Indexed: 12/25/2022]
Abstract
CONTEXT To examine whether widespread tissue expression of the glucagon-like peptide (GLP)-1 receptor supports the possibility of differential effects of GLP-1-based therapeutics on cardiac function, blood pressure, food intake, gastric emptying, and other regulatory activities. GLP-1 receptor agonists (RAs) have demonstrated pleiotropic effects on overweight/obesity, hypertension, dyslipidemia, and cardiovascular (CV) disease. Food-regulatory effects have been demonstrated in preclinical and clinical trials, including reduced gastric motility and food intake leading to body weight reductions. Native GLP-1 and GLP-1 RAs have demonstrated cardioprotective effects in preclinical models. EVIDENCE ACQUISITION Using PubMed, we performed a search of the recent literature on GLP-1 and GLP-1 RAs. EVIDENCE SYNTHESIS Preliminary clinical data indicate native GLP-1 has beneficial effects on endothelial cell function and vascular inflammation. Native GLP-1 and GLP-1 RAs have demonstrated renoprotective and antihypertensive effects, and reductions in lipid parameters. The GLP-1 RA liraglutide has also demonstrated positive effects on such markers of endothelial dysfunction as tumor necrosis factor-α and plasminogen activator inhibitor-1. CONCLUSION Preliminary data suggest GLP-1 RAs could benefit type 2 diabetes patients at risk for CV comorbidities. Additional studies are needed to confirm the extraglycemic and extrapancreatic effects and determine whether outcomes will translate into beneficial effects for patient care.
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Affiliation(s)
- Susan Herzlinger
- Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, United States
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Dokken BB, Piermarini CV, Teachey MK, Gura MT, Dameff CJ, Heller BD, Krate J, Ashgar AM, Querin L, Mitchell JL, Hilwig RW, Kern KB. Glucagon-like peptide-1 preserves coronary microvascular endothelial function after cardiac arrest and resuscitation: potential antioxidant effects. Am J Physiol Heart Circ Physiol 2012; 304:H538-46. [PMID: 23241323 DOI: 10.1152/ajpheart.00282.2012] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) has protective effects in the heart. We hypothesized that GLP-1 would mitigate coronary microvascular and left ventricular (LV) dysfunction if administered after cardiac arrest and resuscitation (CAR). Eighteen swine were subjected to ventricular fibrillation followed by resuscitation. Swine surviving to return of spontaneous circulation (ROSC) were randomized to receive an intravenous infusion of either human rGLP-1 (10 pmol·kg(-1)·min(-1); n = 8) or 0.9% saline (n = 8) for 4 h, beginning 1 min after ROSC. CAR caused a decline in coronary flow reserve (CFR) in control animals (pre-arrest, 1.86 ± 0.20; 1 h post-ROSC, 1.3 ± 0.05; 4 h post-ROSC, 1.25 ± 0.06; P < 0.05). GLP-1 preserved CFR for up to 4 h after ROSC (pre-arrest, 1.31 ± 0.17; 1 h post-ROSC, 1.5 ± 0.01; 4 h post-ROSC, 1.55 ± 0.22). Although there was a trend toward improvement in LV relaxation in the GLP-1-treated animals, overall LV function was not consistently different between groups. 8-iso-PGF(2α), a measure of reactive oxygen species load, was decreased in post-ROSC GLP-1-treated animals [placebo, control (NS): 38.1 ± 1.54 pg/ml; GLP-1: 26.59 ± 1.56 pg/ml; P < 0.05]. Infusion of GLP-1 after CAR preserved coronary microvascular and LV diastolic function. These effects may be mediated through a reduction in oxidative stress.
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Affiliation(s)
- Betsy B Dokken
- Department of Medicine, University of Arizona, Tucson, AZ, USA.
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Y H, HB L, RW S, AE D. GLP-1-dependent and independent effects and molecular mechanisms of a dipeptidyl peptidase 4 inhibitor in vascular endothelial cells. Mol Biol Rep 2012. [DOI: 10.1007/s11033-012-2290-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Glucagon-like peptide-1 receptor agonist protects against hyperglycemia-induced cardiocytes injury by inhibiting high mobility group box 1 expression. Mol Biol Rep 2012; 39:10705-11. [PMID: 23053967 DOI: 10.1007/s11033-012-1961-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Accepted: 10/01/2012] [Indexed: 12/16/2022]
Abstract
Glucagon-like peptide-1 (GLP-1), a gut incretin hormone secreted from L cells, and a GLP-1 receptor agonist, exendin-4 (Ex-4) has been shown to be cardioprotective and could exert beneficial effects through its anti-inflammatory property. However, the mechanism remains unclear. The purpose of this study was to investigate whether Ex-4 could ameliorate myocardial cell injury by inhibiting high mobility group box 1 (HMGB1) expression under high glucose condition. Neonatal rat ventricular myocytes were prepared and then cultured with high glucose and different concentration of Ex-4. Lactate dehydrogenase (LDH), creatine kinase (CK), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. HMGB1 expression was assessed by western blotting. Ex-4 significantly inhibited the increase in LDH, CK, TNF-α, IL-1β and MDA levels induced by high glucose, especially at the 1 and 10 nM concentrations as well as suppressed the decrease in SOD level. Meanwhile, HMGB1 expression was markedly increased after 12 h of hyperglycaemia (P < 0.05), which was significantly inhibited by Ex-4, especially at the 1 and 10 nM concentrations (P < 0.05). The present study suggested that Ex-4 could reduce high glucose-induced cardiocytes injury, which may be associated with the inhibition of HMGB1 expression.
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Cariou B. Harnessing the incretin system beyond glucose control: potential cardiovascular benefits of GLP-1 receptor agonists in type 2 diabetes. DIABETES & METABOLISM 2012; 38:298-308. [PMID: 22672960 DOI: 10.1016/j.diabet.2012.04.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Revised: 04/14/2012] [Accepted: 04/14/2012] [Indexed: 12/25/2022]
Abstract
The management of type 2 diabetes continues to evolve as new data emerge. Although glycaemic control is still important, other risk factors--such as hypertension, dyslipidaemia and obesity--must also be addressed in order to reduce the long-term risks of cardiovascular complications and mortality. In this context, targeting the incretin system, and glucagon-like peptide-1 (GLP-1) in particular, has generated much interest. GLP-1 is released from the gut in response to food ingestion and plays a crucial role in glucose homeostasis. GLP-1 receptors are expressed in the heart and vasculature, prompting evaluation of their physiological role and pharmacological stimulation, both in healthy and disease states. These studies indicate that GLP-1 and GLP-1-based therapies appear to have direct, beneficial effects on the cardiovascular system, in addition to their glucose-lowering properties, such as modulation of blood pressure, endothelial function, and myocardial contractility. Intriguingly, some of these effects appear to be independent of GLP-1 receptor signalling. Data from clinical studies of the GLP-1 receptor agonists, exenatide and liraglutide on cardiovascular risk factors, in patients with type 2 diabetes are also promising and the results from prospective studies to assess cardiovascular outcomes are eagerly awaited.
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Affiliation(s)
- B Cariou
- Université de Nantes, CHU de Nantes, Hôpital Guillaume et René-Laennec, boulevard Jacques-Monod, Saint-Herblain, 44093 Nantes cedex 1, France.
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Cardiovascular benefits of GLP-1-based herapies in patients with diabetes mellitus type 2: effects on endothelial and vascular dysfunction beyond glycemic control. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:635472. [PMID: 22577369 PMCID: PMC3345223 DOI: 10.1155/2012/635472] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Accepted: 02/06/2012] [Indexed: 01/14/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a progressive multisystemic disease accompanied by vascular dysfunction and a tremendous increase in cardiovascular mortality. Numerous adipose-tissue-derived factors and beta cell dysfunction contribute to the increased cardiovascular risk in patients with T2DM. Nowadays, numerous pharmacological interventions are available to lower blood glucose levels in patients with type 2 diabetes. Beside more or less comparable glucose lowering efficacy, some of them have shown limited or probably even unfavorable effects on the cardiovascular system and overall mortality. Recently, incretin-based therapies (GLP-1 receptor agonists and DPP-IV inhibitors) have been introduced in the treatment of T2DM. Beside the effects of GLP-1 on insulin secretion, glucagon secretion, and gastrointestinal motility, recent studies suggested a couple of direct cardiovascular effects of GLP-1-based therapies. The goal of this paper is to provide an overview about the current knowledge of direct GLP-1 effects on endothelial and vascular function and potential consequences on the cardiovascular outcome in patients with T2DM treated with GLP-1 receptor agonists or DPP-IV inhibitors.
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Lim S, Choi SH, Shin H, Cho BJ, Park HS, Ahn BY, Kang SM, Yoon JW, Jang HC, Kim YB, Park KS. Effect of a dipeptidyl peptidase-IV inhibitor, des-fluoro-sitagliptin, on neointimal formation after balloon injury in rats. PLoS One 2012; 7:e35007. [PMID: 22493727 PMCID: PMC3320861 DOI: 10.1371/journal.pone.0035007] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Accepted: 03/08/2012] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Recently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des-fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms. METHODS AND FINDINGS Otsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFκB activation in VSMCs. CONCLUSIONS Sitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes.
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Affiliation(s)
- Soo Lim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- * E-mail:
| | - Sung Hee Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Hayley Shin
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Bong Jun Cho
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ho Seon Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Byung Yong Ahn
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Seon Mee Kang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Won Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Hak Chul Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Young-Bum Kim
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Korea
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Siemianowicz K, Francuz T, Garczorz W. The influence of exendin and GLP-1 on VCAM-1 and ICAM-1 production in endothelium stimulated by TNF-α and glycated albumin. Health (London) 2012. [DOI: 10.4236/health.2012.412a225] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Glucagon-like peptide-1 activates endothelial nitric oxide synthase in human umbilical vein endothelial cells. Acta Pharmacol Sin 2012; 33:75-81. [PMID: 22120969 DOI: 10.1038/aps.2011.149] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
AIM To investigate the effects of glucagon-like peptide-1 (GLP-1) on endothelial NO synthase (eNOS) in human umbilical vein endothelial cells (HUVECs), and elucidate whether GLP-1 receptor (GLP-1R) and GLP-1(9-36) are involved in these effects. METHODS HUVECs were used. The activity of eNOS was measured with NOS assay kit. Phosphorylated and total eNOS proteins were detected using Western blot analysis. The level of eNOS mRNA was quantified with real-time RT-PCR. RESULTS Incubation of HUVECs with GLP-1 (50-5000 pmol/L) for 30 min significantly increased the activity of eNOS. Incubation of HUVECs with GLP-1 (500-5000 pmol/L) for 5 or 10 min increased eNOS phosphorylated at ser-1177. Incubation with GLP-1 (5000 pmol/L) for 48 h elevated the level of eNOS protein, did not affect the level of eNOS mRNA. GLP-1R agonists exenatide and GLP-1(9-36) at the concentration of 5000 pmol/L increased the activity, phosphorylation and protein level of eNOS. GLP-1R antagonist exendin(9-39) or DPP-4 inhibitor sitagliptin, which abolished GLP-1(9-36) formation, at the concentration of 5000 pmol/L partially blocked the effects of GLP-1 on eNOS. CONCLUSION GLP-1 upregulated the activity and protein expression of eNOS in HUVECs through the GLP-1R-dependent and GLP-1(9-36)-related pathways. GLP-1 may prevent or delay the formation of atherosclerosis in diabetes mellitus by improving the function of eNOS.
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Abstract
GLP-1-modulating therapies are a class of anti-diabetic drugs that improve glycemic control by stimulating glucose-dependent insulin secretion from pancreatic beta-cells. In addition, GLP-1-based therapies have a variety of extrapancreatic effects, including satiety induction and gastric mobility reduction, which extend to distinct cardiovascular actions. GLP-1 was found to reduce infarct size in the context of acute myocardial ischemia which depends on the activation of prosurvival pathways including PI3-kinase, Akt, and ERK1/2. Also, GLP-1 augments the left ventricular function in dilative and metabolic cardiomyopathy, possibly by increasing insulin independent cardiomyocyte glucose uptake. Furthermore, experimental and preliminary clinical evidence suggest vasoprotective efficacy of GLP-1 mediated by improved endothelial function and anti-inflammatory capacities leading to atheroprotection. Mechanistically, the GLP-1 receptor is relevant for glucose lowering efficacy of GLP-1. However, many of its vasoprotective actions have also been described for the GLP-1 metabolite (9-37), which does not activate the GLP-1 receptor, suggesting the presence of an additional, yet unknown, signaling pathway. Ongoing research investigates the relevance of these observations in human disease and underlying mechanisms, which are reviewed in the present article.
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Affiliation(s)
- Michael Lehrke
- Department of Internal Medicine I, University Hospital Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
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Abstract
Cardiovascular disease (CVD), a leading cause of death in patients with diabetes mellitus, has several pathogenic mechanisms that are well established. However, the traditional hypoglycemic agents do not have proven positive effects on macrovascular disease. Novel therapeutic agents target the incretin pathway including the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists and the dipeptidyl peptidase-4 inhibitors. The glucose-regulatory actions of these agents function by increasing insulin secretion and suppressing glucagon. They also act to increase weight loss not only by inhibiting gastric emptying, but also by reducing appetite. Although GLP-1 and GLP-1R agonists have demonstrated beneficial effects on myocardium and vascular endothelium including coronary and peripheral mouse vessels, they also have anti-inflammatory and anti-atherogenic actions. These agents also have positive effects on the lipid profile and blood pressure. Although these cardioprotective actions seem to be beyond the effects of glucose control and weight loss, they are mediated through GLP-1R- or GLP-1R-independent actions of cleaved GLP-1 (9-36). Larger randomized controlled trials are necessary to elucidate the clinical promise of these beneficial CVD effects.
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Affiliation(s)
- Ji Sung Yoon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Hyoung Woo Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
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Ishibashi Y, Nishino Y, Matsui T, Takeuchi M, Yamagishi SI. Glucagon-like peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycation end product receptor level. Metabolism 2011; 60:1271-7. [PMID: 21388644 DOI: 10.1016/j.metabol.2011.01.010] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2010] [Revised: 01/07/2011] [Accepted: 01/24/2011] [Indexed: 11/25/2022]
Abstract
Advanced glycation end products (AGE) and receptor for AGE (RAGE) interaction elicits reactive oxygen species (ROS) generation and inflammatory reactions, thereby being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, found that glucagon-like peptide-1 (GLP-1), one of the incretins and a gut hormone secreted from L cells in the intestine in response to food intake, could have anti-inflammatory and antithrombogenic properties in cultured endothelial cells. However, the effects of GLP-1 on renal mesangial cells are largely unknown. Therefore, to elucidate the role of GLP-1 in diabetic nephropathy, this study investigated whether and how GLP-1 blocked AGE-induced monocyte chemoattractant protein-1 expression in human cultured mesangial cells. Gene and protein expression was analyzed by quantitative real-time reverse transcription polymerase chain reactions, Western blots, and enzyme-linked immunosorbent assay. The ROS generation was measured with dihydroethidium staining. Glucagon-like peptide-1 receptor (GLP-1R) was expressed in mesangial cells. Glucagon-like peptide-1 inhibited RAGE gene expression in mesangial cells, which was blocked by small interfering RNAs raised against GLP-1R. Furthermore, GLP-1 decreased ROS generation and subsequently reduced monocyte chemoattractant protein-1 gene and protein expression in AGE-exposed mesangial cells. An analogue of cyclic adenosine monophosphate mimicked the effects of GLP-1 on mesangial cells. Our present study suggests that GLP-1 may directly act on mesangial cells via GLP-1R and that it could work as an anti-inflammatory agent against AGE by reducing RAGE expression via activation of cyclic adenosine monophosphate pathway.
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Affiliation(s)
- Yuji Ishibashi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume 830-0011, Japan
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41
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Vergès B, Bonnard C, Renard E. Beyond glucose lowering: glucagon-like peptide-1 receptor agonists, body weight and the cardiovascular system. DIABETES & METABOLISM 2011; 37:477-88. [PMID: 21871831 DOI: 10.1016/j.diabet.2011.07.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Revised: 07/03/2011] [Accepted: 07/08/2011] [Indexed: 02/07/2023]
Abstract
AIM Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family: in the presence of elevated blood glucose, it stimulates insulin secretion and inhibits glucagon production. In addition, GLP-1 slows gastric emptying. GLP-1 secretion has also been reported to potentially affect patients with type 2 diabetes (T2DM) compared with non-diabetics and, as enzymatic inactivation by dipeptidyl peptidase-4 (DPP-4) shortens the GLP-1 half-life to a few minutes, GLP-1 receptor agonists such as exenatide twice daily (BID) and liraglutide have been developed, and have become part of the management of patients with T2DM. This review focuses on the potential beneficial effects of these compounds beyond those associated with improvements in blood glucose control and weight loss, including changes in the cardiovascular and central nervous systems. METHODS This was a state-of-the-art review of the literature to evaluate the relationships between GLP-1, GLP-1 receptor agonists, weight and the cardiovascular system. RESULTS GLP-1 receptor agonists improve glucose control and do not significantly increase the risk of hypoglycaemia. Also, this new class of antidiabetic drugs was shown to favour weight loss. Mechanisms may involve central action, direct action by reduction of food intake and probably indirect action through slowing of gastric emptying. The relative importance of each activity remains unclear. Weight loss may improve cardiovascular outcomes in patients with T2DM, although GLP-1 receptor agonists may have other direct and indirect effects on the cardiovascular system. Reductions in myocardial infarct size and improvements in cardiac function have been seen in animal models. Beneficial changes in cardiac function were also demonstrated in patients with myocardial infarcts or heart failure. Indirect effects could involve a reduction in blood pressure and potential effects on oxidation. However, the mechanisms involved in the pleiotropic effects of GLP-1 receptor agonists have yet to be completely elucidated and require further study. CONCLUSION These compounds may play an important role in the treatment of patients with T2DM as their potential effects go beyond glucose-lowering (weight loss, potential improvement of cardiovascular risk factors). However, to better understand their place in the management of T2DM, further experimental and clinical prospective studies are required.
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Affiliation(s)
- B Vergès
- Department of Endocrinology and Diabetes, Bocage Hospital and Inserm CRI 866, CHU of Dijon, Dijon, France
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Ansar S, Koska J, Reaven PD. Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins. Cardiovasc Diabetol 2011; 10:61. [PMID: 21736746 PMCID: PMC3184260 DOI: 10.1186/1475-2840-10-61] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2011] [Accepted: 07/07/2011] [Indexed: 11/10/2022] Open
Abstract
Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1) the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2) the ability of incretins to modulate postprandial hyperlipidemia and (3) the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk.
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Affiliation(s)
- Sameer Ansar
- Department of Endocrinology, Phoenix Veteran Affairs Healthcare System, 650 E Indian School Rd, CS111E, Phoenix, AZ 85012, USA
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Gaspari T, Liu H, Welungoda I, Hu Y, Widdop RE, Knudsen LB, Simpson RW, Dear AE. A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model. Diab Vasc Dis Res 2011; 8:117-24. [PMID: 21562063 DOI: 10.1177/1479164111404257] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The glucagon like peptide-1 receptor (GLP-1R) agonist liraglutide attenuates induction of plasminogen activator inhibitor type-1 (PAI-1) and vascular adhesion molecule (VAM) expression in human vascular endothelial cells (hVECs) in vitro and may afford protection against endothelial cell dysfunction (ECD), an early abnormality in diabetic vascular disease. Our study aimed to establish the dependence of the in vitro effects of liraglutide on the GLP-1R and characterise its in vivo effects in a mouse model of ECD. In vitro studies utilised the human vascular endothelial cell line C11-STH and enzyme-linked immunosorbent assays (ELISA) for determination of PAI-1 and VAM expression. In vivo studies of vascular reactivity and immunohistochemical analysis were performed in the ApoE(-/-) mouse model. In vitro studies demonstrated GLP-1R-dependent liraglutide-mediated inhibition of stimulated PAI-1 and VAM expression. In vivo studies demonstrated significant improvement in endothelial function in liraglutide treated mice, a GLP-1R dependent effect. Liraglutide treatment also increased endothelial nitric oxide synthase (eNOS) and reduced intercellular adhesion molecule-1 (ICAM-1) expression in aortic endothelium, an effect again dependent on the GLP-1R. Together these studies identify in vivo protection, by the GLP-1R agonist liraglutide, against ECD and provide a potential molecular mechanism responsible for these effects.
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MESH Headings
- Animals
- Apolipoproteins E/deficiency
- Apolipoproteins E/genetics
- Atherosclerosis/genetics
- Atherosclerosis/metabolism
- Atherosclerosis/physiopathology
- Atherosclerosis/prevention & control
- Cell Line, Transformed
- Cyclic AMP-Dependent Protein Kinases/metabolism
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Enzyme-Linked Immunosorbent Assay
- Glucagon-Like Peptide 1/analogs & derivatives
- Glucagon-Like Peptide 1/pharmacology
- Glucagon-Like Peptide-1 Receptor
- Humans
- Hypoglycemic Agents/pharmacology
- Immunohistochemistry
- Intercellular Adhesion Molecule-1/genetics
- Intercellular Adhesion Molecule-1/metabolism
- Liraglutide
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Nitric Oxide Synthase Type III/metabolism
- Plasminogen Activator Inhibitor 1/metabolism
- RNA, Messenger/metabolism
- Receptors, Glucagon/agonists
- Receptors, Glucagon/metabolism
- Tumor Necrosis Factor-alpha/metabolism
- Vascular Cell Adhesion Molecule-1/genetics
- Vascular Cell Adhesion Molecule-1/metabolism
- Vasodilation/drug effects
- Vasodilator Agents/pharmacology
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Affiliation(s)
- Tracey Gaspari
- Department of Pharmacology, Monash University, Australia
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Chilton R, Wyatt J, Nandish S, Oliveros R, Lujan M. Cardiovascular comorbidities of type 2 diabetes mellitus: defining the potential of glucagonlike peptide-1-based therapies. Am J Med 2011; 124:S35-53. [PMID: 21194579 DOI: 10.1016/j.amjmed.2010.11.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The global epidemic of diabetes mellitus (~95% type 2 diabetes) has been fueled by a parallel increase in obesity and overweight. Together, these metabolic disease epidemics have contributed to the increasing incidence and prevalence of cardiovascular disease. The accumulation of metabolic and cardiovascular risk factors in patients with type 2 diabetes--risk factors that may exacerbate one another--complicates treatment. Inadequate treatment, treatment that fails to achieve goals, increases the risk for cardiovascular morbidity and mortality. From a clinical perspective, type 2 diabetes is a cardiovascular disease, an observation that is supported by a range of epidemiologic, postmortem, and cardiovascular imaging studies. Vascular wall dysfunction, and particularly endothelial dysfunction, has been posited as a "common soil" linking dysglycemic and cardiovascular diseases. Vascular wall dysfunction promoted by environmental triggers (e.g., sedentary lifestyle) and metabolic triggers (chronic hyperglycemia, obesity) has been associated with the upregulation of reactive oxygen species and chronic inflammatory and hypercoagulable states, and as such with the pathogenesis of type 2 diabetes, atherosclerosis, and cardiovascular disease. Glucagon-like peptide-1 (GLP)-1, an incretin hormone, and synthetic GLP-1 receptor agonists represent promising new areas of research and therapeutics in the struggle not only against type 2 diabetes but also against the cardiovascular morbidity and mortality associated with type 2 diabetes. In a number of small trials in humans, as well as in preclinical and in vitro studies, both native GLP-1 and GLP-1 receptor agonists have demonstrated positive effects on a range of cardiovascular disease pathologies and clinical targets, including such markers of vascular inflammation as high-sensitivity C-reactive protein, plasminogen activator inhibitor-1, and brain natriuretic peptide. Reductions in markers of dyslipidemia such as elevated levels of triglycerides and free fatty acids have also been observed, as have cardioprotective functions. Larger trials of longer duration will be required to confirm preliminary findings. In large human trials, GLP-1 receptor agonists have been associated with significant reductions in both blood pressure and weight.
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Affiliation(s)
- Robert Chilton
- Catheterization Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
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Abstract
Atherothrombotic complications are the main cause of mortality in subjects with diabetes. Premature atherosclerosis, increased platelet reactivity and activation of coagulation factors with associated hypofibrinolysis all contribute to increased cardiovascular risk in this population. Blood clot formation represents the last step in the atherothrombotic process, and the structure of the fibrin network has a role in determining predisposition to cardiovascular disease. In this review, we discuss alterations in coagulation factor plasma levels and/or activity in diabetes and clarify their role in predisposition to cardiovascular events. The effect of diabetes on fibrin network structure/fibrinolysis is reviewed and potential mechanisms that modify clot properties are discussed. Finally, modulation of clotting potential by the various therapeutic agents used in diabetes is examined. Understanding the mechanisms by which diabetes influences the coagulation pathway will help to develop more effective treatment strategies to reduce thrombotic events in subjects with this condition.
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Affiliation(s)
- S H Alzahrani
- Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, Leeds, UK
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46
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[Incretins: do they exert cardiovascular effects?]. Herz 2010; 35:130-8. [PMID: 20467925 DOI: 10.1007/s00059-010-3333-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The physiological effects of the incretin hormone glucagon-like peptide-(GLP-)1 have contributed to the important role that incretin-based therapies with GLP-1 analogs or dipeptidyl peptidase-(DPP-)4 inhibitors already play in type 2 diabetes treatment. This development is not only due to the glucose-dependent insulinotropic effect of GLP-1 as well as the positive effects on beta cell function and, probably, beta cell mass, but also to the beneficial effects on body weight.Lately, the data on positive cardiovascular effects of GLP-1 have been growing. In animal models, GLP-1 improves left ventricular function and diminishes myocardial defects in ischemia models. In clinical studies with GLP-1 analogs, a normalization of blood pressure was observed and some of the data from animal studies after myocardial infarction or after invasive cardiologic or cardiosurgical interventions were also found under clinical conditions in humans. Additionally, an improvement of cardiovascular surrogate parameters was observed with incretin-based therapies. This review gives an overview on the cardiovascular effects of GLP-1 and incretin-based therapies.
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Gallwitz B. Preclinical and Clinical Data on Extraglycemic Effects of GLP-1 Receptor Agonists. Rev Diabet Stud 2009; 6:247-59. [PMID: 20043037 DOI: 10.1900/rds.2009.6.247] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The diverse actions of the incretin hormone glucagon-like peptide (GLP)-1 include insulinotropic, beta-cell preservative, cardioprotective and vasodilatory effects. This spectrum makes GLP-1 an appealing therapeutic option for patients with type 2 diabetes. However, its rapid metabolism by the enzyme dipeptidyl peptidase (DPP)-4 renders it impractical. Incretin-based analogues have been developed to extend endogenous GLP-1 action (GLP-1 receptor agonists) and to hamper its degradation (DPP-4 inhibitors). Evidence suggests that GLP-1 receptor agonists and DPP-4 inhibitors have different pharmacodynamic and pharmacokinetic effects. For example, GLP-1 receptor agonists deliver supraphysiologic levels of GLP-1 analogues designed to resist inactivation by DPP-4, whereas DPP-4 inhibition conserves native GLP-1 resulting in concentrations within the physiologic range. Furthermore, GLP-1 receptor agonists induce glucose-dependent insulin secretion, beta-cell protection, and other extraglycemic benefits such as weight loss and improvement in markers of cardiovascular risk. In contrast, DPP-4 inhibitors are weight neutral and have modest effects on glucose control. DPP-4 inhibition is dependent on the availability of endogenous GLP-1, which appears to be adversely affected by type 2 diabetes and its progression. Therefore, DPP-4 inhibitors may be better suited for patients with mild hyperglycemia without comorbidities. This review examines the present understanding of the pancreatic effects of endogenous GLP-1, and the extrapancreatic actions it exerts on human bodily systems. Also, it analyzes available preclinical and clinical data on incretin therapies with respect to glycemia, lipids, blood pressure, and weight.
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Affiliation(s)
- Baptist Gallwitz
- Department of Medicine IV, Universitätsklinikum Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
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Ishibashi Y, Matsui T, Takeuchi M, Yamagishi SI. Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced up-regulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression. Biochem Biophys Res Commun 2009; 391:1405-8. [PMID: 20026306 DOI: 10.1016/j.bbrc.2009.12.075] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2009] [Accepted: 12/11/2009] [Indexed: 12/20/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) is one of the incretins, a gut hormone secreted from L cells in the intestine in response to food intake. It has been proposed as a potential therapeutic target for the treatment of patients with type 2 diabetes. However, the direct effects of GLP-1 on vascular injury in diabetes are largely unknown. Since there is a growing body of evidence that advanced glycation end products (AGE) and their receptor RAGE axis plays an important role in vascular complications in diabetes, this study investigated whether and how GLP-1 blocked the deleterious effects of AGE on human umbilical vein endothelial cells (HUVEC). GLP-1 receptor (GLP-1R) was expressed in HUVEC. GLP-1 dose-dependently inhibited RAGE gene expression in HUVEC, which was blocked by small interfering RNAs raised against GLP-1R. An analogue of cyclic AMP also decreased RAGE mRNA level in HUVEC. Further, GLP-1 decreased reactive oxygen species generation and subsequently reduced vascular cell adhesion molecule-1 mRNA levels in AGE-exposed HUVEC. Our present study suggests that GLP-1 directly acts on HUVEC via GLP-1R and it could work as an anti-inflammatory agent against AGE by reducing RAGE expression via activation of cyclic AMP pathways.
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Affiliation(s)
- Yuji Ishibashi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
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Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, Hale PM, Zdravkovic M, Blonde L. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009; 32:1224-30. [PMID: 19289857 PMCID: PMC2699702 DOI: 10.2337/dc08-2124] [Citation(s) in RCA: 641] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7-11% (previous oral antidiabetes drug [OAD] monotherapy >or=3 months) or 7-10% (previous OAD combination therapy >or=3 months), and BMI <or=45 kg/m(2). RESULTS Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean +/- SE -1.5 +/- 0.1% for both 1.2 and 1.8 mg liraglutide and -0.5 +/- 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 +/- 0.3 and 2.0 +/- 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 +/- 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of beta-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. CONCLUSIONS Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.
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Affiliation(s)
- Bernard Zinman
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada,
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Abstract
Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d'être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to beta-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects.
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Affiliation(s)
- Wook Kim
- National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA
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