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Sun Y, Zhang Y, Shi F, Li Y, Wang C, Yu F, Chen T, Dong X, Xu Y, Zhao Y, Wan P. Characterization and Role of Glucagon-Like Peptide 1 Receptor in the Lacrimal Gland: Novel Insights into Diabetic Dry Eye Pathogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:797-810. [PMID: 39725294 DOI: 10.1016/j.ajpath.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/20/2024] [Accepted: 12/11/2024] [Indexed: 12/28/2024]
Abstract
This study aimed to investigate the expression of glucagon-like peptide 1 receptor (GLP-1R) in the lacrimal gland and explore the effects of topical application of GLP-1R agonist on lacrimal gland function in a murine model of type 1 diabetes. Tear secretion was evaluated using phenol red threads, RNA sequencing was used to explore gene expression profiles associated with hyperglycemia-induced lacrimal gland injuries, and histologic analysis was conducted to evaluate the degree of damage. The expression of GLP-1R in the lacrimal gland was first identified, and a down-regulation trend associated with diabetes was observed. RNA-sequencing data from lacrimal gland tissues revealed that differentially expressed genes were enriched in inflammatory response pathways. Histologic analysis demonstrated persistent hyperglycemia-induced infiltration of inflammatory cells and progressive fibrosis in the lacrimal gland, resulting in atrophy and diminished tear secretion. Topical application of liraglutide effectively attenuated inflammation and alleviated fibrosis, thus promoting tear production in diabetic mice. Additionally, local intervention with liraglutide promoted autophagy degradation function in the lacrimal gland. This study represents the first validation of GLP-1R expression in the lacrimal gland and its down-regulation induced by diabetes. Additionally, these findings demonstrate that topical administration of liraglutide eye drops, a GLP-1R agonist, can effectively mitigate hyperglycemia-induced damage in the lacrimal gland while enhancing tear secretion.
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Affiliation(s)
- Yan Sun
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yue Zhang
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Fan Shi
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ye Li
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Congyao Wang
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Fenfen Yu
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tingting Chen
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xia Dong
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuqi Xu
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu Zhao
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Pengxia Wan
- Department of Ophthalmology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Lu C, Xu C, Li S, Ni H, Yang J. Liraglutide and GLP-1(9-37) alleviated hepatic ischemia-reperfusion injury by inhibiting ferroptosis via GSK3β/Nrf2 pathway and SMAD159/Hepcidin/FTH pathway. Redox Biol 2025; 79:103468. [PMID: 39693850 PMCID: PMC11719303 DOI: 10.1016/j.redox.2024.103468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/07/2024] [Accepted: 12/11/2024] [Indexed: 12/20/2024] Open
Abstract
Ferroptosis plays a pivotal role in the pathogenesis of ischemia-reperfusion injury (IRI). Liraglutide, as a GLP-1 receptor (GLP-1R) agonist, has exhibited extensive biological effects beyond its hypoglycemic action. Recent studies have shed light on the regulatory influence of Liraglutide on ferroptosis, yet the precise underlying mechanism remains elusive. GLP-1(9-37), as a metabolite of GLP-1, has a low affinity to GLP-1R. Its effect on ferroptosis remains unknown. In this study, we investigated the effects of Liraglutide and GLP-1(9-37) on the ferroptosis during hepatic ischemia-repferfusion (I/R), as well as the underlying specific mechanisms. We found that the administration of Liraglutide alleviated I/R-induced liver injury with less iron accumulation and lower lipid peroxidation, which was not entirely dependent on the presence of GLP-1R. Similarly, GLP-1(9-37) also exhibited these effects. Besides, both of them increased GPX4 expression and decreased COX2 expression. These effects were reversed by a High-Iron Diet. In vitro study showed similar results. In mechanism study, we found that both Liraglutide and GLP-1(9-37) treatment promoted the nuclear translocation of Nrf2 by inhibiting GSK-3β, thereby reducing lipid peroxides. Furthermore, they increased FTH and FTL expression via the SMAD159/Hepcidin pathway, which contributed to the decreased iron accumulation. In conclusion, this study determined that both Liraglutide and GLP-1(9-37) alleviated hepatic ischemia-reperfusion injury (HIRI) by suppressing ferroptosis via the activation of the GSK3β/Nrf2 pathway and the SMAD159/Hepcidin/FTH pathway.
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Affiliation(s)
- Chenqi Lu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Cong Xu
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shanglin Li
- Department of General Surgery, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haiqiang Ni
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Jun Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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Lu C, Xu C, Yang J. The Beneficial Effects of GLP-1 Receptor Agonists Other than Their Anti-Diabetic and Anti-Obesity Properties. MEDICINA (KAUNAS, LITHUANIA) 2024; 61:17. [PMID: 39858999 PMCID: PMC11767243 DOI: 10.3390/medicina61010017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/18/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025]
Abstract
As an incretin hormone, Glucagon-like peptide-1 (GLP-1) has obvious effects on blood glucose regulation and weight loss. GLP-1 receptor (GLP-1R) agonists are synthetic products that have similar effects to GLP-1 but are less prone to degradation, and they are widely used in the treatment of type 2 diabetes and obesity. In recent years, different beneficial effects of GLP-1R agonists were discovered, such as reducing ischemia-reperfusion injury, improving the function of various organs, alleviating substance use disorder, affecting tumorigenesis, regulating bone metabolism, changing gut microbiota composition, and prolonging graft survival. Therefore, GLP-1R agonists have great potential for clinical application in various diseases. Here, we briefly summarized the beneficial effects of GLP-1R agonists other than the anti-diabetic and anti-obesity effects.
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Affiliation(s)
- Chenqi Lu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China;
| | - Cong Xu
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Jun Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China;
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Raza FA, Altaf R, Bashir T, Asghar F, Altaf R, Tousif S, Goyal A, Mohammed A, Mohammad MF, Anan M, Ali S. Effect of GLP-1 receptor agonists on weight and cardiovascular outcomes: A review. Medicine (Baltimore) 2024; 103:e40364. [PMID: 39496023 PMCID: PMC11537668 DOI: 10.1097/md.0000000000040364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 10/15/2024] [Indexed: 11/06/2024] Open
Abstract
Diet and lifestyle modifications remain the foundation of obesity treatment, but they have historically proven insufficient for significant, long-term weight loss. As a result, there is a high demand for new pharmacologic treatments to promote weight loss and prevent life-threatening diseases associated with obesity. Researchers are particularly interested in 1 type of drug, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), because of its promising potential in addressing the limitations of non-pharmacologic treatments. In addition to their role in weight loss, these drugs have shown promising early evidence of cardiovascular benefits in obese patients, further enhancing their clinical relevance. Semaglutide and liraglutide, which were initially approved for the treatment of type 2 diabetes, have since been approved by the Food and Drug Administration as weight loss medications due to their effectiveness in promoting significant and sustained weight loss. In this narrative review, we will explore the mechanism of GLP-1 RAs, their effects on weight loss, cardiovascular risk factors and outcomes, common adverse effects, and strategies for managing these effects.
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Affiliation(s)
- Fatima Ali Raza
- Department of Medicine, Karachi Medical and Dental College, Karachi, Pakistan
| | - Rafiya Altaf
- Department of Surgery, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Talha Bashir
- Department of Medicine, Karachi Institute of Medical Sciences, Combined Military Hospital Malir, Karachi City, Pakistan
| | - Fatima Asghar
- Department of Medicine, Ras Al Khaimah College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Rabiya Altaf
- Department of Medicine, Mersey and West Lancashire Teaching Hospitals NHS Trust, Prescot, United Kingdom
| | - Sohaib Tousif
- Department of Medicine, Ziauddin University, Karachi City, Pakistan
| | - Aman Goyal
- Department of Medicine, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, India
| | - Aisha Mohammed
- Department of Medicine, Comanche County Memorial Hospital, Lawton, OK
| | | | - Mahfuza Anan
- Department of Medicine, Bangladesh Medical College, Dhaka, Bangladesh
| | - Sajjad Ali
- Department of Medicine, Ziauddin University, Karachi City, Pakistan
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Jin FX, Wang Y, Li MN, Li RJ, Guo JT. Intestinal glucagon-like peptide-1: A new player associated with impaired counterregulatory responses to hypoglycaemia in type 1 diabetic mice. World J Diabetes 2024; 15:1764-1777. [PMID: 39192849 PMCID: PMC11346100 DOI: 10.4239/wjd.v15.i8.1764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/03/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Impaired hypoglycaemic counterregulation has emerged as a critical concern for diabetic patients who may be hesitant to medically lower their blood glucose levels due to the fear of potential hypoglycaemic reactions. However, the patho-genesis of hypoglycaemic counterregulation is still unclear. Glucagon-like peptide-1 (GLP-1) and its analogues have been used as adjunctive therapies for type 1 diabetes mellitus (T1DM). The role of GLP-1 in counterregulatory dys-function during hypoglycaemia in patients with T1DM has not been reported. AIM To explore the impact of intestinal GLP-1 on impaired hypoglycaemic counterregulation in type 1 diabetic mice. METHODS T1DM was induced in C57BL/6J mice using streptozotocin, followed by intraperitoneal insulin injections to create T1DM models with either a single episode of hypoglycaemia or recurrent episodes of hypoglycaemia (DH5). Immunofluorescence, Western blot, and enzyme-linked immunosorbent assay were employed to evaluate the influence of intestinal GLP-1 on the sympathetic-adrenal reflex and glucagon (GCG) secretion. The GLP-1 receptor agonist GLP-1(7-36) or the antagonist exendin (9-39) were infused into the terminal ileum or injected intraperitoneally to further investigate the role of intestinal GLP-1 in hypoglycaemic counterregulation in the model mice. RESULTS The expression levels of intestinal GLP-1 and its receptor (GLP-1R) were significantly increased in DH5 mice. Consecutive instances of excess of intestinal GLP-1 weakens the sympathetic-adrenal reflex, leading to dysfunction of adrenal counterregulation during hypoglycaemia. DH5 mice showed increased pancreatic δ-cell mass, cAMP levels in δ cells, and plasma somatostatin concentrations, while cAMP levels in pancreatic α cells and plasma GCG levels decreased. Furthermore, GLP-1R expression in islet cells and plasma active GLP-1 levels were significantly increased in the DH5 group. Further experiments involving terminal ileal infusion and intraperitoneal injection in the model mice demonstrated that intestinal GLP-1 during recurrent hypoglycaemia hindered the secretion of the counterregulatory hormone GCG via the endocrine pathway. CONCLUSION Excessive intestinal GLP-1 is strongly associated with impaired counterregulatory responses to hypoglycaemia, leading to reduced appetite and compromised secretion of adrenaline, noradrenaline, and GCG during hypo-glycaemia.
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Affiliation(s)
- Fang-Xin Jin
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Yan Wang
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Min-Ne Li
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Ru-Jiang Li
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Jun-Tang Guo
- Department of Pathological Physiology, Shandong Second Medical University, Weifang 261053, Shandong Province, China
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Jalil JE, Gabrielli L, Ocaranza MP, MacNab P, Fernández R, Grassi B, Jofré P, Verdejo H, Acevedo M, Cordova S, Sanhueza L, Greig D. New Mechanisms to Prevent Heart Failure with Preserved Ejection Fraction Using Glucagon-like Peptide-1 Receptor Agonism (GLP-1 RA) in Metabolic Syndrome and in Type 2 Diabetes: A Review. Int J Mol Sci 2024; 25:4407. [PMID: 38673991 PMCID: PMC11049921 DOI: 10.3390/ijms25084407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/02/2024] [Accepted: 04/07/2024] [Indexed: 04/28/2024] Open
Abstract
This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of β-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.
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Affiliation(s)
- Jorge E. Jalil
- Pontificia Universidad Católica de Chile, School of Medicine, Division of Cardiovascular Diseases, Santiago 8330055, Chile; (L.G.); (P.M.); (R.F.); (H.V.); (M.A.); (S.C.); (L.S.); (D.G.)
| | - Luigi Gabrielli
- Pontificia Universidad Católica de Chile, School of Medicine, Division of Cardiovascular Diseases, Santiago 8330055, Chile; (L.G.); (P.M.); (R.F.); (H.V.); (M.A.); (S.C.); (L.S.); (D.G.)
| | - María Paz Ocaranza
- Pontificia Universidad Católica de Chile, School of Medicine, Division of Cardiovascular Diseases, Santiago 8330055, Chile; (L.G.); (P.M.); (R.F.); (H.V.); (M.A.); (S.C.); (L.S.); (D.G.)
| | - Paul MacNab
- Pontificia Universidad Católica de Chile, School of Medicine, Division of Cardiovascular Diseases, Santiago 8330055, Chile; (L.G.); (P.M.); (R.F.); (H.V.); (M.A.); (S.C.); (L.S.); (D.G.)
| | - Rodrigo Fernández
- Pontificia Universidad Católica de Chile, School of Medicine, Division of Cardiovascular Diseases, Santiago 8330055, Chile; (L.G.); (P.M.); (R.F.); (H.V.); (M.A.); (S.C.); (L.S.); (D.G.)
| | - Bruno Grassi
- Pontificia Universidad Católica de Chile, School of Medicine, Department of Nutrition and Diabetes, Santiago 8330055, Chile; (B.G.); (P.J.)
| | - Paulina Jofré
- Pontificia Universidad Católica de Chile, School of Medicine, Department of Nutrition and Diabetes, Santiago 8330055, Chile; (B.G.); (P.J.)
| | - Hugo Verdejo
- Pontificia Universidad Católica de Chile, School of Medicine, Division of Cardiovascular Diseases, Santiago 8330055, Chile; (L.G.); (P.M.); (R.F.); (H.V.); (M.A.); (S.C.); (L.S.); (D.G.)
| | - Monica Acevedo
- Pontificia Universidad Católica de Chile, School of Medicine, Division of Cardiovascular Diseases, Santiago 8330055, Chile; (L.G.); (P.M.); (R.F.); (H.V.); (M.A.); (S.C.); (L.S.); (D.G.)
| | - Samuel Cordova
- Pontificia Universidad Católica de Chile, School of Medicine, Division of Cardiovascular Diseases, Santiago 8330055, Chile; (L.G.); (P.M.); (R.F.); (H.V.); (M.A.); (S.C.); (L.S.); (D.G.)
| | - Luis Sanhueza
- Pontificia Universidad Católica de Chile, School of Medicine, Division of Cardiovascular Diseases, Santiago 8330055, Chile; (L.G.); (P.M.); (R.F.); (H.V.); (M.A.); (S.C.); (L.S.); (D.G.)
| | - Douglas Greig
- Pontificia Universidad Católica de Chile, School of Medicine, Division of Cardiovascular Diseases, Santiago 8330055, Chile; (L.G.); (P.M.); (R.F.); (H.V.); (M.A.); (S.C.); (L.S.); (D.G.)
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Pandey S, Mangmool S, Parichatikanond W. Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective. Pharmaceuticals (Basel) 2023; 16:836. [PMID: 37375783 DOI: 10.3390/ph16060836] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/01/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetes is one of the chronic metabolic disorders which poses a multitude of life-debilitating challenges, including cardiac muscle impairment, which eventually results in heart failure. The incretin hormone glucagon-like peptide-1 (GLP-1) has gained distinct recognition in reinstating glucose homeostasis in diabetes, while it is now largely accepted that it has an array of biological effects in the body. Several lines of evidence have revealed that GLP-1 and its analogs possess cardioprotective effects by various mechanisms related to cardiac contractility, myocardial glucose uptake, cardiac oxidative stress and ischemia/reperfusion injury, and mitochondrial homeostasis. Upon binding to GLP-1 receptor (GLP-1R), GLP-1 and its analogs exert their effects via adenylyl cyclase-mediated cAMP elevation and subsequent activation of cAMP-dependent protein kinase(s) which stimulates the insulin release in conjunction with enhanced Ca2+ and ATP levels. Recent findings have suggested additional downstream molecular pathways stirred by long-term exposure of GLP-1 analogs, which pave the way for the development of potential therapeutic molecules with longer lasting beneficial effects against diabetic cardiomyopathies. This review provides a comprehensive overview of the recent advances in the understanding of the GLP-1R-dependent and -independent actions of GLP-1 and its analogs in the protection against cardiomyopathies.
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Affiliation(s)
- Sudhir Pandey
- Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Supachoke Mangmool
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
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GLP1 Exerts Paracrine Activity in the Intestinal Lumen of Human Colon. Int J Mol Sci 2022; 23:ijms23073523. [PMID: 35408884 PMCID: PMC8998470 DOI: 10.3390/ijms23073523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/18/2022] [Accepted: 03/22/2022] [Indexed: 02/01/2023] Open
Abstract
GLP1 produced in the upper part of the gut is released after food intake and acts by activating insulin secretion, but the role of GLP1 in the colon, where it is predominantly produced, remains unknown. Here we characterized the apical versus basolateral secretion of GLP1 and PYY and the paracrine mechanisms of action of these enterohormones in the human colon. We stimulated human colon tissue in different ex vivo models with meat peptone and we used immunofluorescence to study the presence of canonical and non-canonical receptors of GLP1. We found that PYY and GLP1 are secreted mainly at the gut lumen in unstimulated and stimulated conditions. We detected DPP4 activity and found that GLP1R and GCGR are widely expressed in the human colon epithelium. Unlike GLP1R, GCGR is not expressed in the lamina propria, but it is located in the crypts of Lieberkühn. We detected GLP1R expression in human colon cell culture models. We show that the apical secretion of PYY and GLP1 occurs in humans, and we provide evidence that GLP1 has a potential direct paracrine function through the expression of its receptors in the colon epithelium, opening new therapeutic perspectives in the use of enterohormones analogues in metabolic pathologies.
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Exploring New Drug Targets for Type 2 Diabetes: Success, Challenges and Opportunities. Biomedicines 2022; 10:biomedicines10020331. [PMID: 35203540 PMCID: PMC8869656 DOI: 10.3390/biomedicines10020331] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 01/02/2023] Open
Abstract
There are substantial shortcomings in the drugs currently available for treatment of type 2 diabetes mellitus. The global diabetic crisis has not abated despite the introduction of new types of drugs and targets. Persistent unaddressed patient needs remain a significant factor in the quest for new leads in routine studies. Drug discovery methods in this area have followed developments in the market, contributing to a recent rise in the number of molecules. Nevertheless, troubling developments and fresh challenges are still evident. Recently, metformin, the most widely used first-line drug for diabetes, was found to contain a carcinogenic contaminant known as N-nitroso dimethylamine (NDMA). Therefore, purity and toxicity are also a big challenge for drug discovery and development. Moreover, newer drug classes against SGLT-2 illustrate both progress and difficulties. The same was true previously in the case of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Furthermore, researchers must study the importance of mechanistic characteristics of novel compounds, as well as exposure-related hazardous aspects of current and newly identified protein targets, in order to identify new pharmacological molecules with improved selectivity and specificity.
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10
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Li Y, Glotfelty EJ, Karlsson T, Fortuno LV, Harvey BK, Greig NH. The metabolite GLP-1 (9-36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration. J Neurochem 2021; 159:867-886. [PMID: 34569615 DOI: 10.1111/jnc.15521] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 09/17/2021] [Accepted: 09/22/2021] [Indexed: 12/23/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) is best known for its insulinotropic action following food intake. Its metabolite, GLP-1 (9-36), was assumed biologically inactive because of low GLP-1 receptor (GLP-1R) affinity and non-insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP-1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP-1 (9-36)'s biological role. We use human SH-SY5Y neuroblastoma cells and a GLP-1R over-expressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP-1 (9-36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP-1 (9-36)'s signaling pathways, including cyclic-adenosine monophosphate (cAMP), protein kinase-A (PKA), and 5' adenosine monophosphate-activated protein kinase (AMPK) via the use of ELISA, pharmacological inhibitors, or GLP-1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti-inflammatory effects of GLP-1 (9-36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP-1 (9-36) to primary dissociation cultures challenged with α-synuclein or amyloid-β and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP-1R, cAMP, PKA, and AMPK-mediated neurotrophic and neuroprotective effects of GLP-1 (9-36). The metabolite significantly reduced IL-6 and TNF-α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP-1 (9-36) in primary neuron cultures challenged with α-synuclein or amyloid-β. These studies enhance understanding of GLP-1 (9-36)'s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts.
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Affiliation(s)
- Yazhou Li
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA
| | - Elliot J Glotfelty
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.,Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Tobias Karlsson
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Lowella V Fortuno
- Molecular Mechanisms of Cellular Stress and Inflammation Unit, Integrative Neuroscience Department, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
| | - Brandon K Harvey
- Molecular Mechanisms of Cellular Stress and Inflammation Unit, Integrative Neuroscience Department, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
| | - Nigel H Greig
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA
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Shi S, Ding F, Liu X, Wang L, Wang X, Zhang S, Zhao G, Song Y. Clinical and radiographic variables related to implants with simultaneous grafts among type 2 diabetic patients treated with different hypoglycemic medications: a retrospective study. BMC Oral Health 2021; 21:214. [PMID: 33906655 PMCID: PMC8080327 DOI: 10.1186/s12903-021-01583-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
Background The influence of different hypoglycemic agents on peri-implant variables among type 2 diabetes mellitus patients is still unclear. Therefore, the aim of this study was to assess the radiographic marginal bone loss and clinical parameters around implants in patients using different hypoglycemic agents. Methods In this retrospective cohort study, the dental implant records of type 2 diabetes mellitus patients who met the inclusion criteria were collected. The patients using only single medication as follows: insulin, metformin, or glucagon-like peptide-1 (GLP-1) drugs, were grouped according to their medication. These patients received implant placement with the same initial status, and all the prosthesis restorations were cement-retained ceramic crowns. The peri-implant marginal bone levels were evaluated by periapical radiographs immediately after implant placement and at 1 and 2-year follow-up visits. The baseline characteristics were compared among groups. The peri-implant radiographic marginal bone loss and clinical parameters were preliminarily compared using the Kruskal–Wallis test, and then the covariates were controlled by covariance analysis. Bonferroni post hoc adjustment test was performed for the multiple comparisons. Results After a review of more than 7000 medical records, a total of 150 patients with 308 implants at 1-year follow-up were assessed. The peri-implant marginal bone loss in the GLP-1 drug group was significantly smaller than the insulin group and metformin group (P < 0.01). The radiographic bone loss in the metformin group was higher than the insulin group (P < 0.05). Some of these included patients were lost to follow-up. Only 74 patients with 129 implants completed the 2-year follow-up. The radiographic bone loss in the metformin group was still higher than the insulin group (P < 0.05) and GLP-1 group (P < 0.01). There was no significant difference in the BOP (+) and the mean PD among groups (P > 0.05). Conclusions The radiographic variables were not exactly the same among the patients with different hypoglycemic agents at both the 1 and 2-year follow-ups. After ensuring consistency in baseline characteristics, the positive effect of GLP-1 drugs on peri-implant bone remodeling may be no less than insulin or metformin. More studies are needed to verify the direct effect of these drugs on peri-implant bone. Clinical trial registration number ChiCTR2000034211 (retrospectively registered).
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Affiliation(s)
- Shaojie Shi
- State key Laboratory of military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Feng Ding
- State key Laboratory of military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Xiangdong Liu
- State key Laboratory of military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Lei Wang
- State key Laboratory of military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Xingxing Wang
- State key Laboratory of military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Sijia Zhang
- State key Laboratory of military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Guoqiang Zhao
- State key Laboratory of military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yingliang Song
- State key Laboratory of military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
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12
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Helmstädter J, Keppeler K, Küster L, Münzel T, Daiber A, Steven S. Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-The role of the GLP-1 receptor. Br J Pharmacol 2021; 179:659-676. [PMID: 33764504 PMCID: PMC8820186 DOI: 10.1111/bph.15462] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/12/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular outcome trials revealed cardiovascular benefits for type 2 diabetes mellitus patients when treated with long‐acting glucagon‐like peptide‐1 (GLP‐1) receptor agonists. In the last decade, major advances were made characterising the physiological effects of GLP‐1 and its action on numerous targets including brain, liver, kidney, heart and blood vessels. However, the effects of GLP‐1 and receptor agonists, and the GLP‐1 receptor on the cardiovascular system have not been fully elucidated. We compare results from cardiovascular outcome trials of GLP‐1 receptor agonists and review pleiotropic clinical and preclinical data concerning cardiovascular protection beyond glycaemic control. We address current knowledge on GLP‐1 and receptor agonist actions on the heart, vasculature, inflammatory cells and platelets, and discuss evidence for GLP‐1 receptor‐dependent versus independent effects secondary of GLP‐1 metabolites. We conclude that the favourable cardiovascular profile of GLP‐1 receptor agonists might expand their therapeutic use for treating cardiovascular disease even in non‐diabetic populations.
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Affiliation(s)
- Johanna Helmstädter
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Karin Keppeler
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Leonie Küster
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.,Center of Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany.,Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.,Center of Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany.,Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Mainz, Germany
| | - Sebastian Steven
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.,Center of Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany
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13
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Huang J, Liu Y, Cheng L, Li J, Zhang T, Zhao G, Zhang H. Glucagon-like peptide-1 cleavage product GLP-1(9-36) reduces neuroinflammation from stroke via the activation of insulin-like growth factor 1 receptor in astrocytes. Eur J Pharmacol 2020; 887:173581. [PMID: 32949596 DOI: 10.1016/j.ejphar.2020.173581] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 12/20/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) is an endogenous gut hormone and a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36), which was formerly considered a "bio-inactive" metabolite mainly due to its low affinity for GLP-1 receptor, possesses unique properties such as cardiovascular protection. Little is known about the effects and mechanisms of GLP-1 (9-36) in cerebral ischemia and reperfusion injury. Here, we report that systemic application of GLP-1 (9-36) in adult mice facilitated functional recovery and reduced infarct volume, astrogliosis, and neuronal apoptosis following middle cerebral artery occlusion and reperfusion. Interestingly, these effects were still observed in GLP-1 receptor knockout (Glp-1rKO) mice but were partially reversed in insulin-like growth factor 1 (IGF-1) receptor knockdown (Igf-1rKD) mice. Primary astrocytes were cultured and subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), and enzyme-linked immunosorbent assay indicated that GLP-1 (9-36) pretreatment reduces tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 levels. This effect was not diminished in Glp-1rKO astrocytes but was reversed in Igf-1rKO astrocytes, emphasizing that the anti-inflammatory effect of GLP-1 (9-36) in astrocytes is independent of GLP-1 receptor signaling and is instead mediated by IGF-1 receptor. Immunoprecipitation experiments showed that GLP-1 (9-36) directly interacts with IGF-1 receptor in astrocytes. Western blot data indicated that GLP-1 (9-36) activates IGF-1 receptor and downstream PI3K-AKT pathway in astrocytes upon OGD/R injury, which was abrogated by preincubation with IGF-1 receptor autophosphorylation inhibitor picropodophyllin. Thus, our findings suggest that GLP-1 (9-36) improved stroke outcome by reducing inflammation in astrocytes via interaction with IGF-1 receptor.
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Affiliation(s)
- Jing Huang
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, China; Department of Neurology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yunhan Liu
- Department of Neurology Impatient, Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Liusiyuan Cheng
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, China
| | - Jihong Li
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, China
| | - Tangrui Zhang
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, China
| | - Gang Zhao
- Department of Neurology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Huinan Zhang
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, China.
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14
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Zhou W, Shao W, Zhang Y, Liu D, Liu M, Jin T. Glucagon-like peptide-1 receptor mediates the beneficial effect of liraglutide in an acute lung injury mouse model involving the thioredoxin-interacting protein. Am J Physiol Endocrinol Metab 2020; 319:E568-E578. [PMID: 32723174 PMCID: PMC7839242 DOI: 10.1152/ajpendo.00292.2020] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Repurposing clinically used drugs is among the important strategies in drug discovery. Glucagon-like peptide-1 (GLP-1) and its diabetes-based drugs, such as liraglutide, possess a spectrum of extra-pancreatic functions, while GLP-1 receptor (GLP-1R) is most abundantly expressed in the lung. Recent studies have suggested that GLP-1-based drugs exert beneficial effects in chronic, as well as acute, lung injury rodent models. Here, we show that liraglutide pretreatment reduced LPS induced acute lung injury in mice. It significantly reduced lung injury score, wet/dry lung weight ratio, bronchoalveolar lavage fluid immune cell count and protein concentration, and cell apoptosis in the lung, and it was associated with reduced lung inflammatory cytokine and chemokine gene expression. Importantly, these effects were virtually absent in GLP-1R-/- mice. A well-known function of GLP-1 and GLP-based drugs in pancreatic β-cells is the attenuation of high-glucose stimulated expression of thioredoxin-interacting protein (TxNIP), a key component of inflammasome. LPS-challenged lungs showed elevated TxNIP mRNA and protein expression, which was attenuated by liraglutide treatment in a GLP-1R-dependent manner. Hence, our observations suggest that GLP-1R is essential in mediating beneficial effects of liraglutide in acute lung injury, with the inflammasome component TxNIP as a potential target.
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Affiliation(s)
- Wenyong Zhou
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Weijuan Shao
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yu Zhang
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Dinghui Liu
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Cardiology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Mingyao Liu
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Tianru Jin
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Banting and Best Diabetes Centre, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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15
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Fan S, Xiong Q, Zhang X, Zhang L, Shi Y. Glucagon-like peptide 1 reverses myocardial hypertrophy through cAMP/PKA/RhoA/ROCK2 signaling. Acta Biochim Biophys Sin (Shanghai) 2020; 52:612-619. [PMID: 32386193 DOI: 10.1093/abbs/gmaa038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 01/10/2020] [Accepted: 03/31/2020] [Indexed: 12/19/2022] Open
Abstract
Myocardial hypertrophy is a major pathological and physiological process during heart failure. Glucagon-like peptide 1 (GLP-1) is a glucagon incretin hormone released from the gut endocrine L-cells that has protective effects on various cardiovascular diseases, including hypertension, atherosclerosis, and myocardial hypertrophy. However, the protective mechanisms of GLP-1 in myocardial hypertrophy remain unclear. Here, we showed that the GLP-1 agonist liraglutide and dipeptidyl peptidase 4 inhibitor alogliptin decreased heart weight and cardiac muscle cell volume in spontaneously hypertensive rats (SHR). In H9C2 cell hypertensive models induced by angiotensin II, GLP-1 treatment reduced myocardial cell volume, inhibited the expressions of atrial natriuretic peptide, brain/B-type natriuretic peptide, β-myosin heavy chain, RhoA, and ROCK2, and decreased MLC and MYPT1 phosphorylation. When H9C2 cells were treated with H89, a PKA inhibitor, the inhibitory effect of GLP-1 disappeared, while the inhibitory role was enhanced under the treatment of Y-27632, a ROCK2 inhibitor. These results suggested that GLP-1 might reverse myocardial hypertrophy through the PKA/RhoA/ROCK2 signaling pathway.
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Affiliation(s)
- Shaohua Fan
- Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China
| | - Qianfeng Xiong
- Department of Cardiology, Fengcheng People’s Hospital, Fengcheng 331100, China
| | - Xin Zhang
- Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China
| | - Lihui Zhang
- Department of Geriatrics, Shanxi Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan 030024, China
| | - Yawei Shi
- Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China
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16
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Wu P, Liu Z, Jiang X, Fang H. An Overview of Prospective Drugs for Type 1 and Type 2 Diabetes. Curr Drug Targets 2020; 21:445-457. [PMID: 31670620 DOI: 10.2174/1389450120666191031104653] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 10/07/2019] [Accepted: 10/16/2019] [Indexed: 12/14/2022]
Abstract
Aims:
The aim of this study is to provide an overview of several emerging anti-diabetic
molecules.
Background:
Diabetes is a complex metabolic disorder involving the dysregulation of glucose homeostasis
at various levels. Insulin, which is produced by β-pancreatic cells, is a chief regulator of glucose
metabolism, regulating its consumption within cells, which leads to energy generation or storage as glycogen.
Abnormally low insulin secretion from β-cells, insulin insensitivity, and insulin tolerance lead to
higher plasma glucose levels, resulting in metabolic complications. The last century has witnessed extraordinary
efforts by the scientific community to develop anti-diabetic drugs, and these efforts have resulted
in the discovery of exogenous insulin and various classes of oral anti-diabetic drugs.
Objective:
Despite these exhaustive anti-diabetic pharmaceutical and therapeutic efforts, long-term
glycemic control, hypoglycemic crisis, safety issues, large-scale economic burden and side effects remain
the core problems.
Method:
The last decade has witnessed the development of various new classes of anti-diabetic drugs
with different pharmacokinetic and pharmacodynamic profiles. Details of their FDA approvals and
advantages/disadvantages are summarized in this review.
Results:
The salient features of insulin degludec, sodium-glucose co-transporter 2 inhibitors, glucokinase
activators, fibroblast growth factor 21 receptor agonists, and GLP-1 agonists are discussed.
Conclusion :
In the future, these new anti-diabetic drugs may have broad clinical applicability. Additional
multicenter clinical studies on these new drugs should be conducted.
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Affiliation(s)
- Ping Wu
- Department of Pharmacology, 3rd Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China
| | - Zhenyu Liu
- Department of Endocrinology, 3rd Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China
| | - Xiaohong Jiang
- Department of Endocrinology, 3rd Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China
| | - Hao Fang
- Department of Pharmacology, 3rd Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China
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17
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Lytvyn Y, Bjornstad P, van Raalte DH, Heerspink HL, Cherney DZI. The New Biology of Diabetic Kidney Disease-Mechanisms and Therapeutic Implications. Endocr Rev 2020; 41:5601424. [PMID: 31633153 PMCID: PMC7156849 DOI: 10.1210/endrev/bnz010] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023]
Abstract
Diabetic kidney disease remains the most common cause of end-stage kidney disease in the world. Despite reductions in incidence rates of myocardial infarction and stroke in people with diabetes over the past 3 decades, the risk of diabetic kidney disease has remained unchanged, and may even be increasing in younger individuals afflicted with this disease. Accordingly, changes in public health policy have to be implemented to address the root causes of diabetic kidney disease, including the rise of obesity and diabetes, in addition to the use of safe and effective pharmacological agents to prevent cardiorenal complications in people with diabetes. The aim of this article is to review the mechanisms of pathogenesis and therapies that are either in clinical practice or that are emerging in clinical development programs for potential use to treat diabetic kidney disease.
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Affiliation(s)
- Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Department of Medicine, Division of Nephrology, Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado
| | - Daniel H van Raalte
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Netherlands
| | - Hiddo L Heerspink
- The George Institute for Global Health, Sydney, Australia.,Department of Clinical Pharmacology, University of Groningen, Groningen, Netherlands
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
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18
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Cui SS, Feng XB, Zhang BH, Xia ZY, Zhan LY. Exendin-4 attenuates pain-induced cognitive impairment by alleviating hippocampal neuroinflammation in a rat model of spinal nerve ligation. Neural Regen Res 2020; 15:1333-1339. [PMID: 31960821 PMCID: PMC7047783 DOI: 10.4103/1673-5374.272620] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Glucagon-like peptide-1 receptor has anti-apoptotic, anti-inflammatory, and neuroprotective effects. It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses; however, it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms. We explored the effects of glucagon-like peptide-1 receptor on nociception, cognition, and neuroinflammation in chronic pain. A rat model of chronic pain was established using left L5 spinal nerve ligation. The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation. Electrophysiological examinations showed that, after treatment with exendin-4, paw withdrawal frequency of the left limb was significantly reduced, and pain was relieved. In addition, in the Morris water maze test, escape latency increased and the time to reach the platform decreased following exendin-4 treatment. Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus, as well as an increase in the expression of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6. All of these effects could be reversed by exendin-4 treatment. These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China (approval No. WDRM 20171214) on September 22, 2017.
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Affiliation(s)
- Shan-Shan Cui
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Xiao-Bo Feng
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Bing-Hong Zhang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Zhong-Yuan Xia
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Li-Ying Zhan
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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19
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Ye F, Liu Y, Li S, Chen JDZ. Hypoglycemic Effects of Intestinal Electrical Stimulation by Enhancing Nutrient-Stimulated Secretion of GLP-1 in Rats. Obes Surg 2019; 28:2829-2835. [PMID: 29728986 DOI: 10.1007/s11695-018-3257-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE To find out the best location for intestinal electrical stimulation (IES) to decrease hyperglycemia, and mechanisms involving intraluminal nutrients and plasma glucagon-like peptide-1 (GLP-1) MATERIALS AND METHODS: Eight rats had electrodes implanted at the duodenum and ileums for IES. The oral glucose tolerance test (OGTT) was performed with IES and sham-IES and with/without GLP-1 antagonist, exendin. To study the role of intraluminal nutrients, the experiment was repeated using intraperitoneal glucose tolerance test (IPGTT). Glucagon was administrated in the OGTT/IPGTT to induce temporary hyperglycemia. RESULTS (1) In the OGTT, IES at the duodenum reduced blood glucose from 30 to 120 min after oral glucose (P < 0.05, vs. sham-IES) and the hypoglycemic effect was more potent than IES at the ileum. (2) The hypoglycemic effect of IES was absent in IPGTT experiment, suggesting the important role of intraluminal nutrients. (3) An increase in GLP-1 was noted in the OGTT with IES at the duodenum in comparison with sham-IES. Moreover, the blocking effect of exendin suggested the role of GLP-1 in the hypoglycemic effect of IES. CONCLUSIONS The best stimulation location for IES to decrease hyperglycemia is in the duodenum. The hypoglycemic effect of IES is attributed to the enhancement in nutrient-stimulated release of GLP-1.
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Affiliation(s)
- Feng Ye
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA
- The 1st Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Division of Gastroenterology and Hepatology, Johns Hopkins Center for Neurogastroenterology, John's Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yi Liu
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA
- The 1st Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Division of Gastroenterology and Hepatology, Johns Hopkins Center for Neurogastroenterology, John's Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shiying Li
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA
| | - Jiande D Z Chen
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA.
- Division of Gastroenterology and Hepatology, Johns Hopkins Center for Neurogastroenterology, John's Hopkins University School of Medicine, Baltimore, MD, USA.
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20
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Sposito AC, Berwanger O, de Carvalho LSF, Saraiva JFK. GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data. Cardiovasc Diabetol 2018; 17:157. [PMID: 30545359 PMCID: PMC6292070 DOI: 10.1186/s12933-018-0800-2] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023] Open
Abstract
Patients with type 2 diabetes (T2DM) have a substantial risk of developing cardiovascular disease. The strong connection between the severity of hyperglycaemia, metabolic changes secondary to T2DM and vascular damage increases the risk of macrovascular complications. There is a challenging demand for the development of drugs that control hyperglycaemia and influence other metabolic risk factors to improve cardiovascular outcomes such as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina and heart failure (major adverse cardiovascular events). In recent years, introduction of the new drug class of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has changed the treatment landscape as GLP-1RAs have become well-established therapies in T2DM. The benefits of GLP-1RAs are derived from their pleiotropic effects, which include appetite control, glucose-dependent secretion of insulin and inhibition of glucagon secretion. Importantly, their beneficial effects extend to the cardiovascular system. Large clinical trials have evaluated the cardiovascular effects of GLP-1RAs in patients with T2DM and elevated risk of cardiovascular disease and the results are very promising. However, important aspects still require elucidation, such as the specific mechanisms involved in the cardioprotective effects of these drugs. Careful interpretation is necessary because of the heterogeneity across the trials concerning the definition of cardiovascular risk or cardiovascular disease, baseline characteristics, routine care and event rates. The aim of this review is to describe the main clinical aspects of the GLP-1RAs, compare them using data from both the mechanistic and randomized controlled trials and discuss potential reasons for improved cardiovascular outcomes observed in these trials. This review may help clinicians to decide which treatment is most appropriate in reducing cardiovascular risk in patients with T2DM.
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Affiliation(s)
- Andrei C Sposito
- Atherosclerosis and Vascular Biology Laboratory (AtheroLab), Cardiology Division, Faculty of Medical Sciences, State University of Campinas (Unicamp), 13084-971, Campinas, Sao Paulo, Brazil.
| | - Otávio Berwanger
- Academic Research Organization (ARO), Albert Einstein Hospital, Av. Albert Einstein 627, Sao Paulo, SP, 05651-901, Brazil
| | - Luiz Sérgio F de Carvalho
- Atherosclerosis and Vascular Biology Laboratory (AtheroLab), Cardiology Division, Faculty of Medical Sciences, State University of Campinas (Unicamp), 13084-971, Campinas, Sao Paulo, Brazil
| | - José Francisco Kerr Saraiva
- Cardiology Division, Pontifical Catholic University of Campinas Medicine School, Rua Engenheiro Carlos Stevenson 560, Campinas, Sao Paulo, 13092-132, Brazil
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Verma RK, Sriramaneni R, Pandey M, Chaudhury H, Gorain B, Gupta G. Current updates on pharmacological roles of glucagon-like peptide 1 in obesity. Panminerva Med 2018; 60:224-225. [DOI: 10.23736/s0031-0808.18.03479-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Neuroendocrinology of Adipose Tissue and Gut-Brain Axis. ADVANCES IN NEUROBIOLOGY 2018; 19:49-70. [PMID: 28933061 DOI: 10.1007/978-3-319-63260-5_3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Food intake and energy expenditure are closely regulated by several mechanisms which involve peripheral organs and nervous system, in order to maintain energy homeostasis.Short-term and long-term signals express the size and composition of ingested nutrients and the amount of body fat, respectively. Ingested nutrients trigger mechanical forces and gastrointestinal peptide secretion which provide signals to the brain through neuronal and endocrine pathways. Pancreatic hormones also play a role in energy balance exerting a short-acting control regulating the start, end, and composition of a meal. In addition, insulin and leptin derived from adipose tissue are involved in long-acting adiposity signals and regulate body weigh as well as the amount of energy stored as fat over time.This chapter focuses on the gastrointestinal-, pancreatic-, and adipose tissue-derived signals which are integrated in selective orexigenic and anorexigenic brain areas that, in turn, regulate food intake, energy expenditure, and peripheral metabolism.
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Petersen N, Frimurer TM, Terndrup Pedersen M, Egerod KL, Wewer Albrechtsen NJ, Holst JJ, Grapin-Botton A, Jensen KB, Schwartz TW. Inhibiting RHOA Signaling in Mice Increases Glucose Tolerance and Numbers of Enteroendocrine and Other Secretory Cells in the Intestine. Gastroenterology 2018; 155:1164-1176.e2. [PMID: 29935151 DOI: 10.1053/j.gastro.2018.06.039] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 06/13/2018] [Accepted: 06/14/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Glucagon-like peptide 1 (GLP1) is produced by L cells in the intestine, and agonists of the GLP1 receptor are effective in the treatment of diabetes. Levels of GLP1 increase with numbers of L cells. Therefore, agents that increase numbers of L cell might be developed for treatment of diabetes. Ras homologue family member A (RhoA) signaling through Rho-associated coiled-coil-containing protein kinases 1 and 2 (ROCK1 and ROCK2) controls cell differentiation, but it is not clear whether this pathway regulates enteroendocrine differentiation in the intestinal epithelium. We investigated the effects of Y-27632, an inhibitor of ROCK1 and ROCK2, on L-cell differentiation. METHODS We collected intestinal tissues from GLU-Venus, GPR41-RFP, and Neurog3-RFP mice, in which the endocrine lineage is fluorescently labeled, for in vitro culture and histologic analysis. Small intestine organoids derived from these mice were cultured with Y-27632 and we measured percentages of L cells, expression of intestinal cell-specific markers, and secretion of GLP1 in medium. Mice were fed a normal chow or a high-fat diet and given Y-27632 or saline (control) and blood samples were collected for measurement of GLP1, insulin, and glucose. RESULTS Incubation of intestinal organoids with Y-27632 increased numbers of L cells and secretion of GLP1. These increases were associated with upregulated expression of genes encoding intestinal hormones, neurogenin 3, neurogenic differentiation factor 1, forkhead box A1 and A2, and additional markers of secretory cells. Mice fed the normal chow diet and given Y-27632 had increased numbers of L cells in intestinal tissues, increased plasma levels of GLP1 and insulin, and lower blood levels of glucose compared with mice fed the normal chow diet and given saline. In mice with insulin resistance induced by the high-fat diet, administration of Y-27632 increased secretion of GLP1 and glucose tolerance compared with administration of saline. CONCLUSIONS In mouse intestinal organoids, an inhibitor of RhoA signaling increased the differentiation of the secretory lineage and the development of enteroendocrine cells. Inhibitors of RhoA signaling or other strategies to increase numbers of L cells might be developed for treatment of patients with type 2 diabetes or for increasing glucose tolerance.
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Affiliation(s)
- Natalia Petersen
- Section of Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Thomas M Frimurer
- Section of Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Kristoffer L Egerod
- Section of Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Biomedical Sciences and the Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Translational Metabolic Physiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences and the Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Translational Metabolic Physiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anne Grapin-Botton
- Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Medical and Health, University of Copenhagen, Copenhagen, Denmark
| | - Kim B Jensen
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Medical and Health, University of Copenhagen, Copenhagen, Denmark
| | - Thue W Schwartz
- Section of Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Thomas MC. The potential and pitfalls of GLP-1 receptor agonists for renal protection in type 2 diabetes. DIABETES & METABOLISM 2018; 43 Suppl 1:2S20-2S27. [PMID: 28431667 DOI: 10.1016/s1262-3636(17)30069-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) offer substantial benefits for the management of glucose levels in type 2 diabetes. In addition, recent data from clinical trials have demonstrated that treatment with Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) are also able to reduce new onset macroalbuminuria. These benefits may be consistent with the known effects of GLP-1 RA on traditional risk factors for progressive kidney disease including glucose lowering, blood pressure lowering, reduced insulin levels and weight reduction. However, emerging evidence suggests that GLP-1 RA can also have direct effects in the kidney, including inhibiting NHE3-dependent sodium reabsorption in the proximal tubule. Additional effects on the intrarenal renin angiotensin system, ischaemia/hypoxia, inflammation, apoptosis and neural signalling may also contribute to renal benefits. The extent to which these effects are mediated by the GLP-1R remains to be established. Recent studies confirm that the metabolic products of GLP-1 retain important antioxidant and anti-apoptotic activities that are GLP-1 R independent. Moreover the divergent peptide sequences of the currently available GLP-1 RA may mean that divergent reno-protective efficacy could be anticipated from different GLP-1 RA on this basis. Kidney disease is an important and deadly clinical outcome, and one worth preventing. Although both experimental and clinical data now support the possibility of renoprotective effects arising from treatment with GLP-1 RA, further work is needed to optimise these effects. A logical synergism with SGLT2 inhibition also exists, and at least in the short term, this combination approach may become the most useful way to protect the kidney in type 2 diabetes.
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Affiliation(s)
- Merlin C Thomas
- Department of Diabetes, Monash University, Level 5, 99 Commercial Rd, Melbourne, Victoria, Australia.
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Panchapakesan U, Pollock C. Drug repurposing in kidney disease. Kidney Int 2018; 94:40-48. [PMID: 29628139 DOI: 10.1016/j.kint.2017.12.026] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 12/17/2017] [Accepted: 12/19/2017] [Indexed: 12/18/2022]
Abstract
Drug repurposing, is the re-tasking of known medications for new clinical indications. Advantages, compared to de novo drug development, include reduced cost and time to market plus the added benefit of a known pharmacokinetic and safety profiles. Suitable drug candidates are identified through serendipitous observations, data mining, or increased understanding of disease mechanisms. This review highlights drugs suited for repurposing in kidney disease. The main cause of mortality in patients with chronic kidney disease is cardiovascular disease. Hence, we have included CV endpoints for the drugs. This review begins with candidates in acute kidney injury: vasodilators levosimendan and vitamin D, followed by candidates in CKD, with particular focus on diabetic kidney disease, autosomal dominant polycystic kidney disease, and focal segmental glomerulosclerosis. Examples include glucose-lowering drugs (sodium glucose co-transporter 2 inhibitors, glucagon-like peptide 1 agonists, and metformin), which have mechanistic potential for cardiac and/or renal protection beyond glucose lowering, with broader applicability to the nondiabetic population; xanthine oxidase inhibitors (allopurinol, febuxostat), selective endothelin receptor A antagonist (atrasentan), Janus kinase inhibitor (baricitinib), selective costimulation modulator (abatacept), pentoxyfylline, and the DNA demethylating agent/vasodilator (hydralazine).
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Affiliation(s)
- Usha Panchapakesan
- Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, New South Wales 2065, Australia.
| | - Carol Pollock
- Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, New South Wales 2065, Australia
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Patel V, Joharapurkar A, Kshirsagar S, Sutariya B, Patel M, Pandey D, Patel H, Ranvir R, Kadam S, Patel D, Bahekar R, Jain M. Coagonist of GLP-1 and glucagon decreases liver inflammation and atherosclerosis in dyslipidemic condition. Chem Biol Interact 2018; 282:13-21. [DOI: 10.1016/j.cbi.2018.01.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 12/13/2017] [Accepted: 01/05/2018] [Indexed: 12/25/2022]
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Paternoster S, Falasca M. Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1. Front Endocrinol (Lausanne) 2018; 9:584. [PMID: 30364192 PMCID: PMC6193070 DOI: 10.3389/fendo.2018.00584] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 09/14/2018] [Indexed: 12/11/2022] Open
Abstract
An aging world population exposed to a sedentary life style is currently plagued by chronic metabolic diseases, such as type-2 diabetes, that are spreading worldwide at an unprecedented rate. One of the most promising pharmacological approaches for the management of type 2 diabetes takes advantage of the peptide hormone glucagon-like peptide-1 (GLP-1) under the form of protease resistant mimetics, and DPP-IV inhibitors. Despite the improved quality of life, long-term treatments with these new classes of drugs are riddled with serious and life-threatening side-effects, with no overall cure of the disease. New evidence is shedding more light over the complex physiology of GLP-1 in health and metabolic diseases. Herein, we discuss the most recent advancements in the biology of gut receptors known to induce the secretion of GLP-1, to bridge the multiple gaps into our understanding of its physiology and pathology.
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Oh YS, Jun HS. Effects of Glucagon-Like Peptide-1 on Oxidative Stress and Nrf2 Signaling. Int J Mol Sci 2017; 19:ijms19010026. [PMID: 29271910 PMCID: PMC5795977 DOI: 10.3390/ijms19010026] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 12/19/2017] [Accepted: 12/20/2017] [Indexed: 12/16/2022] Open
Abstract
Oxidative cellular damage caused by free radicals is known to contribute to the pathogenesis of various diseases such as cancer, diabetes, and neurodegenerative diseases, as well as to aging. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein1 (Keap1) signaling pathways play an important role in preventing stresses including oxidative and inflammatory stresses. Nrf2 is a master regulator of cellular stress responses, induces the expression of antioxidant and detoxification enzymes, and protects against oxidative stress-induced cell damage. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which was originally found to increase insulin synthesis and secretion. It is now widely accepted that GLP-1 has multiple functions beyond glucose control in various tissues and organs including brain, kidney, and heart. GLP-1 and GLP-1 receptor agonists are known to be effective in many chronic diseases, including diabetes, via antioxidative mechanisms. In this review, we summarize the current knowledge regarding the role of GLP-1 in the protection against oxidative damage and the activation of the Nrf2 signaling pathway.
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Affiliation(s)
- Yoon Sin Oh
- Department of Food and Nutrition, Eulji University, Seongnam 13135, Korea.
| | - Hee-Sook Jun
- College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 21936, Korea.
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea.
- Gachon Medical Research Institute, Gil Hospital, Incheon 21565, Korea.
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