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Sadeghi E, Rahmanipour E, Valsecchi N, Kapoor S, Cicinelli MV, Chhablani J. An update on ocular effects of antidiabetic medications. Surv Ophthalmol 2025; 70:704-712. [PMID: 39855606 DOI: 10.1016/j.survophthal.2025.01.010] [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: 07/14/2024] [Revised: 01/15/2025] [Accepted: 01/20/2025] [Indexed: 01/27/2025]
Abstract
The global increase in the prevalence of type 2 diabetes has led to the development and implementation of new classes of antidiabetic medications, introducing advanced therapeutic options for the management of the disease. These new medications, though primarily designed to regulate blood glucose levels, also have applications in weight management, potentially transforming the current approaches to diabetes treatment. Newer medications, however, have ophthalmic side effects with controversies in trials and real-life data. We comprehensively assessed the ocular benefits and adverse effects of traditional and newer-generation anti-diabetic drugs. Our primary focus is on how these newer medications affect the stage of diabetic retinopathy. Additionally, we explore the associations between these medications and other ocular conditions, including age-related macular degeneration, glaucoma, orbital conditions, and diseases impacting the ocular surface. Furthermore, we provide contextual background by discussing the ocular effects of traditional anti-diabetic drugs.
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Affiliation(s)
- Elham Sadeghi
- University of Pittsburgh, School of Medicine, PA, USA.
| | - Elham Rahmanipour
- Immunology Research Center, Mashhad University of Medical Science, Mashhad, Iran.
| | - Nicola Valsecchi
- University of Pittsburgh, School of Medicine, PA, USA; Ophthalmology Unit, Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum University of Bologna, Bologna, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
| | - Saloni Kapoor
- University of Pittsburgh, School of Medicine, PA, USA.
| | | | - Jay Chhablani
- University of Pittsburgh, School of Medicine, PA, USA.
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Xu M, Lv D, Wei H, Li Z, Jin S, Liu Q, Zhang Y, Liu Y. Effects of antidiabetic agents on lipid metabolism of skeletal muscle: A narrative review. Diabetes Obes Metab 2025; 27:1693-1707. [PMID: 39807619 DOI: 10.1111/dom.16189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 12/17/2024] [Accepted: 12/26/2024] [Indexed: 01/16/2025]
Abstract
Metabolic syndrome-related diseases frequently involve disturbances in skeletal muscle lipid metabolism. The accumulation of lipid metabolites, lipid-induced mitochondrial stress in skeletal muscle cells, as well as the inflammation of adjacent adipose tissue, are associated with the development of insulin resistance and metabolic dysfunction. Consequently, when antidiabetic medications are used to treat various chronic conditions related to hyperglycaemia, the impact on skeletal muscle lipid metabolism should not be overlooked. However, current research has predominantly focused on muscle mass rather than skeletal muscle lipid metabolism and its interplay with glucose metabolism. In this review, we summarised the latest research on the effects of antidiabetic drugs and certain natural compounds with antidiabetic activity on skeletal muscle lipid metabolism, focusing on data from preclinical to clinical studies. Given the widespread use of antidiabetic drugs, a better understanding of their effects on skeletal muscle lipid metabolism merits further attention in future research.
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Affiliation(s)
- Ming Xu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Dongqing Lv
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Hongxia Wei
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Zhe Li
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Shuqing Jin
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Qinhao Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
- Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
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Hemmati MA, Foroozanmehr B, Fardin A, Yaribeygi H. Glp-1 mimetic of sitagliptin improved oxidative stress and liver function tests via suppressing NOX-4 enzyme in hepatic tissues of diabetic rats. Biochem Biophys Res Commun 2025; 751:151455. [PMID: 39923462 DOI: 10.1016/j.bbrc.2025.151455] [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: 02/03/2025] [Revised: 02/04/2025] [Accepted: 02/04/2025] [Indexed: 02/11/2025]
Abstract
BACKGROUND AND AIM Oxidative stress acts as a major underlying cause of liver dysfunction in individuals with uncontrolled diabetes mellitus. However, the role of NOX-4 (nicotinamide adenine dinucleotide phosphate oxidase-4) enzymes remains poorly understood. Furthermore, the potential benefits of Sitagliptin in addressing this issue are unclear. Therefore, this experimental study aimed to explore the role of the NOX-4 enzyme and evaluate the potential benefits of Sitagliptin in diabetes-associated impaired liver tests. METHODS Male Wistar rats were randomly assigned to four groups: normal, normal-treated, diabetic, and diabetic-treated. Diabetes was induced by a single dose of Streptozotocin (45 mg/kg). Treated animals received Sitagliptin (20 mg/day, orally) for five weeks. Blood and tissue samples were collected at the end of the five-week period, and the required data were obtained using biochemical and genetic analysis methods. RESULTS In untreated rats, STZ-induced diabetes led to increased NOX-4 enzyme expression in the liver and a reduction in the antioxidant enzymes SOD, CAT, and GLT, collectively contributing to heightened oxidative damage, as indicated by elevated MDA levels. These alterations were associated with elevated circulating levels of SGOT, SGPT, and ALP. However, Sitagliptin reversed these alterations in diabetic animals. It enhanced the activity of antioxidant enzymes, reduced NOX-4 enzyme expression and oxidative damage in liver tissues, and subsequently improved liver function test results. CONCLUSION NOX-4 oxidant enzyme appears to play a critical role in diabetes-induced oxidative stress and subsequent liver failure. However, Sitagliptin may offer extra-glycemic benefits by normalizing NOX-4 enzyme activity levels, thereby improving liver function test results.
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Affiliation(s)
| | - Behina Foroozanmehr
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran; Functional Neusurgery Research Center, Research Institute of Functional Neurosurgery, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Fardin
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | - Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
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Wang M, Wang L, Sun H, Yuan H, Li Y. Mechanisms of ferroptosis and glucagon-like peptide-1 receptor agonist in post-percutaneous coronary intervention restenosis. Mol Cell Biochem 2025; 480:1465-1480. [PMID: 39283562 DOI: 10.1007/s11010-024-05118-6] [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: 08/15/2024] [Accepted: 09/06/2024] [Indexed: 02/21/2025]
Abstract
Cardiovascular disease (CVD) claims millions of lives every year, with atherosclerotic cardiovascular disease (ASCVD) being the main cause. ASCVD treatment includes drug therapy, lifestyle intervention, and Percutaneous Coronary Intervention (PCI) all of which significantly enhance cardiovascular function and reduce mortality. However, hyperplasia can lead to vascular obstruction, worsen angina symptoms, or even cause heart disease, affecting patients' long-term prognosis. Therefore, finding effective ways to combat hyperplasia is crucial for cardiovascular therapy. In recent years, ferroptosis has gained attention as a new form of cell death closely associated with several diseases, including cardiovascular diseases. It involves complex metabolic processes critical for cellular homeostasis and normal function. Abnormal proliferation and phenotypic transformation of vascular smooth muscle cells (VSMC) are crucial mechanisms underlying cardiovascular disease development. Inhibiting ferroptosis in VSMC has the potential to significantly reduce neointima proliferation. Glucagon-like peptide-1 receptor agonist (GLP-1RA) constitutes a widely employed class of hypoglycemic agents with direct implications for the cardiovascular system, mitigating adverse cardiovascular events. Research indicates that the stimulation of GLP-1 holds promise as a therapeutic strategy in mitigating cardiovascular events such as restenosis. Hence, investigating the potential of GLP-1RA as a treatment option for cardiovascular ailments carries immense clinical significance.
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Affiliation(s)
- Miao Wang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Liren Wang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Huanxin Sun
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Hong Yuan
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Yonghong Li
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
- Department of Cardiology, The Affiliated Cardiovascular Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266071, China.
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Forouzanmehr B, Hemmati MA, Atkin SL, Jamialahmadi T, Yaribeygi H, Sahebkar A. GLP-1 mimetics and diabetic ketoacidosis: possible interactions and clinical consequences. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:351-362. [PMID: 39172148 DOI: 10.1007/s00210-024-03384-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 08/14/2024] [Indexed: 08/23/2024]
Abstract
Diabetic ketoacidosis is a serious diabetes-related consequence that occurs in type 1 diabetes and less commonly in type 2 diabetes and is a major cause of death. It results from the metabolic consequences due to a lack of insulin secretion or impaired insulin activity in diabetes leading to dysregulated pathophysiologic pathways resulting in excessive ketone body formation. While ketone bodies are physiologic molecules, their high levels reduce the physiological pH of the blood and induce ketoacidosis, leading to increasing metabolic dysfunction. Glucagon-like peptide-1 (GLP-1) mimetics are a class of recently developed diabetes therapy that do not lead to hypoglycemic, but some reports have suggested a relationship between GLP-1 mimetics and ketogenesis. To clarify the possible interactions between GLP-1 mimetics and ketogenesis in diabetes, this review was undertaken to collate and interpret the literature.
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Affiliation(s)
- Behina Forouzanmehr
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Stephen L Atkin
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Bahrain
| | - Tannaz Jamialahmadi
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Yaribeygi H, Kashian K, Moghaddam KI, Karim SR, Bagheri N, Karav S, Jamialahmadi T, Rizzo M, Sahebkar A. Hepatic effects of GLP-1 mimetics in diabetic milieu: A mechanistic review of involved pathways. J Diabetes Complications 2025; 39:108928. [PMID: 39644538 DOI: 10.1016/j.jdiacomp.2024.108928] [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: 09/07/2024] [Revised: 11/25/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
Patients with diabetic are at a higher risk of developing hepatic disorders compared to non-diabetic individuals. This increased risk can be attributed to the diabetic environment, which triggers and exacerbates harmful pathways involved in both diabetic complications and hepatic disorders. Therefore, it is important to consider the use of antidiabetic agents that offer benefits beyond glycemic control and have positive effects on liver tissues. Glucagon-like peptide-1 (GLP-1) mimetics are a novel class of antidiabetic medications known for their potent blood sugar-lowering effects. Emerging evidence suggests that these drugs also have favorable effects on the liver. However, the precise effects and underlying mechanisms are not yet fully understood. In this review, we aim to provide a mechanistic perspective on the liver benefits of GLP-1 mimetics and outline the mediating mechanisms involved.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Kiana Kashian
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | | | | | - Narges Bagheri
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | - Sercan Karav
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale 17100, Turkey
| | - Tannaz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Manfredi Rizzo
- School of Medicine, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, Italy; Department of Biochemistry, Mohamed Bin Rashid University, Dubai, United Arab Emirates
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Yaribeygi H, Maleki M, Forouzanmehr B, Kesharwani P, Jamialahmadi T, Karav S, Sahebkar A. Exploring the antioxidant properties of semaglutide: A comprehensive review. J Diabetes Complications 2024; 38:108906. [PMID: 39549371 DOI: 10.1016/j.jdiacomp.2024.108906] [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: 07/27/2024] [Revised: 10/02/2024] [Accepted: 11/09/2024] [Indexed: 11/18/2024]
Abstract
Patients with diabetes commonly experience an aberrant production of free radicals and weakened antioxidative defenses, making them highly susceptible to oxidative stress development. This, in turn, can induce and promote diabetic complications. Therefore, utilizing antidiabetic agents with antioxidative properties can offer dual benefits by addressing hyperglycemia and reducing oxidative damage. Semaglutide, a recently approved oral form of glucagon-like peptide-1 (GLP-1) analogues, has shown potent antidiabetic effects. Additionally, recent studies have suggested that it possesses antioxidative properties. However, the exact effects and the molecular pathways involved are not well understood. In this review, we present the latest findings on the antioxidative impacts of semaglutide and draw conclusions about the mechanisms involved.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behina Forouzanmehr
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Tannaz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sercan Karav
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale 17100, Turkey
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Elbarbary NS, Ismail EA, El-Hamamsy MH, Ibrahim MZ, Elkholy AA. The DPP-4 inhibitor sitagliptin improves glycaemic control and early-stage diabetic nephropathy in adolescents with type 1 diabetes using the MiniMed 780G advanced hybrid closed-loop system: a randomised controlled trial. Diabetologia 2024; 67:2637-2649. [PMID: 39271520 PMCID: PMC11604790 DOI: 10.1007/s00125-024-06265-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 07/16/2024] [Indexed: 09/15/2024]
Abstract
AIMS/HYPOTHESIS Dipeptidyl peptidase-4 (DPP-4) inhibition has beneficial effects on various metabolic indicators in diabetes. Stromal cell-derived factor-1 (SDF-1) is expressed in diverse organs including the kidneys and is cleaved and inactivated by DPP-4 enzyme. The aim of this study was to conduct a randomised controlled trial to assess the effect of sitagliptin on diabetic nephropathy when used as an add-on therapy to the advanced hybrid closed-loop (AHCL) system in adolescents with type 1 diabetes and nephropathy. METHODS This open-label, parallel-group, randomised controlled trial took place at the Pediatric Diabetes Clinic, Ain Shams University, Egypt. Forty-six adolescents aged 14.13 ± 2.43 years on the MiniMed 780G system for at least 6 months before study, with HbA1c ≤69 mmol/mol (8.5%) and diabetic nephropathy in the form of microalbuminuria, were randomly assigned to two groups (n=23 for each) based on a computer-generated randomisation sequence. The intervention group received oral sitagliptin 50 mg for 3 months. The other group used AHCL only and served as a control group. The primary outcome measure was the change in urinary albumin/creatinine ratio (UACR) after 3 months of administration of sitagliptin. The key secondary outcome measure was the change from baseline in SDF-1 levels after treatment. RESULTS Data for all participants were analysed. No significant difference was found between the groups as regards baseline clinical and laboratory characteristics as well as AHCL system settings (p>0.05). Serum SDF-1 levels were higher in all individuals with type 1 diabetes vs healthy control individuals (p<0.001). After 3 months, sitagliptin resulted in a significant decrease of SDF-1 levels from 3.58 ± 0.73 to 1.99 ± 0.76 ng/ml (p<0.001), together with improvement of UACR from 7.27 ± 2.41 to 1.32 ± 0.31 mg/mmol (p<0.001). In addition, sitagliptin reduced postprandial glucose, sensor glucose, coefficient of variation and total daily dose of insulin, while time in range 3.9-10.0 mmol/l (70-180 mg/dl) and insulin-to-carbohydrate ratio were significantly increased. Sitagliptin was safe and well-tolerated without severe hypoglycaemia or diabetic ketoacidosis. CONCLUSIONS/INTERPRETATION Sitagliptin as an add-on therapy to AHCL had a reno-protective effect for individuals with type 1 diabetes and diabetic nephropathy, in addition to the improvement of time in range while reducing glycaemic variability and without compromising safety. FUNDING This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. TRIAL REGISTRATION ClinicalTrials.gov NCT06115460.
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Affiliation(s)
- Nancy S Elbarbary
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Eman A Ismail
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Manal H El-Hamamsy
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Marwa Z Ibrahim
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt
| | - Amal A Elkholy
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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Alnaser RI, Alassaf FA, Abed MN. Incretin-Based Therapies: A Promising Approach for Modulating Oxidative Stress and Insulin Resistance in Sarcopenia. J Bone Metab 2024; 31:251-263. [PMID: 39496297 DOI: 10.11005/jbm.24.739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 07/07/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND Recent studies have linked sarcopenia development to the hallmarks of diabetes, oxidative stress, and insulin resistance. The anti-oxidant and insulin sensitivityenhancing effects of incretin-based therapies may provide a promising option for the treatment of sarcopenia. This review aimed to unveil the role of oxidative stress and insulin resistance in the pathogenesis of sarcopenia and explore the potential benefits of incretin-based therapies in individuals with sarcopenia. METHODS PubMed, the Cochrane Library, and Google Scholar databases were searched by applying keywords relevant to the main topic, to identify articles that met our selection criteria. RESULTS Incretin-based therapies manifested anti-oxidant effects by increasing the anti-oxidant defense system and decreasing free radical generation or by indirectly minimizing glucotoxicity, which was mainly achieved by improving insulin signaling and glucose homeostasis. Likewise, these drugs exhibit insulin-sensitizing activities by increasing insulin secretion, transduction, and β-cell function or by reducing inflammation and lipotoxicity. CONCLUSIONS Incretin-based therapies, as modulators of oxidation and insulin resistance, may target the main pathophysiological factors of sarcopenia, thus providing a promising strategy for the treatment of this disease.
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Affiliation(s)
- Raniah I Alnaser
- Nineveh Health Directorate, Mosul, Iraq
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Fawaz A Alassaf
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Mohammed N Abed
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
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Yaribeygi H, Ramezani M, Katsiki N, Mirmohammadkhani M, Tabaei NS. Efficacy of Adding Sitagliptin to Ongoing Metformin on Metabolic Profile, Triglyceride-Glucose Index, Vitamin D3, and Liver Tests in Patients Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease: A Double-Blind Randomized Clinical Trial. CURRENT THERAPEUTIC RESEARCH 2024; 101:100764. [PMID: 39582742 PMCID: PMC11584711 DOI: 10.1016/j.curtheres.2024.100764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 10/04/2024] [Indexed: 11/26/2024]
Abstract
Background Dipeptidyl peptidase-4 inhibitors provide potent antidiabetic effects in patients with type 2 diabetes mellitus (T2DM), but their role in the presence of nonalcoholic fatty liver disease (NAFLD) is not well-known. Objective The aim of this clinical trial was to evaluate the effects of sitagliptin on the metabolic profile and liver test results in metformin-treated patients with T2DM and NAFLD. Methods This was a prospective, 12-week, single-center, comparative randomized clinical trial enrolling 66 adult patients with T2DM and NAFLD (diagnosed by ultrasound). Patients were randomly assigned to either metformin (2000 mg/d, n = 33) or sitagliptin + metformin (100 and 2000 mg/d, respectively, n = 33), administered orally. Certain metabolic parameters, that is, fasting blood sugar (FBS), glycosylated hemoglobin, triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol, vitamin D3 (vitD3), alkaline phosphatase, alanine aminotransferase (SGPT), and aspartate aminotransferase, were measured at baseline and after 12 weeks. Triglyceride-glucose (TG-G) index was also calculated. Results All biochemical variables decreased by a greater extent in the sitagliptin + metformin group than in the metformin group, with differences in FBS (P = 0.030), TC (P = 0.017), TG (P = 0.008), SGPT (P = 0.018), and vitD3 (P = 0.001) reaching statistical significance. Furthermore, the mean reduction of the TG-G index was significantly greater in the sitagliptin + metformin group than in the metformin group (0.67 vs 0.21, respectively; P = 0.017). Conclusions Sitagliptin + metformin therapy led to significantly greater improvements in FBS, TC, TG, SGPT, vitD3, and TG-G compared with the metformin monotherapy group. Other biomarkers also decreased more in the sitagliptin + metformin group than in the metformin group, but these differences did not reach statistical significance. The present findings should be interpreted with caution, although they suggest certain metabolic benefits after sitagliptin addition in metformin-treated patients with T2DM and NAFLD. Further studies are required to elucidate these effects and provide strong evidence for safe conclusions.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Majid Ramezani
- Department of Internal Medicine, School of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Thessaloniki, Greece
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Majid Mirmohammadkhani
- Social Determinants of Health Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Narges Sadat Tabaei
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
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Yaribeygi H, Maleki M, Jamialahmadi T, Sahebkar A. Anti-inflammatory benefits of semaglutide: State of the art. J Clin Transl Endocrinol 2024; 36:100340. [PMID: 38576822 PMCID: PMC10992717 DOI: 10.1016/j.jcte.2024.100340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/06/2024] [Accepted: 03/20/2024] [Indexed: 04/06/2024] Open
Abstract
Individuals with diabetes often have chronic inflammation and high levels of inflammatory cytokines, leading to insulin resistance and complications. Anti-inflammatory agents are proposed to prevent these issues, including using antidiabetic medications with anti-inflammatory properties like semaglutide, a GLP-1 analogue. Semaglutide not only lowers glucose but also shows potential anti-inflammatory effects. Studies suggest it can modulate inflammatory responses and benefit those with diabetes. However, the exact mechanisms of its anti-inflammatory effects are not fully understood. This review aims to discuss the latest findings on semaglutide's anti-inflammatory effects and the potential pathways involved.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tannaz Jamialahmadi
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Scoditti E, Sabatini S, Carli F, Gastaldelli A. Hepatic glucose metabolism in the steatotic liver. Nat Rev Gastroenterol Hepatol 2024; 21:319-334. [PMID: 38308003 DOI: 10.1038/s41575-023-00888-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2023] [Indexed: 02/04/2024]
Abstract
The liver is central in regulating glucose homeostasis, being the major contributor to endogenous glucose production and the greatest reserve of glucose as glycogen. It is both a target and regulator of the action of glucoregulatory hormones. Hepatic metabolic functions are altered in and contribute to the highly prevalent steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this Review, we describe the dysregulation of hepatic glucose metabolism in MASLD and MASH and associated metabolic comorbidities, and how advances in techniques and models for the assessment of hepatic glucose fluxes in vivo have led to the identification of the mechanisms related to the alterations in glucose metabolism in MASLD and comorbidities. These fluxes can ultimately increase hepatic glucose production concomitantly with fat accumulation and alterations in the secretion and action of glucoregulatory hormones. No pharmacological treatment has yet been approved for MASLD or MASH, but some antihyperglycaemic drugs approved for treating type 2 diabetes have shown positive effects on hepatic glucose metabolism and hepatosteatosis. A deep understanding of how MASLD affects glucose metabolic fluxes and glucoregulatory hormones might assist in the early identification of at-risk individuals and the use or development of targeted therapies.
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Affiliation(s)
- Egeria Scoditti
- Institute of Clinical Physiology, National Research Council, Lecce, Italy
| | - Silvia Sabatini
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Fabrizia Carli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy.
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13
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Lonardo MS, Cacciapuoti N, Guida B, Di Lorenzo M, Chiurazzi M, Damiano S, Menale C. Hypothalamic-Ovarian axis and Adiposity Relationship in Polycystic Ovary Syndrome: Physiopathology and Therapeutic Options for the Management of Metabolic and Inflammatory Aspects. Curr Obes Rep 2024; 13:51-70. [PMID: 38172476 PMCID: PMC10933167 DOI: 10.1007/s13679-023-00531-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/27/2023] [Indexed: 01/05/2024]
Abstract
PURPOSE OF REVIEW The goal of the present review is to address the main adiposity-related alterations in Polycystic Ovary Syndrome (PCOS) focusing on hypothalamic-pituitary-ovarian (H-P-O) axis and to provide an overview of nutraceutical and pharmacological therapeutic strategies. RECENT FINDINGS Female reproduction is a complex and delicate interplay between neuroendocrine signals involving the H-P-O axis. Elements that disrupt the balance of these interactions can lead to metabolic and reproductive disorders, such as PCOS. This disorder includes menstrual, metabolic, and biochemical abnormalities as well as hyperandrogenism, oligo-anovulatory menstrual cycles, insulin resistance, and hyperleptinemia which share an inflammatory state with other chronic diseases. Moreover, as in a self-feeding cycle, high androgen levels in PCOS lead to visceral fat deposition, resulting in insulin resistance and hyperinsulinemia, further stimulating ovarian and adrenal androgen production. In fact, regardless of age and BMI, women with PCOS have more adipose tissue and less lean mass than healthy women. Excessive adiposity, especially visceral adiposity, is capable of affecting female reproduction through direct mechanisms compromising the luteal phase, and indirect mechanisms as metabolic alterations able to affect the function of the H-P-O axis. The intricate crosstalk between adiposity, inflammatory status and H-P-O axis function contributes to the main adiposity-related alterations in PCOS, and alongside currently available hormonal treatments, nutraceutical and pharmacological therapeutic strategies can be exploited to treat these alterations, in order to enable a more comprehensive synergistic and tailored treatment.
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Affiliation(s)
- Maria Serena Lonardo
- Department of Clinical Medicine and Surgery, Physiology Nutrition Unit, Federico II University of Naples, Via Sergio Pansini 5, 80131, Napoli, Italy.
| | - Nunzia Cacciapuoti
- Department of Clinical Medicine and Surgery, Physiology Nutrition Unit, Federico II University of Naples, Via Sergio Pansini 5, 80131, Napoli, Italy
| | - Bruna Guida
- Department of Clinical Medicine and Surgery, Physiology Nutrition Unit, Federico II University of Naples, Via Sergio Pansini 5, 80131, Napoli, Italy
| | - Mariana Di Lorenzo
- Department of Clinical Medicine and Surgery, Physiology Nutrition Unit, Federico II University of Naples, Via Sergio Pansini 5, 80131, Napoli, Italy
| | - Martina Chiurazzi
- Department of Clinical Medicine and Surgery, Physiology Nutrition Unit, Federico II University of Naples, Via Sergio Pansini 5, 80131, Napoli, Italy
| | - Simona Damiano
- Department of Clinical Medicine and Surgery, Physiology Nutrition Unit, Federico II University of Naples, Via Sergio Pansini 5, 80131, Napoli, Italy
| | - Ciro Menale
- Department of Clinical Medicine and Surgery, Physiology Nutrition Unit, Federico II University of Naples, Via Sergio Pansini 5, 80131, Napoli, Italy
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14
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Zhou J, Zheng Y, Xu B, Long S, Zhu LE, Liu Y, Li C, Zhang Y, Liu M, Wu X. Exploration of the potential association between GLP-1 receptor agonists and suicidal or self-injurious behaviors: a pharmacovigilance study based on the FDA Adverse Event Reporting System database. BMC Med 2024; 22:65. [PMID: 38355513 PMCID: PMC10865629 DOI: 10.1186/s12916-024-03274-6] [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: 08/18/2023] [Accepted: 01/25/2024] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Establishing whether there is a potential relationship between glucagon-like peptide 1 receptor agonists (GLP-1RAs) and suicidal or self-injurious behaviors (SSIBs) is crucial for public safety. This study investigated the potential association between GLP-1RAs and SSIBs by exploring the FDA Adverse Event Reporting System (FAERS) database. METHODS A disproportionality analysis was conducted using post-marketing data from the FAERS repository (2018 Q1 to 2022 Q4). SSIB cases associated with GLP-1RAs were identified and analyzed through disproportionality analysis using the information component. The parametric distribution with a goodness-of-fit test was employed to analyze the time-to-onset, and the Ω shrinkage was used to evaluate the potential effect of co-medication on the occurrence of SSIBs. RESULTS In total, 204 cases of SSIBs associated with GLP-1RAs, including semaglutide, liraglutide, dulaglutide, exenatide, and albiglutide, were identified in the FAERS database. Time-of-onset analysis revealed no consistent mechanism for the latency of SSIBs in patients receiving GLP-1RAs. The disproportionality analysis did not indicate an association between GLP-1RAs and SSIBs. Co-medication analysis revealed 81 cases with antidepressants, antipsychotics, and benzodiazepines, which may be proxies of mental health comorbidities. CONCLUSIONS We found no signal of disproportionate reporting of an association between GLP-1RA use and SSIBs. Clinicians need to maintain heightened vigilance on patients premedicated with neuropsychotropic drugs. This contributes to the greater acceptance of GLP-1RAs in patients with type 2 diabetes mellitus or obesity.
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Affiliation(s)
- Jianxing Zhou
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China
| | - You Zheng
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China
| | - Baohua Xu
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China
| | - Songjun Long
- School of Medical Imaging, Fujian Medical University, Fuzhou, Fujian, China
| | - Li-E Zhu
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Yunhui Liu
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Chengliang Li
- Department of Respiratory, Shanghai Electric Power Hospital, Shanghai, China
| | - Yifan Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Maobai Liu
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
| | - Xuemei Wu
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
- School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China.
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15
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Niebrzydowska-Tatus M, Pełech A, Bień K, Mekler J, Santiago M, Kimber-Trojnar Ż, Trojnar M. Association of DPP-4 Concentrations with the Occurrence of Gestational Diabetes Mellitus and Excessive Gestational Weight Gain. Int J Mol Sci 2024; 25:1829. [PMID: 38339106 PMCID: PMC10855185 DOI: 10.3390/ijms25031829] [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: 12/15/2023] [Revised: 01/24/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is considered one of the most common diseases that occur during pregnancy. In addition to increasing the risk of numerous complications throughout gestation, it is also believed to have a long-term potential to impact the risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease for the mother and her offspring. While there are clear guidelines for healthy weight gain in pregnancy depending on pre-pregnancy BMI, as well as dietary and training recommendations to achieve this, an increasing number of women are experiencing excessive gestational weight gain (EGWG). Such patients have a higher risk of developing GDM and gestational hypertension, as well as requiring caesarian delivery. Dipeptidyl peptidase-4 (DPP-4) is a glycoprotein that seems to play an important role in glucose metabolism, and inhibition of its activity positively affects glucose regulation. The aim of our study was to compare DPP-4 concentrations in patients with GDM and EGWG with healthy women. DPP-4 levels were assessed in serum and urine samples collected on the day of delivery. The bioelectrical impedance analysis (BIA) method was also used to analyze the body composition of patients on the second day of the postpartum period. DPP-4 serum concentrations were significantly higher in patients in the GDM and EGWG groups compared to healthy women. Urinary DPP-4 concentrations were significantly higher in the control and GDM groups than in the EGWG group. Serum DPP-4 levels were positively correlated with BMI measured before pregnancy, on the delivery day, and in the early postpartum period, among other factors. According to our knowledge, this is the first study to determine DPP-4 levels in EGWG patients. DPP-4 may be related to the occurrence of GDM and EGWG; however, this requires further research.
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Affiliation(s)
- Magdalena Niebrzydowska-Tatus
- Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland; (M.N.-T.); (A.P.)
| | - Aleksandra Pełech
- Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland; (M.N.-T.); (A.P.)
| | - Katarzyna Bień
- Student’s Scientific Association at the Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland; (K.B.); (J.M.); (M.S.)
| | - Julia Mekler
- Student’s Scientific Association at the Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland; (K.B.); (J.M.); (M.S.)
| | - Miracle Santiago
- Student’s Scientific Association at the Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland; (K.B.); (J.M.); (M.S.)
| | - Żaneta Kimber-Trojnar
- Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland; (M.N.-T.); (A.P.)
| | - Marcin Trojnar
- Chair and Department of Internal Diseases, Medical University of Lublin, 20-059 Lublin, Poland;
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Mashayekhi M, Nian H, Mayfield D, Devin JK, Gamboa JL, Yu C, Silver HJ, Niswender K, Luther JM, Brown NJ. Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals With Obesity and Prediabetes. Diabetes 2024; 73:38-50. [PMID: 37874653 PMCID: PMC10784656 DOI: 10.2337/db23-0356] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 10/16/2023] [Indexed: 10/26/2023]
Abstract
Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. ARTICLE HIGHLIGHTS Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss-independent, GLP-1 receptor (GLP-1R)-dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R-dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1.
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Affiliation(s)
- Mona Mashayekhi
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN
| | - Hui Nian
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Dustin Mayfield
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Jessica K. Devin
- UCHealth Endocrinology, Yampa Valley Medical Center, Steamboat Springs, CO
| | - Jorge L. Gamboa
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Chang Yu
- Department of Population Health, NYU Grossman School of Medicine, New York, NY
| | - Heidi J. Silver
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN
| | - Kevin Niswender
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN
| | - James M. Luther
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Nancy J. Brown
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
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17
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Yaribeygi H, Maleki M, Santos RD, Jamialahmadi T, Sahebkar A. Glp-1 Mimetics and Autophagy in Diabetic Milieu: State-of-the-Art. Curr Diabetes Rev 2024; 20:e250124226181. [PMID: 38299271 DOI: 10.2174/0115733998276570231222105959] [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: 08/09/2023] [Revised: 11/20/2023] [Accepted: 12/01/2023] [Indexed: 02/02/2024]
Abstract
The diabetic milieu is associated with cascades of pathophysiological pathways that culminate in diabetic complications and tissue injuries. Autophagy is an essential process mandatory for cell survival and tissue homeostasis by degrading damaged organelles and removing injured cells. However, it may turn into a pathological process in an aberrant mode in the diabetic and/or malignant milieu. Moreover, autophagy could serve as a promising therapeutic target for many complications related to tissue injury. Glp-1 mimetics are a class of newer antidiabetic agents that reduce blood glucose through several pathways. However, some evidence suggests that they can provide extra glycemic benefits by modulating autophagy, although there is no complete understanding of this mechanism and its underlying molecular pathways. Hence, in the current review, we aimed to provide new insights on the possible impact of Glp-1 mimetics on autophagy and consequent benefits as well as mediating pathways.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Raul D Santos
- Lipid Clinic Heart Institute (Incor), University of São Paulo, Medical School Hospital, São Paulo, Brazil
| | - Tannaz Jamialahmadi
- Medical Toxicolgy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Medical Toxicolgy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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18
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Jiang H, Zang L. GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD. Curr Pharm Des 2024; 30:100-114. [PMID: 38532322 DOI: 10.2174/0113816128283153231226103218] [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: 10/12/2023] [Accepted: 12/14/2023] [Indexed: 03/28/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a global public health concern. Currently, the cornerstone of NAFLD treatment is lifestyle modification and, if necessary, weight loss. However, compliance is a challenge, and this approach alone may not be sufficient to halt and treat the more serious disease development, so medication is urgently needed. Nevertheless, no medicines are approved to treat NAFLD. Glucagon-like peptide-1 (GLP-1) is an enteropeptide hormone that inhibits glucagon synthesis, promotes insulin secretion, and delays gastric emptying. GLP-1 has been found in recent studies to be beneficial for the management of NAFLD, and the marketed GLP-1 agonist drugs have different degrees of effectiveness for NAFLD while lowering blood glucose. In this article, we review GLP-1 and its physiological roles, the pathogenesis of NAFLD, the correlation between NAFLD and GLP-1 signaling, and potential strategies for GLP-1 treatment of NAFLD.
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Affiliation(s)
- Haoran Jiang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Linquan Zang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
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19
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Zhou L, Qu H, Yang L, Shou L. Effects of GLP1RAs on pregnancy rate and menstrual cyclicity in women with polycystic ovary syndrome: a meta-analysis and systematic review. BMC Endocr Disord 2023; 23:245. [PMID: 37940910 PMCID: PMC10631119 DOI: 10.1186/s12902-023-01500-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 10/27/2023] [Indexed: 11/10/2023] Open
Abstract
PURPOSE This study was aimed to assess the effectiveness of Glucagon-like peptide 1 receptor agonists on pregnancy rate, menses, anthropometric and hormonal parameters in PCOS patients. METHODS We conducted searches of the published literature in PubMed, EMBASE, Cochrane Library, Web of Science up to September 2022. Data from randomized controlled trials were obtained to assess the effects of GLP1RAs in PCOS women. Weighted mean difference, standardized mean difference, and risks ratio were employed for effect size estimation using a random-effects model. RESULTS A total of 840 patients with 469 individuals in GLP1RAs group and 371 individuals in control group from 11 RCTs were included. GLP1RAs usage was associated with an improvement in natural pregnancy rate (RR: 1.72, 95% CI 1.22 to 2.43, P = 0.002, I2 = 0%) and menstrual regularity (SMD: 1.72, 95% CI 0.60 to 2.85, P < 0.001, I2 = 95.6%). There were no statistically significant differences in total pregnancy rate, IVF pregnancy rate between two groups, but total PR elevated in a short time after GLP1RAs as shown in subgroup analysis. Randomization to GLP1RAs treatment was associated with great improvement in HOMA-IR, BMI, WC, SHBG and a slight reduction in TT compared to control group. A decrease in TBF was seen in European population. GLP1RAs monotherapy was not superior to metformin when it came to fT, DHEAS, FAI. CONCLUSIONS Prescription of GLP1RAs improves natural pregnancy rate, menstrual cyclicity and insulin sensitivity, anthropometrics, hormonal indexes in PCOS women.
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Affiliation(s)
- Lingling Zhou
- Metabolic Disease Center, Department of Endocrinology and Metabolic Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
| | - Huanjia Qu
- Metabolic Disease Center, Department of Endocrinology and Metabolic Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
| | - Lu Yang
- Metabolic Disease Center, Department of Endocrinology and Metabolic Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
| | - Lan Shou
- Metabolic Disease Center, Department of Endocrinology and Metabolic Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China.
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20
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Greco M, Munir A, Musarò D, Coppola C, Maffia M. Restoring autophagic function: a case for type 2 diabetes mellitus drug repurposing in Parkinson's disease. Front Neurosci 2023; 17:1244022. [PMID: 38027497 PMCID: PMC10654753 DOI: 10.3389/fnins.2023.1244022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Parkinson's disease (PD) is a predominantly idiopathic pathological condition characterized by protein aggregation phenomena, whose main component is alpha-synuclein. Although the main risk factor is ageing, numerous evidence points to the role of type 2 diabetes mellitus (T2DM) as an etiological factor. Systemic alterations classically associated with T2DM like insulin resistance and hyperglycemia modify biological processes such as autophagy and mitochondrial homeostasis. High glucose levels also compromise protein stability through the formation of advanced glycation end products, promoting protein aggregation processes. The ability of antidiabetic drugs to act on pathways impaired in both T2DM and PD suggests that they may represent a useful tool to counteract the neurodegeneration process. Several clinical studies now in advanced stages are looking for confirmation in this regard.
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Affiliation(s)
- Marco Greco
- Department of Biological and Environmental Science and Technology, University of Salento, Lecce, Italy
| | - Anas Munir
- Department of Biological and Environmental Science and Technology, University of Salento, Lecce, Italy
- Department of Mathematics and Physics “E. De Giorgi”, University of Salento, Lecce, Italy
| | - Debora Musarò
- Department of Biological and Environmental Science and Technology, University of Salento, Lecce, Italy
| | - Chiara Coppola
- Department of Biological and Environmental Science and Technology, University of Salento, Lecce, Italy
- Department of Mathematics and Physics “E. De Giorgi”, University of Salento, Lecce, Italy
| | - Michele Maffia
- Department of Biological and Environmental Science and Technology, University of Salento, Lecce, Italy
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21
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Liu X, Song L, Zhang Y, Li H, Cui C, Liu D. PEGylated exenatide injection (PB-119) improves beta-cell function and insulin resistance in treatment-naïve type 2 diabetes mellitus patients. Front Pharmacol 2023; 14:1088670. [PMID: 37781697 PMCID: PMC10539604 DOI: 10.3389/fphar.2023.1088670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 08/28/2023] [Indexed: 10/03/2023] Open
Abstract
Objective: PB-119, a PEGylated exenatide injection, is a once-weekly glucagon-like peptide-1 receptor agonist. In the present study, we aimed to evaluate the effects of PB-119 on insulin resistance and beta-cell function in Chinese patients with type 2 diabetes mellitus (T2DM) to uncover its antidiabetic characteristics. Methods: A total of 36 Chinese T2DM patients were randomized to receive 25 μg and 50 μg PB-119 once weekly and exenatide (5-10 μg injected under the skin 2 times a day adjusted by the doctor) for 12 weeks. Oral mixed meal tolerance tests were conducted before the study and on Day 79. The data were fitted to estimate beta-cell function and insulin sensitivity parameters using the SAAM II package integrating the oral minimal model (OMM), which was compared with Homeostatic Model Assessment (HOMA) analysis results. Results: Exenatide or PB-119 treatment, compared with their baseline, was associated with higher beta-cell function parameters (φb, φs and φtot), disposition index, insulin secretion rates, and a lower glucose area under the curve. High-dose PB-119 also has a higher insulin resistance parameter (SI) than the baseline, but HOMA-IR did not. For the homeostatic model assessment parameters, HOMA-IR showed no statistically significant changes within or between treatments. Only high-dose PB-119 improved HOMA-β after 12 weeks of treatment. Conclusion: After 12 weeks of treatment, PB-119 decreased glycemic levels by improving beta-cell function and insulin resistance.
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Affiliation(s)
- Xu Liu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Ling Song
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Yuanhui Zhang
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
| | - Haiyan Li
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Cheng Cui
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Dongyang Liu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
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22
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Anala AD, Saifudeen ISH, Ibrahim M, Nanda M, Naaz N, Atkin SL. The Potential Utility of Tirzepatide for the Management of Polycystic Ovary Syndrome. J Clin Med 2023; 12:4575. [PMID: 37510690 PMCID: PMC10380206 DOI: 10.3390/jcm12144575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 06/27/2023] [Accepted: 07/02/2023] [Indexed: 07/30/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women of reproductive age. The metabolic dysfunction associated with PCOS increases the probability of developing type 2 diabetes (T2D), endometrial cancer, and cardiovascular disease. Research has shown that the metabolic features of PCOS may be improved by weight loss following treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists. Tirzepatide is a dual GLP-GIP (gastric inhibitory polypeptide) receptor agonist that shares a very similar mechanism of action with GLP-1R agonists, and it is hypothesized that it may be a potential contender in the treatment of PCOS. The success of GLP-1R agonists is usually hindered by their adverse gastrointestinal effects, leading to reduced compliance. The mechanism of action of Tirzepatide partly addresses this issue, as its dual receptor affinity may reduce the intensity of gastrointestinal symptoms. Tirzepatide has been licensed for the treatment of type 2 diabetes and given the metabolic issues and obesity that accompanies PCOS, it may be of value in its management for those PCOS patients who are obese with metabolic syndrome, although it may not benefit those who are of normal weight. This study reviews the current therapies for the treatment of PCOS and evaluates the potential use of Tirzepatide to address the symptoms of PCOS, including reproductive dysfunction, obesity, and insulin resistance.
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Affiliation(s)
- Alekya Devi Anala
- School of Medicine, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | | | - Maryam Ibrahim
- School of Medicine, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | - Moksha Nanda
- School of Medicine, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | - Nida Naaz
- School of Medicine, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | - Stephen L Atkin
- School of Medicine, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
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23
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Rabinovitch A, Koshelev D, Lagunas-Rangel FA, Kosheleva L, Gavra T, Schiöth HB, Levit S. Efficacy of combination therapy with GABA, a DPP-4i and a PPI as an adjunct to insulin therapy in patients with type 1 diabetes. Front Endocrinol (Lausanne) 2023; 14:1171886. [PMID: 37293502 PMCID: PMC10246767 DOI: 10.3389/fendo.2023.1171886] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 05/09/2023] [Indexed: 06/10/2023] Open
Abstract
Introduction The purpose of this retrospective clinic chart review study was to determine the potential of a combination therapy (CT) consisting of γ-aminobutyric acid (GABA), a dipeptidyl peptidase-4 inhibitor (DPP-4i), and a proton pump inhibitor (PPI) to improve glycemic control as an adjunct to insulin therapy in patients with type 1 diabetes (T1D). Research design and methods Nineteen patients with T1D on insulin therapy were treated with additional CT in oral form. Fasting blood glucose (FBG), HbA1c, insulin dose-adjusted HbA1c (IDA-A1c), daily insulin dose, insulin/weight ratio (IWR), and fasting plasma C-peptide were measured after 26-42 weeks of treatments. Results FBG, HbA1c, IDA-A1c, insulin dose and IWR were all significantly decreased while plasma C-peptide was significantly increased by the CT. Treatment outcomes were further analyzed by separation of the 19 patients into two groups. One group started on the CT within 12 months of insulin treatment (early therapy, 10 patients) and another group started on this therapy only after 12 months of insulin treatment (late therapy, 9 patients). FBG, IDA-A1c, insulin dose, and IWR decreased significantly in both the early and late CT groups, however to a better extent in the early therapy group. Moreover, plasma C-peptide increased significantly only in the early therapy group, and 7 of the 10 patients in this group were able to discontinue insulin treatment while maintaining good glycemic control to study end compared with none of the 9 patients in the late therapy group. Conclusion These results support the concept that the combination of GABA, a DPP-4i and a PPI as an adjunct to insulin therapy improves glycemic control in patients with T1D, and that the insulin dose required for glycemic control can be reduced or even eliminated in some patients receiving this novel therapy.
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Affiliation(s)
| | - Daniil Koshelev
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
- Levicure LTD, Rishon Lezion, Israel
| | | | - Liudmila Kosheleva
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
- Levicure LTD, Rishon Lezion, Israel
| | - Tali Gavra
- Research Unit, Assuta Medical Centers, Tel Aviv, Israel
| | - Helgi B. Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Shmuel Levit
- Levicure LTD, Rishon Lezion, Israel
- Diabetes and Metabolism Institute, Assuta Medical Centers, Tel Aviv, Israel
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24
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Babu A, Ramanathan G. Multi-omics insights and therapeutic implications in polycystic ovary syndrome: a review. Funct Integr Genomics 2023; 23:130. [PMID: 37079114 DOI: 10.1007/s10142-023-01053-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 04/04/2023] [Accepted: 04/08/2023] [Indexed: 04/21/2023]
Abstract
Polycystic ovary syndrome (PCOS) is a common gynecological disease that causes adverse effects in women in their reproductive phase. Nonetheless, the molecular mechanisms remain unclear. Over the last decade, sequencing and omics approaches have advanced at an increased pace. Omics initiatives have come to the forefront of biomedical research by presenting the significance of biological functions and processes. Thus, multi-omics profiling has yielded important insights into understanding the biology of PCOS by identifying potential biomarkers and therapeutic targets. Multi-omics platforms provide high-throughput data to leverage the molecular mechanisms and pathways involving genetic alteration, epigenetic regulation, transcriptional regulation, protein interaction, and metabolic alterations in PCOS. The purpose of this review is to outline the prospects of multi-omics technologies in PCOS research by revealing novel biomarkers and therapeutic targets. Finally, we address the knowledge gaps and emerging treatment strategies for the management of PCOS. Future PCOS research in multi-omics at the single-cell level may enhance diagnostic and treatment options.
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Affiliation(s)
- Achsha Babu
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Gnanasambandan Ramanathan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
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25
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Lin WR, Liu KH, Ling TC, Wang MC, Lin WH. Role of antidiabetic agents in type 2 diabetes patients with chronic kidney disease. World J Diabetes 2023; 14:352-363. [PMID: 37122432 PMCID: PMC10130897 DOI: 10.4239/wjd.v14.i4.352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/10/2023] [Accepted: 04/04/2023] [Indexed: 04/12/2023] Open
Abstract
Insulin resistance is a condition in which the target tissues have a decreased response to insulin signaling, resulting in glucose uptake defect, and an increased blood sugar level. Pancreatic beta cells thus enhance insulin production to compensate. This situation may cause further beta cell dysfunction and failure, which can lead diabetes mellitus (DM). Insulin resistance is thus an important cause of the development of type 2 DM. Insulin resistance has also been found to have a strong relationship with cardiovascular disease and is common in chronic kidney disease (CKD) patients. The mechanisms of insulin resistance in CKD are complex and multifactorial. They include physical inactivity, inflammation and oxidative stress, metabolic acidosis, vitamin D deficiency, adipose tissue dysfunction, uremic toxins, and renin-angiotensin-aldosterone system activation. Currently, available anti-diabetic agents, such as biguanides, sulfonylureas, thiazolidinediones, alfa-glucosidase inhibitors, glucagon-like peptide-1-based agents, and sodium-glucose co-transporter-2 inhibitors, have different effects on insulin resistance. In this short review, we describe the potential mechanisms of insulin resistance in CKD patients. We also review the interaction of currently available anti-diabetic medications with insulin resistance.
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Affiliation(s)
- Wei-Ren Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Kuan-Hung Liu
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Tsai-Chieh Ling
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Ming-Cheng Wang
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Wei-Hung Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
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26
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Rakic D, Jakovljevic V, Jovic N, Bicanin Ilic M, Dimitrijevic A, Vulovic T, Arsenijevic P, Sretenovic J, Nikolic M, Petrovich Fisenko V, Bolevich S, Zarkovic G, Joksimovic Jovic J. The Potential of SGLT-2 Inhibitors in the Treatment of Polycystic Ovary Syndrome: The Current Status and Future Perspectives. Biomedicines 2023; 11:biomedicines11040998. [PMID: 37189616 DOI: 10.3390/biomedicines11040998] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/14/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy during women’s reproductive age. PCOS is a heterogeneous disorder featuring specific cardiometabolic properties. The association between the presence of metabolic disorders and PCOS supports the claim that the regulation of glycemic status is very important in these patients. There is a wide range of therapeutic options (including those treating diabetes mellitus type 2) with potential advantages available for the management of PCOS. Sodium–glucose cotransporter type 2 inhibitors (SGLT-2is) improve glucose metabolism, reduce fat tissue, lower blood pressure, reduce oxidative stress and inflammation, and protect the cardiovascular system. Currently, the use of SGLT-2is is not widespread in PCOS therapy, although these drugs represent a promising new therapeutic approach. Therefore, it is necessary to initiate further study in order to determine more effective therapies for PCOS and investigate the effect of SGLT-2is, both as a monotherapy and in combination with other drugs. It is necessary to understand the mechanisms underlying SGLT-2is in PCOS and their effects on long-term complications, especially since the gold standard treatment for PCOS, such as metformin and oral contraceptives, do not have long-term cardioprotective effects. The effects of SGLT-2is seem to involve cardiac protection, while diminishing endocrine and reproductive abnormalities in PCOS. In the current narrative review, we examine the most recent clinical evidence and discuss the potential applications of SGLT-2is for PCOS therapy.
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27
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Kurniati NF, Fathadina A. Combination of Empagliflozin and Liraglutide protects heart against isoproterenol-induced myocardial infarction in rats. PHARMACIA 2023. [DOI: 10.3897/pharmacia.70.e96975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2023] Open
Abstract
Cardiovascular benefit of new anti-hyperglycemic agent such as glucagon like peptide-1 receptor agonist (GLP-1RA) or sodium glucose co-transporter-2 inhibitor (SGLT2i) has been proven, with the proposed-mechanism that might be complementary. We investigated the effects of its combination on blood glucose profile and cardiac biomarkers. The rats were given lipid emulsion for 2 weeks, followed by a single dose of streptozotocin (STZ) 35 mg/kg BW, then treated with empagliflozin and/ liraglutide for 30 days while receiving isoproterenol (ISO) 85 mg/kg on day 29 and 30. The results showed no superior improvement on fasting blood glucose (FBG) and insulin sensitivity (KITT) in the combination group compared to empagliflozin/liraglutide group. However, the combination group showed a higher inhibition in almost all biomarkers, specifically against the elevation of CK-MB compared to one of these agents alone. The histopathological examination using H&E staining even showed a minimal inflammation and gap between cardiomyocytes. These findings may indicate the combination of empagliflozin and liraglutide has a better cardiac protection effect.
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28
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Singh S, Pal N, Shubham S, Sarma DK, Verma V, Marotta F, Kumar M. Polycystic Ovary Syndrome: Etiology, Current Management, and Future Therapeutics. J Clin Med 2023; 12:1454. [PMID: 36835989 PMCID: PMC9964744 DOI: 10.3390/jcm12041454] [Citation(s) in RCA: 135] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/27/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, typically characterized by anovulation, infertility, obesity, insulin resistance, and polycystic ovaries. Lifestyle or diet, environmental pollutants, genetics, gut dysbiosis, neuroendocrine alterations, and obesity are among the risk factors that predispose females to PCOS. These factors might contribute to upsurging metabolic syndrome by causing hyperinsulinemia, oxidative stress, hyperandrogenism, impaired folliculogenesis, and irregular menstrual cycles. Dysbiosis of gut microbiota may play a pathogenic role in the development of PCOS. The restoration of gut microbiota by probiotics, prebiotics, or a fecal microbiota transplant (FMT) might serve as an innovative, efficient, and noninvasive way to prevent and mitigate PCOS. This review deliberates on the variety of risk factors potentially involved in the etiology, prevalence, and modulation of PCOS, in addition to plausible therapeutic interventions, including miRNA therapy and the eubiosis of gut microbiota, that may help treat and manage PCOS.
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Affiliation(s)
- Samradhi Singh
- ICMR—National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhopal 462030, India
| | - Namrata Pal
- ICMR—National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhopal 462030, India
| | - Swasti Shubham
- ICMR—National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhopal 462030, India
| | - Devojit Kumar Sarma
- ICMR—National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhopal 462030, India
| | - Vinod Verma
- Stem Cell Research Centre, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of MedicalSciences, Lucknow 226014, India
| | - Francesco Marotta
- ReGenera R&D International for Aging Intervention, 20144 Milano, Lombardia, Italy
| | - Manoj Kumar
- ICMR—National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhopal 462030, India
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29
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Zhao X, An X, Yang C, Sun W, Ji H, Lian F. The crucial role and mechanism of insulin resistance in metabolic disease. Front Endocrinol (Lausanne) 2023; 14:1149239. [PMID: 37056675 PMCID: PMC10086443 DOI: 10.3389/fendo.2023.1149239] [Citation(s) in RCA: 148] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Insulin resistance (IR) plays a crucial role in the development and progression of metabolism-related diseases such as diabetes, hypertension, tumors, and nonalcoholic fatty liver disease, and provides the basis for a common understanding of these chronic diseases. In this study, we provide a systematic review of the causes, mechanisms, and treatments of IR. The pathogenesis of IR depends on genetics, obesity, age, disease, and drug effects. Mechanistically, any factor leading to abnormalities in the insulin signaling pathway leads to the development of IR in the host, including insulin receptor abnormalities, disturbances in the internal environment (regarding inflammation, hypoxia, lipotoxicity, and immunity), metabolic function of the liver and organelles, and other abnormalities. The available therapeutic strategies for IR are mainly exercise and dietary habit improvement, and chemotherapy based on biguanides and glucagon-like peptide-1, and traditional Chinese medicine treatments (e.g., herbs and acupuncture) can also be helpful. Based on the current understanding of IR mechanisms, there are still some vacancies to follow up and consider, and there is also a need to define more precise biomarkers for different chronic diseases and lifestyle interventions, and to explore natural or synthetic drugs targeting IR treatment. This could enable the treatment of patients with multiple combined metabolic diseases, with the aim of treating the disease holistically to reduce healthcare expenditures and to improve the quality of life of patients to some extent.
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Affiliation(s)
| | | | | | | | - Hangyu Ji
- *Correspondence: Fengmei Lian, ; Hangyu Ji,
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30
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Helvaci N, Yildiz BO. Current and emerging drug treatment strategies for polycystic ovary syndrome. Expert Opin Pharmacother 2023; 24:105-120. [PMID: 35912829 DOI: 10.1080/14656566.2022.2108702] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Polycystic ovary syndrome (PCOS) is a common hormonal, metabolic, and reproductive disorder with a heterogeneous phenotype. As the exact etiology of PCOS is still unclear, available pharmacotherapies are mostly directed toward alleviating symptoms and associated metabolic abnormalities. AREAS COVERED Herein, we present an overview of the current and emerging pharmacotherapies for the management of women with PCOS who do not seek pregnancy. We performed a literature search in PubMed database up to January 2022 and reviewed papers assessing drug treatments for PCOS. We aimed to outline the most recent evidence to support treatment recommendations in these patients. EXPERT OPINION Targets for medical treatment include hormonal, reproductive, and metabolic abnormalities in PCOS. However, none of the available pharmacological options can cover the entire spectrum of clinical manifestations observed in these patients. Considering the heterogeneity of PCOS, treatment should be individualized and adapted to specific needs of each patient. Better understanding of the molecular mechanisms underlying the pathogenesis of PCOS would help development of novel, safer, and more effective multi-targeted therapeutic strategies for the syndrome.
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Affiliation(s)
- Nafiye Helvaci
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hitit University School of Medicine, Corum, Turkey
| | - Bulent Okan Yildiz
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hacettepe University School of Medicine, Ankara, Turkey
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31
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Alkabbani D, Dahabiyeh LA, Taha MO. Dipeptidyl Peptidase-IV Blockers Potently Inhibit Monoglyceride Lipase: Investigation By Docking Studies And In Vitro Bioassay. Med Chem Res 2023; 32:165-175. [DOI: 10.1007/s00044-022-02998-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 11/30/2022] [Indexed: 01/07/2023]
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32
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Yaribeygi H, Maleki M, Nasimi F, Jamialahmadi T, Stanford FC, Sahebkar A. Benefits of GLP-1 Mimetics on Epicardial Adiposity. Curr Med Chem 2023; 30:4256-4265. [PMID: 36642880 PMCID: PMC10293101 DOI: 10.2174/0929867330666230113110431] [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: 07/18/2022] [Revised: 11/01/2022] [Accepted: 11/03/2022] [Indexed: 01/17/2023]
Abstract
The epicardial adipose tissue, which is referred to as fats surrounding the myocardium, is an active organ able to induce cardiovascular problems in pathophysiologic conditions through several pathways, such as inflammation, fibrosis, fat infiltration, and electrophysiologic problems. So, control of its volume and thickness, especially in patients with diabetes, is highly important. Incretin-based pharmacologic agents are newly developed antidiabetics that could provide further cardiovascular benefits through control and modulating epicardial adiposity. They can reduce cardiovascular risks by rapidly reducing epicardial adipose tissues, improving cardiac efficiency. We are at the first steps of a long way, but current evidence demonstrates the sum of possible mechanisms. In this study, we evaluate epicardial adiposity in physiologic and pathologic states and the impact of incretin-based drugs.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Nasimi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Tannaz Jamialahmadi
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatima C. Stanford
- Massachusetts General Hospital, MGH Weight Center, Department of Medicine-Division of Endocrinology-Neuroendocrine, Department of Pediatrics-Division of Endocrinology, Nutrition Obesity Research Center at Harvard (NORCH), Harvard Medical School, Boston, MA, USA
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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33
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Wang Y, Song X, Wang Y, Wang N. Specific interaction of insulin receptor and GLP-1 receptor mediates crosstalk between their signaling. Biochem Biophys Res Commun 2022; 636:31-39. [DOI: 10.1016/j.bbrc.2022.10.094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 10/27/2022] [Indexed: 11/02/2022]
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34
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Jensterle M, Herman R, Janež A. Therapeutic Potential of Glucagon-like Peptide-1 Agonists in Polycystic Ovary Syndrome: From Current Clinical Evidence to Future Perspectives. Biomedicines 2022; 10:1989. [PMID: 36009535 PMCID: PMC9405922 DOI: 10.3390/biomedicines10081989] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/30/2022] [Accepted: 08/14/2022] [Indexed: 11/16/2022] Open
Abstract
Despite the continuous effort to understand the pathophysiology and determine potential therapeutic targets, PCOS treatment largely depends on lifestyle intervention and symptomatic management of individual signs and symptoms. International guidelines recognize the importance of weight reduction as a cornerstone for the achievement of better metabolic, reproductive, and cardiovascular outcomes in PCOS women who are overweight or obese. With its profound weight loss potential in patients with or without diabetes, the administration of GLP-1 receptor agonists has been investigated in overweight/obese women with PCOS in several single-center randomized control trials with considerable variation in the dosing regimen, follow-up duration, and outcome measurements over recent years. Most trials reported superior weight loss effects of GLP-1 receptor agonists compared to lifestyle changes or metformin, with additional metabolic, reproductive, and cardiovascular benefits in this population. However, their use is currently not widely accepted by the clinical community that treats this population. The major concern is how to balance the reproductive and metabolic treatment strategies since the use of GLP-1 receptor agonists requires effective contraception while on therapy and a washout period before pregnancy. Both approaches are not mutually exclusive, yet the best choice requires a careful assessment of the clinical context. Knowing a patient's individual circumstances, precise clinical sub-phenotyping, and regular monitoring are crucial components for the safe and effective use of these new tools. In the present narrative review, we explore the current clinical evidence and provide the future perspectives and challenges for their implementation in PCOS management.
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Affiliation(s)
- Mojca Jensterle
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Rok Herman
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Andrej Janež
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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35
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Sultana R, Sissoho F, Kaushik VP, Raji MA. The Case for Early Use of Glucagon-like Peptide-1 Receptor Agonists in Obstructive Sleep Apnea Patients with Comorbid Diabetes and Metabolic Syndrome. Life (Basel) 2022; 12:1222. [PMID: 36013401 PMCID: PMC9410036 DOI: 10.3390/life12081222] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/22/2022] [Accepted: 08/09/2022] [Indexed: 06/15/2023] Open
Abstract
Patients with obstructive sleep apnea (OSA) have high rates of co-occurring type 2 diabetes, hypertension, obesity, stroke, congestive heart failure, and accelerated atherosclerotic cardiovascular diseases. These conditions frequently require multiple medications, raising the risk of polypharmacy, adverse drug-drug and drug-disease interactions, decreased quality of life, and increased healthcare cost in these patients. The current review of extant literature presents evidence supporting glucagon-like peptide-1 receptor agonists (GLP-1RA) as one pharmacologic intervention that provides a "one-stop shop" for OSA patients because of the multiple effects GLP-1RA has on comorbidities (e.g., hypertension, diabetes, obesity, metabolic syndrome, and atherosclerotic cardiovascular diseases) that commonly co-occur with OSA. Examples of glucagon-like peptide-1 receptor agonists approved by the FDA for diabetes (some of which are also approved for obesity) are liraglutide, exenatide, lixisenatide, dulaglutide, semaglutide, and albiglutide. Prescribing of GLP-1RAs to address these multiple co-occurring conditions has enormous potential to reduce polypharmacy, cost, and adverse drug events, and to improve quality of life for patients living with OSA and diabetes. We thus strongly advocate for increased and early use of GLP-1RA in OSA patients with co-occurring diabetes and other cardiometabolic conditions common in OSA.
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Affiliation(s)
- Rizwana Sultana
- Division of Pulmonary Critical Care and Sleep Medicine, Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA
| | - Fatoumatta Sissoho
- Division of Geriatrics & Palliative Medicine, Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA
| | - Vinod P. Kaushik
- Division of Geriatrics & Palliative Medicine, Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA
| | - Mukaila A. Raji
- Division of Geriatrics & Palliative Medicine, Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA
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36
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The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome. Int J Mol Sci 2022; 23:ijms23084334. [PMID: 35457152 PMCID: PMC9029608 DOI: 10.3390/ijms23084334] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/07/2022] [Accepted: 04/12/2022] [Indexed: 02/01/2023] Open
Abstract
Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS). Although it is not included in the diagnostic criteria of PCOS, there is a crucial role of this metabolic impairment, which along with hormonal abnormalities, increase each other in a vicious circle of PCOS pathogenesis. Insulin resistance in this group of patients results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: Excess visceral fat, chronic inflammation, and reactive oxygen species. While lifestyle intervention has a first-line role in the prevention and management of excess weight in PCOS, the role of anti-obesity pharmacological agents in achieving and maintaining weight loss is being increasingly recognized. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism. They also tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia. GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level.
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Najafi S, Bahrami M, Butler AE, Sahebkar A. The effect of Glucagon-like peptide-1 receptor agonists on serum uric acid concentration: A systematic review and meta-analysis. Br J Clin Pharmacol 2022; 88:3627-3637. [PMID: 35384008 DOI: 10.1111/bcp.15344] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 03/12/2022] [Accepted: 03/30/2022] [Indexed: 11/30/2022] Open
Abstract
AIMS Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of medications mainly used for the treatment of type 2 diabetes. They improve glucose tolerance, increase insulin secretion, and induce weight loss. There is controversy about the effect of GLP-1RAs on serum uric acid (SUA) concentration. Our systematic review aims to objectively answer whether GLP-1RAs affect SUA levels. METHODS We performed a systematic search on PubMed, Web of Science, Embase, Scopus, and Google Scholar datasets up to 27August,2021 with a language restriction of English only. Randomized controlled trials, observational studies, uncontrolled trials, and conference abstracts were included. Studies with insufficient data, irrelevant types of study, and follow-up duration of less than a month were excluded from the review. After critical appraisal by the Joanna Briggs Institute checklists, articles underwent data extraction using a pre-specified Microsoft Excel sheet. RESULTS Of 1004 identified studies, 17 were eligible for inclusion in this systematic review. Pre- to post-administration analysis of GLP-1RA effects on SUA demonstrated that GLP-1RAs could significantly reduce SUA concentration (difference in means=-0.341;SE=0.063;P-value<0.001). However, when compared to placebo, GLP-1 RAs did not perform any better in lowering SUA concentration (difference in means=-0.455;SE=0.259;P-value=0.079). Surprisingly, the active controls, that included insulin, metformin, sodium-glucose co-transporter 2 (SGLT-2) inhibitors, and dipeptidyl-peptidase 4 (DPP-4) inhibitors, did outperform GLP-1RAs in reducing SUA concentration (difference in means=0.250;SE=0.038;P-value<0.001). CONCLUSIONS Administration of GLP-1RAs can result in a significant reduction in SUA concentration. However, this reduction is less than that seen with the use of insulin, metformin, and SGLT-2 inhibitors.
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Affiliation(s)
- Sara Najafi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Milad Bahrami
- Student Research Committee, Faculty of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Bahrain, Adliya, Bahrain
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Medicine, The University of Western Australia, Perth, Australia.,Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Janjusevic M, Fluca AL, Gagno G, Pierri A, Padoan L, Sorrentino A, Beltrami AP, Sinagra G, Aleksova A. Old and Novel Therapeutic Approaches in the Management of Hyperglycemia, an Important Risk Factor for Atherosclerosis. Int J Mol Sci 2022; 23:ijms23042336. [PMID: 35216451 PMCID: PMC8878509 DOI: 10.3390/ijms23042336] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 12/13/2022] Open
Abstract
Hyperglycemia is considered one of the main risk factors for atherosclerosis, since high glucose levels trigger multiple pathological processes, such as oxidative stress and hyperproduction of pro-inflammatory mediators, leading to endothelial dysfunction. In this context, recently approved drugs, such as glucagon-like-peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), could be considered a powerful tool for to reduce glucose concentration and cardiovascular risk. Interestingly, many patients with type 2 diabetes mellitus (T2DM) and insulin resistance have been found to be deficient in vitamin D. Recent studies pointed out the unfavorable prognostic values of T2DM and vitamin D deficiency in patients with cardiac dysfunction, either when considered individually or together, which shed light on the role of vitamin D in general health status. New evidence suggests that SGLT2i could adversely affect the production of vitamin D, thereby increasing the risk of fractures, which are common in patients with T2DM. Therefore, given the biological effects of vitamin D as an anti-inflammatory mediator and a regulator of endothelial function and calcium equilibrium, these new findings should be taken into consideration as well. The aim of this review is to gather the latest advancements regarding the use of antidiabetic and antiplatelet drugs coupled with vitamin D supplementation to control glucose levels, therefore reducing the risk of coronary artery disease (CAD).
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Affiliation(s)
- Milijana Janjusevic
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and Deparment of Medical Surgical and Health Science, University of Trieste, 34149 Trieste, Italy; (M.J.); (A.L.F.); (G.G.); (A.P.); (A.S.); (G.S.)
| | - Alessandra Lucia Fluca
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and Deparment of Medical Surgical and Health Science, University of Trieste, 34149 Trieste, Italy; (M.J.); (A.L.F.); (G.G.); (A.P.); (A.S.); (G.S.)
| | - Giulia Gagno
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and Deparment of Medical Surgical and Health Science, University of Trieste, 34149 Trieste, Italy; (M.J.); (A.L.F.); (G.G.); (A.P.); (A.S.); (G.S.)
| | - Alessandro Pierri
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and Deparment of Medical Surgical and Health Science, University of Trieste, 34149 Trieste, Italy; (M.J.); (A.L.F.); (G.G.); (A.P.); (A.S.); (G.S.)
| | - Laura Padoan
- Cardiology and Cardiovascular Physiopathology, Azienda Ospedaliero-Universitaria S. Maria Della Misericordia, 06156 Perugia, Italy;
| | - Annamaria Sorrentino
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and Deparment of Medical Surgical and Health Science, University of Trieste, 34149 Trieste, Italy; (M.J.); (A.L.F.); (G.G.); (A.P.); (A.S.); (G.S.)
| | | | - Gianfranco Sinagra
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and Deparment of Medical Surgical and Health Science, University of Trieste, 34149 Trieste, Italy; (M.J.); (A.L.F.); (G.G.); (A.P.); (A.S.); (G.S.)
| | - Aneta Aleksova
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and Deparment of Medical Surgical and Health Science, University of Trieste, 34149 Trieste, Italy; (M.J.); (A.L.F.); (G.G.); (A.P.); (A.S.); (G.S.)
- Correspondence: or ; Tel.: +39-3405507762; Fax: +39-040-3994878
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Pyroglutamate Aβ cascade as drug target in Alzheimer's disease. Mol Psychiatry 2022; 27:1880-1885. [PMID: 34880449 PMCID: PMC9126800 DOI: 10.1038/s41380-021-01409-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/19/2021] [Accepted: 11/25/2021] [Indexed: 02/07/2023]
Abstract
One of the central aims in Alzheimer's disease (AD) research is the identification of clinically relevant drug targets. A plethora of potential molecular targets work very well in preclinical model systems both in vitro and in vivo in AD mouse models. However, the lack of translation into clinical settings in the AD field is a challenging endeavor. Although it is long known that N-terminally truncated and pyroglutamate-modified Abeta (AβpE3) peptides are abundantly present in the brain of AD patients, form stable and soluble low-molecular weight oligomers, and induce neurodegeneration in AD mouse models, their potential as drug target has not been generally accepted in the past. This situation has dramatically changed with the report that passive immunization with donanemab, an AβpE3-specific antibody, cleared aymloid plaques and stabilized cognitive deficits in a group of patients with mild AD in a phase II trial. This review summarizes the current knowledge on the molecular mechanisms of generation of AβpE, its biochemical properties, and the intervention points as a drug target in AD.
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Lagunas-Rangel FA, Koshelev D, Nedorubov A, Kosheleva L, Trukhan V, Rabinovitch A, Schiöth HB, Levit S. Triple drug therapy with GABA, sitagliptin, and omeprazole prevents type 1 diabetes onset and promotes its reversal in non-obese diabetic mice. Front Endocrinol (Lausanne) 2022; 13:1028114. [PMID: 36339443 PMCID: PMC9633961 DOI: 10.3389/fendo.2022.1028114] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/10/2022] [Indexed: 12/03/2022] Open
Abstract
Previous studies have reported that dual drug combinations consisting of γ-aminobutyric acid (GABA) together with a dipeptidyl-peptidase-4 inhibitor (DPP-4i), also a DPP-4i with a proton pump inhibitor (PPI), could improve pancreatic β-cell function and ameliorate diabetes in diabetic mice. In this study, we sought to determine if a triple drug combination of GABA, a DPP-4i and a PPI might have superior therapeutic effects compared with double drug therapies in the prevention and reversal of diabetes in the non-obese diabetic (NOD) mouse model of human type 1 diabetes (T1D). In a diabetes prevention arm of the study, the triple drug combination of GABA, a DPP-4i, and a PPI exhibited superior therapeutic effects in preventing the onset of diabetes compared with all the double drug combinations and placebo. Also, the triple drug combination significantly increased circulating C-peptide and serum insulin levels in the mice. In a diabetes reversal arm of the study, the triple drug combination was superior to all of the double drug combinations in reducing hyperglycemia in the mice. In addition, the triple drug combination was the most effective in increasing circulating levels of C-peptide and serum insulin, thereby significantly reducing exogenous insulin needs. The combination of GABA, a DPP-4i and a PPI appears to be a promising and easily scalable therapy for the treatment and prevention of T1D.
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Affiliation(s)
| | - Daniil Koshelev
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
- Levicure LTD, Tel Aviv, Israel
| | - Andrej Nedorubov
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Liudmila Kosheleva
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
- Levicure LTD, Tel Aviv, Israel
| | | | | | - Helgi B. Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
- *Correspondence: Helgi B. Schiöth,
| | - Shmuel Levit
- Levicure LTD, Tel Aviv, Israel
- Institute of Endocrinology, Diabetes & Metabolism, Tel Aviv, Israel
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Yaribeygi H, Maleki M, Butler AE, Jamialahmadi T, Sahebkar A. The Impact of Incretin-Based Medications on Lipid Metabolism. J Diabetes Res 2021; 2021:1815178. [PMID: 35005028 PMCID: PMC8731296 DOI: 10.1155/2021/1815178] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
Pathophysiological pathways that are induced by chronic hyperglycemia negatively impact lipid metabolism. Thus, diabetes is commonly accompanied by varying degrees of dyslipidemia which is itself a major risk factor for further macro- and microvascular diabetes complications such as atherosclerosis and nephropathy. Therefore, normalizing lipid metabolism is an attractive goal for therapy in patients with diabetes. Incretin-based medications are a novel group of antidiabetic agents with potent hypoglycemic effects. While the impact of incretins on glucose metabolism is clear, recent evidence indicates their positive modulatory roles on various aspects of lipid metabolism. Therefore, incretins may offer additional beneficial effects beyond that of glucose normalization. In the current review, how these antidiabetic medications can regulate lipid homeostasis and the possible cellular pathways involved are discussed, incorporating related clinical evidence about incretin effects on lipid homeostasis.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alexandra E. Butler
- Research Department, Royal College of Surgeons in Ireland, PO Box 15503, Adliya, Bahrain
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Manigrasso MB, Rabbani P, Egaña-Gorroño L, Quadri N, Frye L, Zhou B, Reverdatto S, Ramirez LS, Dansereau S, Pan J, Li H, D’Agati VD, Ramasamy R, DeVita RJ, Shekhtman A, Schmidt AM. Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice. Sci Transl Med 2021; 13:eabf7084. [PMID: 34818060 PMCID: PMC8669775 DOI: 10.1126/scitranslmed.abf7084] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The macro- and microvascular complications of type 1 and 2 diabetes lead to increased disease severity and mortality. The receptor for advanced glycation end products (RAGE) can bind AGEs and multiple proinflammatory ligands that accumulate in diabetic tissues. Preclinical studies indicate that RAGE antagonists have beneficial effects on numerous complications of diabetes. However, these antagonists target the extracellular domains of RAGE, which bind distinct RAGE ligands at diverse sites in the immunoglobulin-like variable domain and two constant domains. The cytoplasmic tail of RAGE (ctRAGE) binds to the formin, Diaphanous-1 (DIAPH1), and this interaction is important for RAGE signaling. To comprehensively capture the breadth of RAGE signaling, we developed small-molecule antagonists of ctRAGE-DIAPH1 interaction, termed RAGE229. We demonstrated that RAGE229 is effective in suppressing RAGE-DIAPH1 binding, Förster resonance energy transfer, and biological activities in cellular assays. Using solution nuclear magnetic resonance spectroscopy, we defined the molecular underpinnings of the interaction of RAGE229 with RAGE. Through in vivo experimentation, we showed that RAGE229 assuaged short- and long-term complications of diabetes in both male and female mice, without lowering blood glucose concentrations. Last, the treatment with RAGE229 reduced plasma concentrations of TNF-α, IL-6, and CCL2/JE-MCP1 in diabetic mice, in parallel with reduced pathological and functional indices of diabetes-like kidney disease. Targeting ctRAGE-DIAPH1 interaction with RAGE229 mitigated diabetic complications in rodents by attenuating inflammatory signaling.
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Affiliation(s)
- Michaele B. Manigrasso
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Piul Rabbani
- Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, NY 10016, USA
| | - Lander Egaña-Gorroño
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Nosirudeen Quadri
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Laura Frye
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Boyan Zhou
- Departments of Population Health (Biostatistics) and Environmental Medicine, NYU Langone Health, New York, NY 10016, USA
| | - Sergey Reverdatto
- Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA
| | - Lisa S. Ramirez
- Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA
| | - Stephen Dansereau
- Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA
| | - Jinhong Pan
- Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA
| | - Huilin Li
- Departments of Population Health (Biostatistics) and Environmental Medicine, NYU Langone Health, New York, NY 10016, USA
| | - Vivette D. D’Agati
- Department of Pathology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Ravichandran Ramasamy
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Robert J. DeVita
- RJD Medicinal Chemistry and Drug Discovery Consulting LLC, Westfield, NJ 07091, USA
| | - Alexander Shekhtman
- Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
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Przezak A, Bielka W, Pawlik A. Incretins in the Therapy of Diabetic Kidney Disease. Int J Mol Sci 2021; 22:ijms222212312. [PMID: 34830194 PMCID: PMC8617946 DOI: 10.3390/ijms222212312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/09/2021] [Accepted: 11/12/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetic kidney disease is a microvascular complication that occurs in patients with diabetes. It is strongly associated with increased risk of kidney replacement therapy and all-cause mortality. Incretins are peptide hormones derived from the gastrointestinal tract, that besides causing enhancement of insulin secretion after oral glucose intake, participate in many other metabolic processes. Antidiabetic drug classes, such as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide receptor agonists, which way of action is based on incretins facility, not only show glucose-lowering properties but also have nephroprotective functions. The aim of this article is to present the latest information about incretin-based therapy and its influence on diabetic kidney disease appearance and progression, point its potential mechanisms of kidney protection and focus on future therapeutic possibilities bound with these two antidiabetic drug classes.
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Rezaei S, Tabrizi R, Nowrouzi-Sohrabi P, Jalali M, Atkin SL, Al-Rasadi K, Jamialahmadi T, Sahebkar A. GLP-1 Receptor Agonist Effects on Lipid and Liver Profiles in Patients with Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Can J Gastroenterol Hepatol 2021; 2021:8936865. [PMID: 34805029 PMCID: PMC8604595 DOI: 10.1155/2021/8936865] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/04/2021] [Accepted: 10/25/2021] [Indexed: 12/13/2022] Open
Abstract
AIMS This meta-analysis of randomized placebo-controlled clinical trials assessed the effect of glucose-like peptide-1-receptor agonists (GLP-1RA) on the lipid profile and liver enzymes in patients with nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS Randomized placebo-controlled trials investigating GLP-1RA on the lipid profile and liver enzymes in patients with NAFLD were searched in PubMed-Medline, Scopus, Web of Science, and Google Scholar databases (from inception to January 2020). A random-effects model and a generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted. Weighted random-effects meta-regression was performed on potential confounders on lipid profile and liver enzyme concentrations. RESULTS 12 studies were identified (12 GLP-1RA arms; 677 subjects) that showed treatment with GLP-1RA reduced alanine transaminase (ALT) concentrations (WMD = -10.14, 95%CI = [-15.84, -0.44], P < 0.001), gamma-glutamyl transferase (GGT) (WMD = -11.53, 95%CI = [-15.21,-7.85], P < 0.001), and alaline phosphatase (ALP) (WMD = -8.29, 95%CI = [-11.34, -5.24], P < 0.001). Aspartate aminotransferase (AST) (WMD = -2.95, 95% CI = [-7.26, 1.37], P=0.18) was unchanged. GLP-1 therapy did not alter triglycerides (TC) (WMD = -7.07, 95%CI = [-17.51, 3.37], P=0.18), total cholesterol (TC) (WMD = -1.17 (-5.25, 2.91), P=0.57), high-density lipoprotein (HDL-C) (WMD = 0.97, 95%CI = [-1.63, 3.58], P=0.46), or low-density lipoprotein (LDL-C) (WMD = -1.67, 95%CI = [-10.08, 6.74], P=0.69) in comparison with controls. CONCLUSION The results of this meta-analysis suggest that GLP-1RA treatment significantly reduces liver enzymes in patients with NAFLD, but the lipid profile is unaffected.
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Affiliation(s)
- Shahla Rezaei
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Clinical Nutrition, School of Health & Nutrition, Shiraz University of Medical Sciences, Shiraz, Iran
- Nutrition Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Tabrizi
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Peyman Nowrouzi-Sohrabi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Jalali
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Nutrition Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | - Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Ballan R, Saad SMI. Characteristics of the Gut Microbiota and Potential Effects of Probiotic Supplements in Individuals with Type 2 Diabetes mellitus. Foods 2021; 10:foods10112528. [PMID: 34828808 PMCID: PMC8622611 DOI: 10.3390/foods10112528] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/13/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
The increasing prevalence of type 2 diabetes mellitus (T2DM) worldwide has become a burden to healthcare systems. In 2019, around 463 million adults were living with diabetes mellitus, and T2DM accounted for 90 to 95% of cases. The relationship between the gut microbiota and T2DM has been explored with the advent of metagenomic techniques. Genome-wide association studies evaluating the microbiota of these individuals have pointed to taxonomic, functional, and microbial metabolite imbalances and represent a potential intervention in T2DM management. Several microbial metabolites and components, such as imidazole propionate, trimethylamine, and lipopolysaccharides, appear to impair insulin signaling, while short-chain fatty acids, secondary bile acids, and tryptophan metabolites may improve it. In addition, the use of probiotics with the aim of transiently restoring the microbial balance or reducing the effects of microbial metabolites that impair insulin sensitivity has been explored. Herein, we critically review the available literature on the changes in the gut microbiota in T2DM together with potential adjuvant therapies that may improve the health status of this population.
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Affiliation(s)
- Rafael Ballan
- Department of Pharmaceutical and Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil;
- Food Research Center, University of São Paulo, São Paulo 05508-080, SP, Brazil
| | - Susana Marta Isay Saad
- Department of Pharmaceutical and Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil;
- Food Research Center, University of São Paulo, São Paulo 05508-080, SP, Brazil
- Correspondence: ; Tel.: +55-11-3091-2378
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Yaribeygi H, Maleki M, Atkin SL, Jamialahmadi T, Sahebkar A. Impact of Incretin-Based Therapies on Adipokines and Adiponectin. J Diabetes Res 2021; 2021:3331865. [PMID: 34660808 PMCID: PMC8516550 DOI: 10.1155/2021/3331865] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/27/2021] [Indexed: 12/14/2022] Open
Abstract
Adipokines are a family of hormones and cytokines with both pro- and anti-inflammatory effects released into the circulation to exert their hormonal effects. Adipokines are closely involved in most metabolic pathways and play an important modulatory role in lipid and carbohydrate homeostasis as they are involved in the pathophysiology of most metabolic disorders. Incretin-based therapy is a newly introduced class of antidiabetic drugs that restores euglycemia through several cellular processes; however, its effect on adipokines expression/secretion is not fully understood. In this review, we propose that incretin-based therapy may function through adipokine modulation that may result in pharmacologic properties beyond their direct antidiabetic effects, resulting in better management of diabetes and diabetes-related complications.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Barakat B, Almeida MEF. Biochemical and immunological changes in obesity. Arch Biochem Biophys 2021; 708:108951. [PMID: 34102165 DOI: 10.1016/j.abb.2021.108951] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 05/25/2021] [Accepted: 05/31/2021] [Indexed: 12/18/2022]
Abstract
Obesity is a syndemia that promotes high expenditures for public health, and is defined by the excess of adipose tissue that is classified according to its function and anatomical distribution. In obese people, this tissue generates oxidative stress associated with a chronic inflammatory response, in which there is an imbalance in relation to the release of hormones and adipokines that cause loss of body homeostasis and predisposition to the development of some comorbidities. The purpose of this review is to summarize the main events that occur during the onset and progression of obesity with a special focus on biochemical and immunological changes. Hypertrophied and hyperplasia adipocytes have biomarkers and release adipokines capable of regulating pathways and expressing genes that culminate in the development of metabolic changes, such as changes in energy balance and intestinal microbiota, and the development of some comorbidities, diabetes mellitus, dyslipidemias, arterial hypertension, liver disease, cancer, allergies, osteoporosis, sarcopenia and obstructive sleep apnea. Thus, it is necessary to treat and/or prevent pathology, using traditional methods based on healthy eating, and regular physical and leisure activities.
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Affiliation(s)
- Beatriz Barakat
- Institute of Biological and Health Sciences, Federal University of Viçosa (UFV), Rio Paranaíba Campus, Rio Paranaíba, Minas Gerais, Brazil.
| | - Martha E F Almeida
- Institute of Biological and Health Sciences, Federal University of Viçosa (UFV), Rio Paranaíba Campus, Rio Paranaíba, Minas Gerais, Brazil
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Antioxidative Potentials of Incretin-Based Medications: A Review of Molecular Mechanisms. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9959320. [PMID: 34007411 PMCID: PMC8099522 DOI: 10.1155/2021/9959320] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/11/2021] [Accepted: 04/16/2021] [Indexed: 12/16/2022]
Abstract
Glucagon-like peptide 1 receptor agonists and dipeptidyl-peptidase 4 inhibitors are medications used for managing diabetes, mimicking the metabolic effects of incretin hormones. Recent evidence suggests that these medications have antioxidative potentials in the diabetic milieu. The pathophysiology of most diabetic complications involves oxidative stress. Therefore, if incretin-based antidiabetic medications can alleviate the free radicals involved in oxidative stress, they can potentially provide further therapeutic effects against diabetic complications. However, the molecular mechanisms by which these medications protect against oxidative stress are not fully understood. In the current review, we discuss the potential molecular mechanisms behind these pharmacologic agents' antioxidative properties.
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Jichitu A, Bungau S, Stanescu AMA, Vesa CM, Toma MM, Bustea C, Iurciuc S, Rus M, Bacalbasa N, Diaconu CC. Non-Alcoholic Fatty Liver Disease and Cardiovascular Comorbidities: Pathophysiological Links, Diagnosis, and Therapeutic Management. Diagnostics (Basel) 2021; 11:689. [PMID: 33921359 PMCID: PMC8069361 DOI: 10.3390/diagnostics11040689] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/09/2021] [Accepted: 04/11/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has a growing prevalence in recent years. Its association with cardiovascular disease has been intensively studied, and certain correlations have been identified. The connection between these two entities has lately aroused interest regarding therapeutic management. In order to find the best therapeutic options, a detailed understanding of the pathophysiology that links (NAFLD) to cardiovascular comorbidities is needed. This review focuses on the pathogenic mechanisms that are behind these two diseases and on the therapeutic management available at this time.
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Affiliation(s)
- Alexandra Jichitu
- Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania; (A.J.); (C.C.D.)
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania;
| | - Ana Maria Alexandra Stanescu
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Cosmin Mihai Vesa
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (C.M.V.); (C.B.)
| | - Mirela Marioara Toma
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania;
| | - Cristiana Bustea
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (C.M.V.); (C.B.)
| | - Stela Iurciuc
- Department of Cardiology, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Marius Rus
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Nicolae Bacalbasa
- Department 13, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Surgery, “Ion Cantacuzino” Clinical Hospital, 030167 Bucharest, Romania
| | - Camelia Cristina Diaconu
- Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania; (A.J.); (C.C.D.)
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
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Comparing the Anti-diabetic Effect of Sleeve Gastrectomy with Transit Bipartition Against Sleeve Gastrectomy and Roux-en-Y Gastric Bypass Using a Diabetic Rodent Model. Obes Surg 2021; 31:2203-2210. [PMID: 33507518 DOI: 10.1007/s11695-021-05256-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/15/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE Roux-en-Y gastric bypass (RYGB) has superior long-term diabetes remission outcomes to sleeve gastrectomy (SG). However, in regions with a high prevalence of gastric cancer, RYGB may not be the best option. This study aimed to investigate the anti-diabetic effect of SG with transit bipartition (SG-TB) compared with SG and RYGB. MATERIALS AND METHODS A total of 32 diabetic Sprague-Dawley rat models were assigned to one of four groups: SG (n = 8), RYGB (n = 8), SG-TB (n = 8), and SHAM (n = 8). Body weight, food intake, blood glucose, and hormonal changes (glucagon-like peptide-1 (GLP-1), insulin, and glucagon) were measured to investigate the effect of surgery in all groups. Oral glucose tolerance test and insulin tolerance test were performed before and 8 weeks after surgery. RESULTS There were no significant differences in the postoperative changes in body weight and food intake among the SG, RYGB, and SG-TB groups. Postoperatively, the RYGB and SG-TB groups had significantly higher GLP-1 levels and lower insulin levels than the SG group. Further, RYGB and SG-TB had significantly better glucose control improvements than SG. There were no significant differences in GLP-1, insulin, glucagon, and homeostasis model assessment of insulin resistance levels between RYGB and SG-TB. The preoperative and postoperative values of all variables in the SHAM group did not show significant differences. CONCLUSION In this study using a diabetes-induced rodent model, we found that the anti-diabetic effect of SG-TB is superior to that of SG and non-inferior to that of RYGB.
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