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AL-Noshokaty TM, Abdelhamid R, Abdelmaksoud NM, Khaled A, Hossam M, Ahmed R, Saber T, Khaled S, Elshaer SS, Abulsoud AI. Unlocking the multifaceted roles of GLP-1: Physiological functions and therapeutic potential. Toxicol Rep 2025; 14:101895. [PMID: 39911322 PMCID: PMC11795145 DOI: 10.1016/j.toxrep.2025.101895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 02/07/2025] Open
Abstract
Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.
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Affiliation(s)
- Tohada M. AL-Noshokaty
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Rehab Abdelhamid
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | | | - Aya Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mariam Hossam
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Razan Ahmed
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Toka Saber
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shahd Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed I. Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11231, Egypt
- Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
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Breit S, Hubl D. The effect of GLP-1RAs on mental health and psychotropics-induced metabolic disorders: A systematic review. Psychoneuroendocrinology 2025; 176:107415. [PMID: 40138849 DOI: 10.1016/j.psyneuen.2025.107415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/17/2025] [Accepted: 02/22/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Mental illnesses and psychotropic drug use are associated with an increased risk of weight gain and metabolic disorders. Growing evidence suggests that agonists of the glucagon-like peptide-1 receptor (GLP-1RAs) might be safe and effective weight loss medications. However, the current evidence for the use of GLP-1RAs in individuals with obesity and mental illness is limited. OBJECTIVE Evaluation of the safety and the impact of GLP-1RAs on mental health and psychotropics-induced metabolic disorders such as obesity and type 2 diabetes (T2D). METHODS A literature search from January 1st, 2010 to August 31st, 2024 was conducted using PubMed and Cochrane Library online databases. Studies comprising adults with obesity or/and T2D and mental illness were included. Studies that examined individuals with obesity or/and T2D without mental illness and completed psychiatric questionnaires before and after GLP-1RAs treatment were also included. RESULTS From the 36 included studies 18 examined the weight-reducing effect of GLP-1RAs in patients with mental disorders and the other studies examined patients without mental illness. GLP-1RAs lead to a significant weight loss and improvement of glycemic control in patients with mental illness on psychotropics. They showed a beneficial effect on mental health in patients with and without mental disorders and were not associated with a worsening of mental state, suicidality, new-onset mental illness, or increased psychiatric admissions. CONCLUSION GLP-1RAs are safe and effective weight loss treatments for individuals with obesity and mental illness exerting a positive effect on mental state and quality of life. There is a need for RCTs with larger sample sizes, a longer treatment duration and longer follow-up periods to evaluate the long-term effect of GLP-1RAs. It would be of great interest to conduct studies investigating the use of GLP-1RAs with the purpose to treat mental illness in order to directly assess their use in improving mental health.
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Affiliation(s)
- Sigrid Breit
- Translational Research Center, University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland.
| | - Daniela Hubl
- Translational Research Center, University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
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Klausen M, Knudsen G, Vilsbøll T, Fink‐Jensen A. Effects of GLP-1 Receptor Agonists in Alcohol Use Disorder. Basic Clin Pharmacol Toxicol 2025; 136:e70004. [PMID: 39891507 PMCID: PMC11786240 DOI: 10.1111/bcpt.70004] [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: 08/26/2024] [Revised: 12/12/2024] [Accepted: 01/20/2025] [Indexed: 02/03/2025]
Abstract
In the search for novel treatment strategies for alcohol use disorder (AUD), glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) approved for treating Type 2 diabetes and obesity have caught much attention. GLP-1 is a naturally occurring peptide produced in the small intestines and the brain, regulating plasma glucose levels and satiety. This focused review will report on the preclinical studies, case stories, register-based cohort studies, brain-imaging data and secondary analysis of clinical data supporting the role of GLP-1RAs as a novel treatment of AUD. Several clinical trials are ongoing, examining the potential effects of the GLP-1RA semaglutide in AUD.
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Affiliation(s)
- Mette Kruse Klausen
- Psychiatric Centre Copenhagen, Mental Health Services in the Capitol Region of DenmarkCopenhagen University Hospital FrederiksbergFrederiksbergDenmark
| | - Gitte Moos Knudsen
- Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Neurobiology Research UnitCopenhagen University Hospital RigshospitaletCopenhagenDenmark
| | - Tina Vilsbøll
- Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Clinical ResearchSteno Diabetes Center CopenhagenCopenhagenDenmark
| | - Anders Fink‐Jensen
- Psychiatric Centre Copenhagen, Mental Health Services in the Capitol Region of DenmarkCopenhagen University Hospital FrederiksbergFrederiksbergDenmark
- Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
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Klausen MK, Kuzey T, Pedersen JN, Justesen SK, Rasmussen L, Knorr UB, Mason G, Ekstrøm CT, Holst JJ, Koob G, Benveniste H, Volkow ND, Knudsen GM, Vilsbøll T, Fink-Jensen A. Does semaglutide reduce alcohol intake in Danish patients with alcohol use disorder and comorbid obesity? Trial protocol of a randomised, double-blinded, placebo-controlled clinical trial (the SEMALCO trial). BMJ Open 2025; 15:e086454. [PMID: 39779270 PMCID: PMC11749217 DOI: 10.1136/bmjopen-2024-086454] [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: 03/14/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
INTRODUCTION Alcohol use disorder (AUD) is a massive burden for the individual, relatives and society. Despite this, the treatment gap is wide compared with other mental health disorders. Treatment options are sparse, with only three Food and Drug Administration (FDA)-approved pharmacotherapies. Glucagon-like peptide-1 (GLP-1) receptor agonists have shown promising effects in reducing alcohol consumption in preclinical experiments, and clinical trials are in high demand to investigate these potentially beneficial effects in patients diagnosed with AUD. METHODS AND ANALYSIS The effects of the once-weekly GLP-1 receptor agonist semaglutide will be investigated in a 26-week, randomised, placebo-controlled, double-blinded clinical trial. 108 patients diagnosed with AUD and comorbid obesity (body mass index (BMI)≥30 kg/m2)) will be randomised to treatment with either semaglutide or placebo in combination with cognitive behavioural therapy. A subgroup of the patients will have structural, functional and neurochemical brain imaging performed at baseline and after 26 weeks of treatment. The primary endpoint is the reduction in heavy drinking days, defined as days with excess consumption of 48/60 g of alcohol per day (women and men, respectively). Secondary endpoints include changes from baseline to week 26 in alcohol consumption, smoking status, quality of life, fibrosis-4 score, plasma concentration of phosphatidylethanol, brain gamma-aminobutyric acid (GABA) levels, alcohol cue reactivity, functional connectivity and white matter tract integrity. STATUS Recruitment started in June 2023. ETHICS AND DISSEMINATION The study is approved by the Ethics Committee of the Capital Region of Denmark, the Danish Board of Health and the Danish Data Protection Agency. All patients will sign the written consent form before being included in the trial. Results will be disseminated through peer-reviewed publications and conference presentations. After the results are published, all de-identified data will be available in the Mendeley database. TRIAL REGISTRATION NUMBER NCT05895643.
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Affiliation(s)
- Mette Kruse Klausen
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
| | - Tugba Kuzey
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
| | - Julie Niemann Pedersen
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
| | - Signe Keller Justesen
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
| | - Line Rasmussen
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
| | - Ulla B Knorr
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Graeme Mason
- Department of Radiology and Biomedical Imaging, Psychiatry, and Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Claus Thorn Ekstrøm
- Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - George Koob
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | | | - Nora D Volkow
- The National Institute on Drug abuse, National Institutes of Health, Bethesda, MD, USA
| | - Gitte M Knudsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark
| | - Tina Vilsbøll
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Centre Copenhagen, University of Copenhagen, Herlev, Denmark
| | - Anders Fink-Jensen
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Butt MD, Ong SC, Rafiq A, Batool N, Saifi R, Yaseen S, Kaukab I, Ramzan B. Long-Term clinical efficacy of liraglutide for type 2 diabetes: real-world evidence and outcomes from Pakistan. J Pharm Policy Pract 2024; 17:2432462. [PMID: 39640418 PMCID: PMC11619037 DOI: 10.1080/20523211.2024.2432462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 11/16/2024] [Indexed: 12/07/2024] Open
Abstract
Background Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated efficacy in improving glycemic control and promoting weight loss in clinical trials. However, real-world data from diverse populations, particularly from South Asia, are limited. The study aims to evaluate the long-term efficacy and safety of liraglutide in a real-world setting among Pakistani patients with type 2 diabetes mellitus (T2DM). Methodology A retrospective cohort study of 624 patients initiated on liraglutide was conducted. Data were collected at baseline and 6, 12, 18, and 24 months. Primary outcomes were HbA1c and weight changes. Secondary outcomes included fasting plasma glucose, lipid profile, and blood pressure. Statistical analyses were performed using appropriate methods. Results In study population the mean HbA1c reduction of -1.45 ± 0.67% was observed at 24 months, with 30.6% achieving HbA1c ≤ 7.5%. A rapid and sustained weight loss of -7.51 kg was achieved, with 27.2% experiencing ≥5% weight loss. Additionally, liraglutide led to a significant reduction in LDL cholesterol, with 46.7% of patients achieving a ≥ 10% reduction at 24 months. Liraglutide was well-tolerated, with a low discontinuation rate of 4.6%. Conclusion Liraglutide demonstrated sustained efficacy and safety in a diverse Pakistani population with T2DM, regardless of baseline characteristics. These findings support the use of liraglutide as an effective treatment option for T2DM in real-world clinical practice.
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Affiliation(s)
- Muhammad Daoud Butt
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, USM Penang, Malaysia
- Department of Medicine, Faculty of Medicine, Centre of Excellence for Research in AIDS, University of Malaya, Kuala Lumpur, Malaysia
| | - Siew Chin Ong
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, USM Penang, Malaysia
| | - Azra Rafiq
- Department of Pharmacy, Riphah International University, Lahore, Pakistan
- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey
| | - Nighat Batool
- Department of Pharmacy, Pak Austria Fachhochschule Institute of Applied Sciences and Technology, Mang Haripur KPK, Pakistan
| | - Rumana Saifi
- Department of Medicine, Faculty of Medicine, Centre of Excellence for Research in AIDS, University of Malaya, Kuala Lumpur, Malaysia
- Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Samina Yaseen
- Department of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Irum Kaukab
- Department of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Basit Ramzan
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, USM Penang, Malaysia
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Enyew Belay K, Jemal RH, Tuyizere A. Innovative Glucagon-based Therapies for Obesity. J Endocr Soc 2024; 8:bvae197. [PMID: 39574787 PMCID: PMC11579655 DOI: 10.1210/jendso/bvae197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Indexed: 11/24/2024] Open
Abstract
Obesity poses a significant global health challenge, with an alarming rise in prevalence rates. Traditional interventions, including lifestyle modifications, often fall short of achieving sustainable weight loss, ultimately leading to surgical interventions, which carry a significant burden and side effects. This necessitates the exploration of effective and relatively tolerable pharmacological alternatives. Among emerging therapeutic avenues, glucagon-based treatments have garnered attention for their potential to modulate metabolic pathways and regulate appetite. This paper discusses current research on the physiological mechanisms underlying obesity and the role of glucagon in energy homeostasis. Glucagon, traditionally recognized for its glycemic control functions, has emerged as a promising target for obesity management due to its multifaceted effects on metabolism, appetite regulation, and energy expenditure. This review focuses on the pharmacological landscape, encompassing single and dual agonist therapies targeting glucagon receptors (GcgRs), glucagon-like peptide-1 receptors (GLP-1Rs), glucose-dependent insulinotropic polypeptide receptors (GIPRs), amylin, triiodothyronine, fibroblast growth factor 21, and peptide tyrosine tyrosine. Moreover, novel triple-agonist therapies that simultaneously target GLP-1R, GIPR, and GcgR show promise in augmenting further metabolic benefits. This review paper tries to summarize key findings from preclinical and clinical studies, elucidating the mechanisms of action, safety profiles, and therapeutic potential of glucagon-based therapies in combating obesity and its comorbidities. Additionally, it explores ongoing research endeavors, including phase III trials, aimed at further validating the efficacy and safety of these innovative treatment modalities.
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Affiliation(s)
- Kibret Enyew Belay
- Department of Internal Medicine, Endocrinology and Metabolism Unit, Bahir Dar University, Bahir Dar 6000, Ethiopia
| | - Rebil Heiru Jemal
- Department of Internal Medicine, Adama Hospital Medical College, Adama 1000, Ethiopia
| | - Aloys Tuyizere
- Department of Internal Medicine, Endocrinology, Diabetes and Metabolism Unit, University of Rwanda, Kigali 00200, Rwanda
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Nestor LJ, Ersche KD. Gut Hormones: Possible Mediators of Addictive Disorders? Eur Addict Res 2024; 30:339-346. [PMID: 39389039 DOI: 10.1159/000540743] [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: 04/16/2024] [Accepted: 08/02/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND Alcohol and drug dependence are major health and economic burdens to society. One of the major challenges to reducing this burden will be to develop more effective and better tolerated medications that target alternative mechanisms in the brain. While the dopamine system has been well characterized for mediating the reward value of drugs, there is evidence that the endocrine system also conveys signals to the same neural systems using gut hormones. SUMMARY These gut hormones, produced in the stomach and intestine and that regulate food intake, have also been shown to control the use of other substances, such as alcohol and drugs of abuse. Examples of such hormones are ghrelin and glucagon-like peptide-1, which exert their effects on dopamine transmission in parts of the brain known to be involved in some of the core features of addiction, such as reward sensitivity. KEY MESSAGES This raises the possibility that gut hormone systems may play a pivotal role in addictive disorders. This review will briefly outline emerging evidence that the ghrelin and glucagon-like peptide-1 hormones are contrasting mediators of alcohol and drug use and may present a promising alternative target for treatment intervention in addictive disorders.
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Affiliation(s)
- Liam J Nestor
- Department of Psychiatry, University of Cambridge, Cambridge, UK
| | - Karen D Ersche
- Department of Psychiatry, University of Cambridge, Cambridge, UK
- Department of Systems Neuroscience, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Department of Addictive Behaviour and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
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Lin D, Hu D, Song Y, He X, Wu L. Long-term efficacy of washed microbiota transplantation in overweight patients. Eur J Clin Invest 2024; 54:e14260. [PMID: 38858775 DOI: 10.1111/eci.14260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/15/2024] [Accepted: 05/22/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND Faecal microbiota transplantation holds promise in mitigating fat accumulation and improving obesity. This study aimed to evaluate the long-term efficacy of washed microbiota transplantation (WMT) among overweight patients. METHODS The clinical data pertaining to the treatment of patients with WMT were collected retrospectively. Compared alterations in body mass index (BMI), blood glucose, blood lipids and blood pressure prior to and following WMT treatment. Comprehensive efficacy evaluation and atherosclerosis cardiovascular disease (ASCVD) grading evaluation were carried out, with an analysis of gut microbiota composition before and after WMT. RESULTS A total of 186 patients were included (80 overweight, 106 normal weight). WMT not only had the effect of improving overweight patients to the normal weight patients (p < .001), but also could significantly reduce BMI in the long term by restoring gut microbiota homeostasis (p < .001). In addition, the BMI improvement value of multi course was more significant than that of single course or double course. WMT had a significant ASCVD downgrade effect on the high-risk and medium-risk groups outside 1 year, while it did not increase the risk of upgrading ASCVD for low-risk group. CONCLUSIONS WMT could significantly reduce the BMI of overweight patients and still had an improvement effect in the long term.
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Affiliation(s)
- Dejiang Lin
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Dongxia Hu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Youlin Song
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xingxiang He
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Lei Wu
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
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Kołodziej-Sobczak D, Sobczak Ł, Łączkowski KZ. Protein Tyrosine Phosphatase 1B (PTP1B): A Comprehensive Review of Its Role in Pathogenesis of Human Diseases. Int J Mol Sci 2024; 25:7033. [PMID: 39000142 PMCID: PMC11241624 DOI: 10.3390/ijms25137033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Overexpression of protein tyrosine phosphatase 1B (PTP1B) disrupts signaling pathways and results in numerous human diseases. In particular, its involvement has been well documented in the pathogenesis of metabolic disorders (diabetes mellitus type I and type II, fatty liver disease, and obesity); neurodegenerative diseases (Alzheimer's disease, Parkinson's disease); major depressive disorder; calcific aortic valve disease; as well as several cancer types. Given this multitude of therapeutic applications, shortly after identification of PTP1B and its role, the pursuit to introduce safe and selective enzyme inhibitors began. Regrettably, efforts undertaken so far have proved unsuccessful, since all proposed PTP1B inhibitors failed, or are yet to complete, clinical trials. Intending to aid introduction of the new generation of PTP1B inhibitors, this work collects and organizes the current state of the art. In particular, this review intends to elucidate intricate relations between numerous diseases associated with the overexpression of PTP1B, as we believe that it is of the utmost significance to establish and follow a brand-new holistic approach in the treatment of interconnected conditions. With this in mind, this comprehensive review aims to validate the PTP1B enzyme as a promising molecular target, and to reinforce future research in this direction.
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Affiliation(s)
- Dominika Kołodziej-Sobczak
- Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, Poland;
| | - Łukasz Sobczak
- Hospital Pharmacy, Multidisciplinary Municipal Hospital in Bydgoszcz, Szpitalna 19, 85-826 Bydgoszcz, Poland
| | - Krzysztof Z. Łączkowski
- Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, Poland;
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Milani I, Guarisco G, Chinucci M, Gaita C, Leonetti F, Capoccia D. Sex-Differences in Response to Treatment with Liraglutide 3.0 mg. J Clin Med 2024; 13:3369. [PMID: 38929898 PMCID: PMC11204191 DOI: 10.3390/jcm13123369] [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: 05/07/2024] [Revised: 05/23/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
Background: Sex differences characterize the prevalence and attitudes toward weight management. Despite limited evidence suggesting greater weight loss in women with anti-obesity pharmacotherapy, sex-specific analysis remains underexplored. This retrospective study aimed to evaluate the sex-specific response to liraglutide 3.0 mg treatment in people with obesity without type 2 diabetes (T2D). Methods: Data were collected from 47 patients (31 women, 16 men) with age > 18 years; BMI ≥ 30 kg/m2; absence of T2D; and exclusion of prior anti-obesity treatment, comorbidities, or bariatric surgery. Only patients who maintained the liraglutide 3.0 mg dose for at least 6 months were included. Results: Both sexes showed significant reductions in weight and BMI at 3 and 6 months. Men achieved greater weight loss (WL), BMI reduction, %WL, WL > 5%, and >10% than women, and they also showed more significant improvements in metabolic parameters (total and LDL cholesterol, Fibrosis-4 Index FIB-4). No significant sex differences were observed in glucose metabolism or renal function. Conclusions: This study showed a greater therapeutic effect of liraglutide 3.0 mg in men. Given men's higher risk of cardiovascular disease (CVD), and underrepresentation in clinical weight loss programs, these findings may increase male engagement and improve their CVD risk.
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Affiliation(s)
| | | | | | | | | | - Danila Capoccia
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
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Conroy LJ, McCann A, Zhang N, de Gaetano M. The role of nanosystems in the delivery of glucose-lowering drugs for the preemption and treatment of diabetes-associated atherosclerosis. Am J Physiol Cell Physiol 2024; 326:C1398-C1409. [PMID: 38525540 DOI: 10.1152/ajpcell.00695.2023] [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: 12/14/2023] [Revised: 03/19/2024] [Accepted: 03/19/2024] [Indexed: 03/26/2024]
Abstract
Diabetes is one of the most prevalent diseases worldwide. In recent decades, type-2 diabetes has become increasingly common, particularly in younger individuals. Diabetes leads to many vascular complications, including atherosclerosis. Atherosclerosis is a cardiovascular disease characterized by lipid-rich plaques within the vasculature. Plaques develop over time, restricting blood flow, and can, therefore, be the underlying cause of major adverse cardiovascular events, including myocardial infarction and stroke. Diabetes and atherosclerosis are intrinsically linked. Diabetes is a metabolic syndrome that accelerates atherosclerosis and increases the risk of developing other comorbidities, such as diabetes-associated atherosclerosis (DAA). Gold standard antidiabetic medications focus on attenuating hyperglycemia. Though recent evidence suggests that glucose-lowering drugs may have broader applications, beyond diabetes management. This review mainly evaluates the role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide and semaglutide in DAA. These drugs mimic gut hormones (incretins), which inhibit glucagon secretion while stimulating insulin secretion, thus improving insulin sensitivity. This facilitates delayed gastric emptying and increased patient satiety; hence, they are also indicated for the treatment of obesity. GLP-1 RAs have significant cardioprotective effects, including decreasing low-density lipoprotein (LDL) cholesterol and triglycerides levels. Liraglutide and semaglutide have specifically been shown to decrease cardiovascular risk. Liraglutide has displayed a myriad of antiatherosclerotic properties, with the potential to induce plaque regression. This review aims to address how glucose-lowering medications can be applied to treat diseases other than diabetes. We specifically focus on how nanomedicines can be used for the site-specific delivery of antidiabetic medicines for the treatment of diabetes-associated atherosclerosis.
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Affiliation(s)
- Luke James Conroy
- Diabetes Complications Research Centre, Conway Institute & School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Alyssa McCann
- School of Mechanical and Materials Engineering, University College Dublin, Dublin, Ireland
| | - Nan Zhang
- School of Mechanical and Materials Engineering, University College Dublin, Dublin, Ireland
| | - Monica de Gaetano
- Diabetes Complications Research Centre, Conway Institute & School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
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12
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Ding X, Wang Y, Zhang S, Zhang R, Chen D, Liu C, Xu J, Chen L. Reductive amination of ω-conotoxin MVIIA: synthesis, determination of modification sites, and self-assembly. Amino Acids 2024; 56:26. [PMID: 38554247 PMCID: PMC10981597 DOI: 10.1007/s00726-023-03366-2] [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: 10/04/2023] [Accepted: 12/13/2023] [Indexed: 04/01/2024]
Abstract
Peptide drugs have disadvantages such as low stability, short half-life and side effects, which limit their widespread use in clinical practice. Therefore, peptide drugs can be modified to improve these disadvantages. Numerous studies have shown that alkyl-modified peptide drugs can self-assemble to prolong the duration of efficacy and/or reduce side effects. However, the commonly used solid-phase synthesis method for alkyl-modified peptides is time-consuming. To overcome this, a simple reductive amination reaction was employed, which can directly graft the alkyl chain to the peptide sequence and effectively avoid stepwise synthesis from C- to N-terminal with amino acids. In this study, ω-conotoxin MVIIA was used as the peptide drug, while myristic aldehyde was used as the alkylating agent. To obtain the maximum productivity of modified peptides, the molar ratio of peptide MVIIA to myristic aldehyde in the reductive amination reaction was optimized. Furthermore, the peptide modification sites in this reaction were confirmed by secondary mass spectrometry analysis. Besides, alkyl-modified peptide MVIIA was able to form micelles by self-assembly and improved stability in serum, which was related to our previous work where myristoylated peptide MVIIA micelles can improve the drug stability. Finally, this study was intended to provide a methodological basis for modifying the alkyl chain of peptide drugs.
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Affiliation(s)
- Xiufang Ding
- State Key Laboratory of NBC Protection for Civilian, Beijing, 102205, China
| | - Yue Wang
- State Key Laboratory of NBC Protection for Civilian, Beijing, 102205, China
- Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Sida Zhang
- State Key Laboratory of NBC Protection for Civilian, Beijing, 102205, China
| | - Ruihua Zhang
- State Key Laboratory of NBC Protection for Civilian, Beijing, 102205, China
| | - Dong Chen
- State Key Laboratory of NBC Protection for Civilian, Beijing, 102205, China
| | - Changcai Liu
- State Key Laboratory of NBC Protection for Civilian, Beijing, 102205, China
| | - Jianfu Xu
- State Key Laboratory of NBC Protection for Civilian, Beijing, 102205, China.
| | - Long Chen
- Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
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13
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Patil M, Casari I, Warne LN, Falasca M. G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype? Biomed Pharmacother 2024; 172:116245. [PMID: 38340396 DOI: 10.1016/j.biopha.2024.116245] [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: 09/18/2023] [Revised: 01/23/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
'Globesity' is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like-peptide-1 (GLP-1) has been highly captivated during the last decade owing to its multisystemic pleiotropic clinical outcomes beyond inherent glucoregulatory action. That fostered a pharmaceutical interest in synthetic GLP-1 analogues to tackle type-2 diabetes (T2D), obesity and related complications. Besides, mechanistic insights on metabolic surgeries allude to an incretin-based hormonal combination strategy for weight loss that emerged as a forerunner for the discovery of injectable 'unimolecular poly-incretin-agonist' therapies. Physiologically, intestinal enteroendocrine L-cells (EECs) are the prominent endogenous source of GLP-1 peptide. Despite comprehending the potential of various G protein-coupled receptors (GPCRs) to stimulate endogenous GLP-1 secretion, decades of translational GPCR research have failed to yield regulatory-approved endogenous GLP-1 secretagogue oral therapy. Lately, a dual/poly-GPCR agonism strategy has emerged as an alternative approach to the traditional mono-GPCR concept. This review aims to gain a comprehensive understanding by revisiting the pharmacology of a few potential GPCR-based complementary avenues that have drawn attention to the design of orally active poly-GPCR agonist therapy. The merits, challenges and recent developments that may aid future poly-GPCR drug discovery are critically discussed. Subsequently, we project the mechanism-based therapeutic potential and limitations of oral poly-GPCR agonism strategy to augment intestinal GLP-1 for weight loss. We further extend our discussion to compare the poly-GPCR agonism approach over invasive surgical and injectable GLP-1-based regimens currently in clinical practice for obesity.
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Affiliation(s)
- Mohan Patil
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Ilaria Casari
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Leon N Warne
- Little Green Pharma, West Perth, Western Australia 6872, Australia
| | - Marco Falasca
- University of Parma, Department of Medicine and Surgery, Via Volturno 39, 43125 Parma, Italy.
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14
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Wang R, Luo S, Xiao Z, Zhou Z. Efficacy and safety of fixed-ratio combination insulin degludec/liraglutide in type 2 diabetes: A systematic review and meta-analysis of randomised controlled trials. Diabetes Metab Res Rev 2024; 40:e3752. [PMID: 38013215 DOI: 10.1002/dmrr.3752] [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: 06/02/2023] [Revised: 09/30/2023] [Accepted: 11/05/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND The efficacy and safety of fixed-ratio combination insulin degludec/liraglutide (IDegLira) for type 2 diabetes (T2DM) were extensively investigated by the global DUAL trials. However, the evidence on its efficacy and safety in T2DM has not been systematically reviewed. METHODS Randomized controlled trials published in English that compared IDegLira with placebo or GLP-1 agonists or insulin in patients with T2DM were selected up to December 2022. Data on the study characteristics, efficacy and safety outcomes were extracted. We compared the efficacy and safety between "IDegLira versus Insulin," "IDegLira versus GLP-1RA," and "IDegLira versus Placebo". The risk of potential bias was assessed. RESULTS In terms of glycaemic efficacy, IDegLira reduced levels of glycated haemoglobin (HbA1c; weighted mean differences (WMDs) 0.52%, 95% CI 0.33%-0.71%); fasting blood glucose (0.32 mg/dL, 0.14-0.50 mg/dL), and the nine-point self-measured plasma glucose (0.25 mmol/L, 0.25-0.36 mmol/L). Furthermore, IDegLira was generally better in the attainment of HbA1c < 7.0% or ≤6.5%, HbA1c < 7.0% or ≤6.5% without weight gain and/or without severe or blood glucose-confirmed hypoglycaemic episodes. In non-glycaemic efficacy aspects, IDegLira decreased systolic blood pressure but elevated heart rate. In terms of safety outcomes, IDegLira did not appear to be associated with a risk of hypoglycaemia (RR 1.23, 0.85-1.78) and nocturnal hypoglycaemia (0.89, 0.52-1.52) occurring when compared with other hypoglycaemic agents or placebo. CONCLUSIONS IDegLira improves better glycaemic and non-glycaemic outcomes without weight gain and/or without severe or blood glucose-confirmed hypoglycaemic episodes in T2DM. Side effects of IDegLira are mild.
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Affiliation(s)
- Rui Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zilin Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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15
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Niu X, Lu P, Huang L, Sun Y, Jin M, Liu J, Li X. The effect of metformin combined with liraglutide on gut microbiota of Chinese patients with type 2 diabetes. Int Microbiol 2024; 27:265-276. [PMID: 37316616 DOI: 10.1007/s10123-023-00380-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/17/2022] [Accepted: 05/18/2023] [Indexed: 06/16/2023]
Abstract
BACKGROUND Metformin (MET) is a first-line therapy for type-2 diabetes mellitus (T2DM). Liraglutide (LRG) is a glucagon-like peptide-1 receptor agonist used as a second-line therapy in combination with MET. METHODS We performed a longitudinal analysis comparing the gut microbiota of overweight and/or pre-diabetic participants (NCP group) with that of each following their progression to T2DM diagnosis (UNT group) using 16S ribosomal RNA gene sequencing of fecal bacteria samples. We also examined the effects of MET (MET group) and MET plus LRG (MET+LRG group) on the gut microbiota of these participants following 60 days of anti-diabetic drug therapy in two parallel treatment arms. RESULTS In the UNT group, the relative abundances of Paraprevotella (P = 0.002) and Megamonas (P = 0.029) were greater, and that of Lachnospira (P = 0.003) was lower, compared with the NCP group. In the MET group, the relative abundance of Bacteroides (P = 0.039) was greater, and those of Paraprevotella (P = 0.018), Blautia (P = 0.001), and Faecalibacterium (P = 0.005) were lower, compared with the UNT group. In the MET+LRG group, the relative abundances of Blautia (P = 0.005) and Dialister (P = 0.045) were significantly lower than in the UNT group. The relative abundance of Megasphaera in the MET group was significantly greater than in the MET+LRG group (P = 0.041). CONCLUSIONS Treatment with MET and MET+LRG results in significant alterations in gut microbiota, compared with the profiles of patients at the time of T2DM diagnosis. These alterations differed significantly between the MET and MET+LRG groups, which suggests that LRG exerted an additive effect on the composition of gut microbiota.
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Affiliation(s)
- Xiaohong Niu
- Department of Endocrinology, Changzhi Medical College Affiliated Heji Hospital, Changzhi, 046011, China
| | - Panpan Lu
- Department of Endocrinology, Changzhi Medical College, Changzhi, 046013, China
| | - Linqing Huang
- Department of Endocrinology, Changzhi Medical College, Changzhi, 046013, China
| | - Yan Sun
- Department of Endocrinology, Changzhi Medical College Affiliated Heji Hospital, Changzhi, 046011, China
| | - Miaomiao Jin
- Department of Endocrinology, Changzhi Medical College Affiliated Heji Hospital, Changzhi, 046011, China
| | - Jing Liu
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Xing Li
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, China.
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16
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Sweeney P, Gimenez LE, Hernandez CC, Cone RD. Targeting the central melanocortin system for the treatment of metabolic disorders. Nat Rev Endocrinol 2023; 19:507-519. [PMID: 37365323 DOI: 10.1038/s41574-023-00855-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/18/2023] [Indexed: 06/28/2023]
Abstract
A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders such as obesity and cachexia, as well as anorexia nervosa. Setmelanotide, which functions by engaging the central melanocortin circuitry, was approved by the FDA in 2020 for use in certain forms of syndromic obesity. Furthermore, the FDA approvals in 2019 of two peptide drugs targeting melanocortin receptors for the treatment of generalized hypoactive sexual desire disorder (bremelanotide) and erythropoietic protoporphyria-associated phototoxicity (afamelanotide) demonstrate the safety of this class of peptides. These approvals have also renewed excitement in the development of therapeutics targeting the melanocortin system. Here, we review the anatomy and function of the melanocortin system, discuss progress and challenges in developing melanocortin receptor-based therapeutics, and outline potential metabolic and behavioural disorders that could be addressed using pharmacological agents targeting these receptors.
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Affiliation(s)
- Patrick Sweeney
- School of Molecular and Cellular Biology, College of Liberal Arts and Sciences, University of Illinois Urbana-Champaign, Champaign, IL, USA
| | - Luis E Gimenez
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | | | - Roger D Cone
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
- Department of Molecular and Integrative Physiology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
- Department of Molecular, Cellular, and Developmental Biology, College of Literature Science and the Arts, University of Michigan, Ann Arbor, MI, USA.
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17
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Rohani P, Malekpour Alamdari N, Bagheri SE, Hekmatdoost A, Sohouli MH. The effects of subcutaneous Tirzepatide on obesity and overweight: a systematic review and meta-regression analysis of randomized controlled trials. Front Endocrinol (Lausanne) 2023; 14:1230206. [PMID: 37621649 PMCID: PMC10446893 DOI: 10.3389/fendo.2023.1230206] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 07/19/2023] [Indexed: 08/26/2023] Open
Abstract
Background Despite the fact that obesity and overweight are serious major health problems worldwide, fighting against them is also considered a challenging issue. Several interventional studies have evaluated the potential weight-reduction effect of Tirzepatide. In order to obtain a better viewpoint from them, this study aimed to comprehensively investigate the effects of subcutaneous Tirzepatide on obesity and overweight. Methods Scopus, PubMed/Medline, Web of Science, Cochrane, and Embase databases were searched using standard keywords to identify all controlled trials investigating the weight loss effects of Tirzepatide. Pooled weighted mean difference and 95% confidence intervals were achieved by random-effects model analysis for the best estimation of outcomes. The statistical heterogeneity and publication bias were determined using the Cochran's Q test and I2 statistics and using the funnel plot and Egger's test, respectively. Results Twenty three treatments arm with 7062 participants' were included in this systematic review and meta-regression analysis. The pooled findings showed that Tirzepatide vs placebo significantly reduced body weight (weighted mean difference (WMD): -11.34 kg, 95% confidence interval (CI): -12.79 to -9.88, P< 0.001), body mass index (BMI) (WMD: -3.11 kg/m2, 95% CI: -4.36 to -1.86, P< 0.001), and waist circumference (WC) (WMD: -7.24 cm, 95% CI -10.12 to -4.36, P< 0.001). These reductions were even greater, especially with higher doses and duration of Tirzepatide. Conclusions Tirzepatide medication had significant effects on weight management with the reduction of body weight, BMI, and WC. Administration of Tirzepatide can be considered a therapeutic strategy for overweight or obese people.
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Affiliation(s)
- Pejman Rohani
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasser Malekpour Alamdari
- Department of General Surgery, School of Medicine, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassan Sohouli
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Student Research Commitee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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18
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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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19
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Webster CM, Mittal N, Dhurandhar EJ, Dhurandhar NV. Potential contributors to variation in weight-loss response to liraglutide. Obes Rev 2023:e13568. [PMID: 37069131 DOI: 10.1111/obr.13568] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 03/02/2023] [Accepted: 03/30/2023] [Indexed: 04/19/2023]
Abstract
Obesity treatment requires a chronic state of negative energy balance. Obesity medications can help with this, increasing long-term dietary compliance by promoting satiety or reducing hunger. However, efficacy and safety of obesity medications vary for individuals. Early identification of non-responders to obesity medications may limit drug exposure while optimizing benefits for responders. This review summarizes factors that impact weight-loss response to liraglutide. Factors linked to greater weight loss on liraglutide include being female, not having diabetes, having relatively high baseline weight, and losing at least 4% of initial weight after 16 weeks of treatment. Other covariates that may predict treatment response but require further confirmation include central effects, nausea, gastric emptying of solids, and genotype. Baseline body mass index, race, and age seem less relevant for predicting weight-loss response to liraglutide. Lesser known and harder-to-measure factors such as cerebral blood flow, food cue reactivity, gut hormone levels, and dietary adherence possibly impact variability of response to liraglutide. This information should assist healthcare providers with establishing realistic weight-loss probability for individual patients. Future research should improve the ability to identify responders to liraglutide. Importantly, this review may provide a framework to identify responders to other obesity medications.
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Affiliation(s)
- Chelsi M Webster
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA
| | - Neha Mittal
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | | | - Nikhil V Dhurandhar
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA
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20
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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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21
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Perone F, Pingitore A, Conte E, Halasz G, Ambrosetti M, Peruzzi M, Cavarretta E. Obesity and Cardiovascular Risk: Systematic Intervention Is the Key for Prevention. Healthcare (Basel) 2023; 11:healthcare11060902. [PMID: 36981559 PMCID: PMC10048800 DOI: 10.3390/healthcare11060902] [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: 01/29/2023] [Revised: 03/09/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
Obesity is a serious public health issue and associated with an increased risk of cardiovascular disease events and mortality. The risk of cardiovascular complications is directly related to excess body fat mass and ectopic fat deposition, but also other obesity-related complications such as pre-type 2 diabetes, obstructive sleep apnoea, and non-alcoholic fatty liver diseases. Body mass index and waist circumference are used to classify a patient as overweight or obese and to stratify cardiovascular risk. Physical activity and diet, despite being key points in preventing adverse events and reducing cardiovascular risk, are not always successful strategies. Pharmacological treatments for weight reduction are promising strategies, but are restricted by possible safety issues and cost. Nonetheless, these treatments are associated with improvements in cardiovascular risk factors, and studies are ongoing to better evaluate cardiovascular outcomes. Bariatric surgery is effective in reducing the incidence of death and cardiovascular events such as myocardial infarction and stroke. Cardiac rehabilitation programs in obese patients improve cardiovascular disease risk factors, quality of life, and exercise capacity. The aim of this review was to critically analyze the current role and future aspects of lifestyle changes, medical and surgical treatments, and cardiac rehabilitation in obese patients, to reduce cardiovascular disease risk and mortality, and to highlight the need for a multidisciplinary approach to improving cardiovascular outcomes.
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Affiliation(s)
- Francesco Perone
- Cardiac Rehabilitation Unit, Rehabilitation Clinic "Villa delle Magnolie", 81020 Castel Morrone, Caserta, Italy
| | - Annachiara Pingitore
- Department of General and Specialistic Surgery "Paride Stefanini", Sapienza University of Rome, 00161 Rome, Italy
| | - Edoardo Conte
- Department of Clinical Cardiology and Cardiovascular Imaging, Galeazzi-Sant'Ambrogio Hospital IRCCS, 20100 Milan, Lombardy, Italy
| | - Geza Halasz
- Cardiology Department, Azienda Ospedaliera San Camillo Forlanini, 00152 Rome, Italy
| | - Marco Ambrosetti
- Cardiovascular Rehabilitation Unit, ASST Crema Santa Marta Hospital, 26027 Rivolta D'Adda, Cremona, Italy
| | - Mariangela Peruzzi
- Department of Clinical Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy
- Mediterranea Cardiocentro, 80122 Naples, Campania, Italy
| | - Elena Cavarretta
- Mediterranea Cardiocentro, 80122 Naples, Campania, Italy
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Latina, Italy
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Kosmalski M, Deska K, Bąk B, Różycka-Kosmalska M, Pietras T. Pharmacological Support for the Treatment of Obesity-Present and Future. Healthcare (Basel) 2023; 11:433. [PMID: 36767008 PMCID: PMC9914730 DOI: 10.3390/healthcare11030433] [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: 11/15/2022] [Revised: 01/25/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
Obesity is a growing civilization problem, associated with a number of negative health consequences affecting almost all tissues and organs. Currently, obesity treatment includes lifestyle modifications (including diet and exercise), pharmacologic therapies, and in some clinical situations, bariatric surgery. These treatments seem to be the most effective method supporting the treatment of obesity. However, they are many limitations to the options, both for the practitioners and patients. Often the comorbidities, cost, age of the patient, and even geographic locations may influence the choices. The pharmacotherapy of obesity is a fast-growing market. Currently, we have at our disposal drugs with various mechanisms of action (directly reducing the absorption of calories-orlistat, acting centrally-bupropion with naltrexone, phentermine with topiramate, or multidirectional-liraglutide, dulaglutide, semaglutide). The drugs whose weight-reducing effect is used in the course of the pharmacotherapy of other diseases (e.g., glucose-sodium cotransporter inhibitors, exenatide) are also worth mentioning. The obesity pharmacotherapy is focusing on novel therapeutic agents with improved safety and efficacy profiles. These trends also include an assessment of the usefulness of the weight-reducing properties of the drugs previously used for other diseases. The presented paper is an overview of the studies related to both drugs currently used in the pharmacotherapy of obesity and those undergoing clinical trials, taking into account the individual approach to the patient.
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Affiliation(s)
- Marcin Kosmalski
- Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Łódź, Poland
| | - Kacper Deska
- Students’ Scientific Association Clinical Pharmacology, Medical University of Lodz, 90-153 Łódź, Poland
| | - Bartłomiej Bąk
- 2nd Department of Psychiatry, Institute of Psychiatry and Neurology in Warsaw, 02-957 Warszawa, Poland
| | | | - Tadeusz Pietras
- Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Łódź, Poland
- 2nd Department of Psychiatry, Institute of Psychiatry and Neurology in Warsaw, 02-957 Warszawa, Poland
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Ding R, Zhao Z, He J, Tao Y, Zhang H, Yuan R, Sun K, Shi Y. Preparation, Drug Distribution, and In Vivo Evaluation of the Safety of Protein Corona Liposomes for Liraglutide Delivery. NANOMATERIALS (BASEL, SWITZERLAND) 2023; 13:nano13030540. [PMID: 36770503 PMCID: PMC9920406 DOI: 10.3390/nano13030540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/17/2023] [Accepted: 01/17/2023] [Indexed: 05/13/2023]
Abstract
The development of oral drug delivery systems is challenging, and issues related to the mucus layer and low intestinal epithelial permeability have not yet been surmounted. The purpose of this study was to develop a promising formulation that is more adapted to in vivo absorption and to facilitate the administration of oral liraglutide. Cationic liposomes (CLs) linked to AT-1002 were prepared using a double-emulsion method, and BSA was adsorbed on the surface of the AT-CLs, resulting in protein corona cationic liposomes with AT-1002 (Pc-AT-CLs). The preparation method was determined by investigating various process parameters. The particle size, potential, and encapsulation efficiency (EE%) of the Pc-AT-CLs were 202.9 ± 12.4 nm, 1.76 ± 4.87 mV, and 84.63 ± 5.05%, respectively. The transmission electron microscopy (TEM) imaging revealed a nearly spherical structure of the Pc-AT-CLs, with a recognizable coating. The circular dichroism experiments confirmed that the complex preparation process did not affect the secondary structure of liraglutide. With the addition of BSA and AT-1002, the mucosal accumulation of the Pc-AT-CLs was nearly two times lower than that of the AT-CLs, and the degree of enteric metaplasia was 1.35 times higher than that of the PcCLs. The duration of the intestinal absorption of the Pc-AT-CLs was longer, offering remarkable biological safety.
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Affiliation(s)
- Ruihuan Ding
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 261400, China
| | - Zhenyu Zhao
- School of Life Science, Yantai University, Yantai 261400, China
| | - Jibiao He
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 261400, China
| | - Yuping Tao
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 261400, China
| | - Houqian Zhang
- School of Life Science, Yantai University, Yantai 261400, China
| | - Ranran Yuan
- School of Life Science, Yantai University, Yantai 261400, China
| | - Kaoxiang Sun
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 261400, China
- Correspondence: (K.S.); (Y.S.)
| | - Yanan Shi
- School of Life Science, Yantai University, Yantai 261400, China
- Correspondence: (K.S.); (Y.S.)
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Valadez LZM, Frigolet ME, Dominguez RM, Pescarus R, Zerrweck C, Boudreau V, Doumouras A, Cookson T, Anvari M. Metabolic and Bariatric Surgery in Diabetes Management. THE DIABETES TEXTBOOK 2023:673-690. [DOI: 10.1007/978-3-031-25519-9_42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Therapeutics in Metabolic Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1396:255-273. [DOI: 10.1007/978-981-19-5642-3_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
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Lyu X, Yan K, Wang X, Xu H, Guo X, Zhu H, Pan H, Wang L, Yang H, Gong F. A novel anti-obesity mechanism for liraglutide by improving adipose tissue leptin resistance in high-fat diet-fed obese mice. Endocr J 2022; 69:1233-1244. [PMID: 35705299 DOI: 10.1507/endocrj.ej21-0802] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Liraglutide has been approved for the treatment of obesity in the past few years. Both oxidative stress and leptin resistance are the critical drivers of obesity. The present study investigated the mechanism of liraglutide protection against obesity by ameliorating leptin resistance and oxidative stress. Male C57BL/6J mice were fed a high-fat diet (HFD) and subcutaneously injected with 200 μg/kg/d liraglutide for 20 weeks. Body weight, fat mass, serum levels of leptin, insulin, and superoxide dismutase (SOD) activities were measured. In addition, glucose and insulin tolerance tests were performed. The expressions of leptin, its signaling genes, and antioxidant enzymes were detected using RT-qPCR and western blot methods in liver and white adipose tissue (WAT) of mice. The results depicted that liraglutide treatment significantly slowed weight gain of body, reduced the fat mass, ameliorated glucose and lipid metabolism, and hepatic steatosis in HFD-fed obese mice. Further study demonstrated that liraglutide treatment resulted in decreased serum levels and the transcript levels of leptin as well as leptin signaling inhibitory regulators. However, it increased leptin receptor expression and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) in WAT (p < 0.05). In addition, the antioxidant enzyme expression was elevated in both liver and WAT of liraglutide-treated mice (p < 0.05). In conclusion, liraglutide conspicuously prevented obesity and ameliorated glucose and lipid metabolism in obese mice through a novel mechanism that improves peripheral leptin resistance in WAT and enhance the antioxidant enzyme expression in both liver and WAT.
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Affiliation(s)
- Xiaorui Lyu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Kemin Yan
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Xin Wang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Hanyuan Xu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Xiaonan Guo
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Huijuan Zhu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Hui Pan
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Linjie Wang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Hongbo Yang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Fengying Gong
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
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Activation of glucagon-like peptide-1 receptors reduces the acquisition of aggression-like behaviors in male mice. Transl Psychiatry 2022; 12:445. [PMID: 36229445 PMCID: PMC9561171 DOI: 10.1038/s41398-022-02209-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 09/21/2022] [Accepted: 09/27/2022] [Indexed: 11/17/2022] Open
Abstract
Aggression is a complex social behavior, which is provoked in the defense of limited resources including food and mates. Recent advances show that the gut-brain hormone ghrelin modulates aggressive behaviors. As the gut-brain hormone glucagon-like peptide-1 (GLP-1) reduces food intake and sexual behaviors its potential role in aggressive behaviors is likely. Therefore, we investigated a tentative link between GLP-1 and aggressive behaviors by combining preclinical and human genetic-association studies. The influence of acute or repeated injections of a GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex4), on aggressive behaviors was assessed in male mice exposed to the resident-intruder paradigm. Besides, possible mechanisms participating in the ability of Ex4 to reduce aggressive behaviors were evaluated. Associations of polymorphisms in GLP-1R genes and overt aggression in males of the CATSS cohort were assessed. In male mice, repeated, but not acute, Ex4 treatment dose-dependently reduced aggressive behaviors. Neurochemical and western blot studies further revealed that putative serotonergic and noradrenergic signaling in nucleus accumbens, specifically the shell compartment, may participate in the interaction between Ex4 and aggression. As high-fat diet (HFD) impairs the responsiveness to GLP-1 on various behaviors the possibility that HFD blunts the ability of Ex4 to reduce aggressive behaviors was explored. Indeed, the levels of aggression was similar in vehicle and Ex4 treated mice consuming HFD. In humans, there were no associations between polymorphisms of the GLP-1R genes and overt aggression. Overall, GLP-1 signaling suppresses acquisition of aggressive behaviors via central neurotransmission and additional studies exploring this link are warranted.
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Klausen MK, Jensen ME, Møller M, Le Dous N, Jensen AMØ, Zeeman VA, Johannsen CF, Lee A, Thomsen GK, Macoveanu J, Fisher PM, Gillum MP, Jørgensen NR, Bergmann ML, Enghusen Poulsen H, Becker U, Holst JJ, Benveniste H, Volkow ND, Vollstädt-Klein S, Miskowiak KW, Ekstrøm CT, Knudsen GM, Vilsbøll T, Fink-Jensen A. Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial. JCI Insight 2022; 7:e159863. [PMID: 36066977 PMCID: PMC9675448 DOI: 10.1172/jci.insight.159863] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 08/31/2022] [Indexed: 11/17/2022] Open
Abstract
BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI > 30 kg/m2). Adverse events were mainly gastrointestinal.ConclusionThis randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registrationEudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).FundingNovavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foghts Foundation; Hartmann Foundation; Aase and Ejnar Danielsen Foundation; P.A. Messerschmidt and Wife Foundation; and Lundbeck Foundation.
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Affiliation(s)
- Mette Kruse Klausen
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mathias Ebbesen Jensen
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marco Møller
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Nina Le Dous
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | | | | | | | - Alycia Lee
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, and
- Mannheim Center for Translational Neurosciences, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
| | - Gerda Krog Thomsen
- Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Julian Macoveanu
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | | | - Matthew Paul Gillum
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences and
| | - Niklas Rye Jørgensen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Centre of Diagnostic Investigation, University of Copenhagen, Copenhagen, Denmark
| | - Marianne Lerbæk Bergmann
- Department of Biochemistry and Immunology, University Hospital of Southern Denmark, Vejle, Denmark
| | - Henrik Enghusen Poulsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg/Frederiksberg Hospital, University Hospital Copenhagen, Copenhagen, Denmark
| | - Ulrik Becker
- National Institute of Public Health, University of Southern Denmark and University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences and
| | - Helene Benveniste
- Department of Anesthesiology and Pediatric Anesthesiology, Yale University, New Haven, Connecticut, USA
| | - Nora D. Volkow
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Sabine Vollstädt-Klein
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, and
- Mannheim Center for Translational Neurosciences, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
| | - Kamilla Woznica Miskowiak
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Psychology
| | | | - Gitte Moos Knudsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Tina Vilsbøll
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
| | - Anders Fink-Jensen
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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de Boer N, Cahn W. Antipsychotic-induced weight gain: Is the weight over? New guidelines needed. Acta Psychiatr Scand 2022; 146:185-189. [PMID: 35951775 DOI: 10.1111/acps.13485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Nini de Boer
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Wiepke Cahn
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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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: 11] [Impact Index Per Article: 3.7] [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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Controlling the uncontrolled variation in the diet induced obese mouse by microbiomic characterization. Sci Rep 2022; 12:13767. [PMID: 35962158 PMCID: PMC9374709 DOI: 10.1038/s41598-022-17242-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 07/22/2022] [Indexed: 11/24/2022] Open
Abstract
Group sizes in an animal study are calculated from estimates on variation, effect, power and significance level. Much of the variation in glucose related parameters of the diet-induced obese (DIO) mouse model is due to inter-individual variation in gut microbiota composition. In addition, standard tandem repeats (STRs) in the non-coding DNA shows that inbred mice are not always homogenic. C57BL/6NTac (B6NTac) mice from Taconic and C57BL/6NRj (B6NRj) mice from Janvier Labs were fed a high calorie diet and treated with liraglutide. The fecal microbiota was sequenced before high-calorie feeding (time 1) and after diet-induced obesity instantly before liraglutide treatment (time 2) and mice were divided into clusters on the basis of their microbiota. Although liraglutide in both sub-strains alleviated glucose intolerance and reduced body weight, in a one-way ANOVA a borderline reduction in glycosylated hemoglobin (HbA1c) could only be shown in B6NTac mice. However, if the microbiota clusters from time 1 or time 2 were incorporated in a two-way ANOVA, the HbA1c effect was significant in B6NTac mice in both analyses, while this did not change anything in B6NRj mice. In a one-way ANOVA the estimated group size needed for a significant HbA1c effect in B6NTac mice was 42, but in two-way ANOVAs based upon microbiota clusters of time 1 or time 2 it was reduced to 21 or 12, respectively. The lowering impact on glucose tolerance was also powered by incorporation of microbiota clusters of both times in both sub-strains. B6NRj had up to six, while B6NTac had maximum three alleles in some of their STRs. In B6NRj mice in 28.8% of the STRs the most prevalent allele had a gene frequency less than 90%, while this was only 6.6% in the B6NTac mice. However, incorporation of the STRs with the highest number of alleles or the most even distribution of frequencies in two-way ANOVAs only had little impact on the outcome of data evaluation. It is concluded that the inclusion of microbiota clusters in a two-way ANOVA in the evaluation of the glucose related effects of an intervention in the DIO mouse model might be an efficient tool for increasing power and reducing group sizes in mouse sub-strains, if these have a microbiota, which influences these parameters.
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Investigating Potential GLP-1 Receptor Agonists in Cyclopeptides from Pseudostellaria heterophylla, Linum usitatissimum, and Drymaria diandra, and Peptides Derived from Heterophyllin B for the Treatment of Type 2 Diabetes: An In Silico Study. Metabolites 2022; 12:metabo12060549. [PMID: 35736482 PMCID: PMC9227353 DOI: 10.3390/metabo12060549] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/06/2022] [Accepted: 06/14/2022] [Indexed: 02/05/2023] Open
Abstract
GLP-1 receptor agonists stimulate GLP-1R to promote insulin secretion, whereas DPP4 inhibitors slow GLP-1 degradation. Both approaches are incretin-based therapies for T2D. In addition to GLP-1 analogs, small nonpeptide GLP-1RAs such as LY3502970, TT-OAD2, and PF-06882961 have been considered as possible therapeutic alternatives. Pseudostellaria heterophylla, Linum usitatissimum, and Drymaria diandra are plants rich in cyclopeptides with hypoglycemic effects. Our previous study demonstrated the potential of their cyclopeptides for DPP4 inhibition. Reports of cyclic setmelanotide as an MC4R (GPCR) agonist and cyclic α-conotoxin chimeras as GLP-1RAs led to docking studies of these cyclopeptides with GLP-1R. Heterophyllin B, Pseudostellarin B, Cyclolinopeptide B, Cyclolinopeptide C, Drymarin A, and Diandrine C are abundant in these plants, with binding affinities of −9.5, −10.4, −10.3, −10.6, −11.2, and −11.9 kcal/mol, respectively. The configuration they demonstrated established multiple hydrogen bonds with the transmembrane region of GLP-1R. DdC:(cyclo)-GGPYWP showed the most promising docking score. The results suggest that, in addition to DPP4, GLP-1R may be a hypoglycemic target of these cyclopeptides. This may bring about more discussion of plant cyclopeptides as GLP-1RAs. Moreover, peptides derived from the HB precursor (IFGGLPPP), including IFGGWPPP, IFPGWPPP, IFGGYWPPP, and IFGYGWPPPP, exhibited diverse interactions with GLP-1R and displayed backbones available for further research.
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De Sarro C, Tallarico M, Pisano M, Gallelli L, Citraro R, De Sarro G, Leo A. Liraglutide chronic treatment prevents development of tolerance to antiseizure effects of diazepam in genetically epilepsy prone rats. Eur J Pharmacol 2022; 928:175098. [PMID: 35700834 DOI: 10.1016/j.ejphar.2022.175098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 06/09/2022] [Accepted: 06/09/2022] [Indexed: 11/30/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) is a hormone that can regulate several neuronal functions. The modulation of GLP-1 receptors emerged as a potential target to treat several neurological diseases, such as epilepsy. Here, we studied the effects of acute and chronic treatment with liraglutide (LIRA), in genetically epilepsy prone rats (GEPR-9s). We have also investigated the possible development of tolerance to antiseizure effects of diazepam, and how LIRA could affect this phenomenon over the same period of treatment. The present data indicate that an acute treatment with LIRA did not diminish the severity score of audiogenic seizures (AGS) in GEPR-9s. By contrast, a chronic treatment with LIRA has shown only a modest antiseizure effect that was maintained until the end of treatment, in GEPR-9s. Not surprisingly, acute administration of diazepam reduced, in a dose dependent manner, the severity of the AGS in GEPR-9s. However, when diazepam was chronically administered, an evident development of tolerance to its antiseizure effects was detected. Interestingly, following an add-on treatment with LIRA, a reduced development of tolerance and an enhanced diazepam antiseizure effect was observed in GEPR-9s. Overall, an add-on therapy with LIRA demonstrate benefits superior to single antiseizure medications and could be utilized to treat epilepsy as well as associated issues. Therefore, the potential use of GLP1 analogs for the treatment of epilepsy in combination with existing antiseizure medications could thus add a new and long-awaited dimension to its management.
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Affiliation(s)
- Caterina De Sarro
- System and Applied Pharmacology@University Magna Grecia, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Martina Tallarico
- System and Applied Pharmacology@University Magna Grecia, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Maria Pisano
- System and Applied Pharmacology@University Magna Grecia, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Luca Gallelli
- System and Applied Pharmacology@University Magna Grecia, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Rita Citraro
- System and Applied Pharmacology@University Magna Grecia, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.
| | - Giovambattista De Sarro
- System and Applied Pharmacology@University Magna Grecia, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.
| | - Antonio Leo
- System and Applied Pharmacology@University Magna Grecia, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
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Münster A, Sommer S, Kúkeľová D, Sigrist H, Koros E, Deiana S, Klinder K, Baader-Pagler T, Mayer-Wrangowski S, Ferger B, Bretschneider T, Pryce CR, Hauber W, von Heimendahl M. Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions. Neuropharmacology 2022; 213:109078. [PMID: 35561791 DOI: 10.1016/j.neuropharm.2022.109078] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 05/02/2022] [Accepted: 05/04/2022] [Indexed: 11/25/2022]
Abstract
Apathy, deficiency of motivation including willingness to exert effort for reward, is a common symptom in many psychiatric and neurological disorders, including depression and schizophrenia. Despite improved understanding of the neurocircuitry and neurochemistry underlying normal and deficient motivation, there is still no approved pharmacological treatment for such a deficiency. GPR139 is an orphan G protein-coupled receptor expressed in brain regions which contribute to the neural circuitry that controls motivation including effortful responding for reward, typically sweet gustatory reward. The GPR139 agonist TAK-041 is currently under development for treatment of negative symptoms in schizophrenia which include apathy. To date, however, there are no published preclinical data regarding its potential effect on reward motivation or deficiencies thereof. Here we report in vitro evidence confirming that TAK-041 increases intracellular Ca2+ mobilization and has high selectivity for GPR139. In vivo, TAK-041 was brain penetrant and showed a favorable pharmacokinetic profile. It was without effect on extracellular dopamine concentration in the nucleus accumbens. In addition, TAK-041 did not alter the effort exerted to obtain sweet gustatory reward in rats that were moderately food deprived. By contrast, TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived; furthermore, this effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress. Overall, this study provides preclinical evidence in support of GPR139 agonism as a molecular target mechanism for treatment of apathy.
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Affiliation(s)
- Alexandra Münster
- Systems Neurobiology Research Unit, University of Stuttgart, Stuttgart, Germany
| | - Susanne Sommer
- Systems Neurobiology Research Unit, University of Stuttgart, Stuttgart, Germany
| | - Diana Kúkeľová
- Preclinical Laboratory, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich (PUK) and University of Zurich (UZH), Zurich, Switzerland
| | - Hannes Sigrist
- Preclinical Laboratory, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich (PUK) and University of Zurich (UZH), Zurich, Switzerland
| | | | | | | | - Tamara Baader-Pagler
- Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany
| | | | - Boris Ferger
- CNS Diseases Research, Germany; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany
| | | | - Christopher R Pryce
- Preclinical Laboratory, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich (PUK) and University of Zurich (UZH), Zurich, Switzerland; Neuroscience Center Zurich, Zurich, Switzerland
| | - Wolfgang Hauber
- Systems Neurobiology Research Unit, University of Stuttgart, Stuttgart, Germany
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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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Zhang Y, Wang S, Chen X, Wang Z, Wang X, Zhou Q, Fang W, Zheng C. Liraglutide prevents high glucose induced HUVECs dysfunction via inhibition of PINK1/Parkin-dependent mitophagy. Mol Cell Endocrinol 2022; 545:111560. [PMID: 35032624 DOI: 10.1016/j.mce.2022.111560] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/25/2021] [Accepted: 01/11/2022] [Indexed: 01/11/2023]
Abstract
Functional loss of endothelial cells will lead to development and progression of atherosclerosis in diabetic patients. However, dysfunction of endothelial cells in diabetes has yet to be fully understood. We aimed to characterize the potential effects of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on preventing high glucose-induced endothelial dysfunction and excessive mitophagic response. Pretreatment with liraglutide prevented downregulation of eNOS phosphorylation and NO secretion, and reduced apoptosis and oxidative stress of the human umbilical vein endothelial cells (HUVECs) exposed to high glucose. We further demonstrated that liraglutide likely mediated such protective effects by reducing PINK1/Parkin mediated mitophagy. Liraglutide markedly decreased high glucose-induced mitochondrial ROS, lessened PINK1 expression and mitochondrial accumulation of Parkin, but recovered SIRT1 expression. Seahorse analysis revealed that liraglutide mitigated high glucose-induced reduction of basal and maximum respiration rates as well as spare respiration capacity. Inhibition of Parkin by RNA silencing not only resulted in increased mitochondrial and cytosolic ROS and reduced mitochondrial mass and mitochondrial membrane potential, but also led to increased apoptotic responses in high glucose treated HUVECs which were not preventable by liraglutide. Together, our study reveals that liraglutide acts upstream of the PINK1/Parkin pathway to effectively counteract high glucose induced cell dysfunction by suppression of the PINK1/Parkin-dependent mitophagy. Therefore, its use as an adjunct therapy for type 2 diabetes mellitus is warranted to reduce the risk of atherosclerosis. Further research is required to examine the exact molecules, including SIRT1, upstream of the PINK1/parkin pathway that liraglutide targets to maintain the mitochondrial homeostasis.
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Affiliation(s)
- Yikai Zhang
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Shengyao Wang
- Department of Endocrinology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Xia Chen
- Department of Endocrinology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Zhe Wang
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Xinyi Wang
- Department of Endocrinology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Qiao Zhou
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Weihuan Fang
- Institute of Preventive Veterinary Medicine & Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Chao Zheng
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Department of Endocrinology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
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Kim HS. Drug Repositioning: Exploring New Indications for Existing Drug-Disease Relationships. Endocrinol Metab (Seoul) 2022; 37:62-64. [PMID: 35255602 PMCID: PMC8901967 DOI: 10.3803/enm.2022.1403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 01/20/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Hun-Sung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul,
Korea
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Cifuentes L, Acosta A. Homeostatic regulation of food intake. Clin Res Hepatol Gastroenterol 2022; 46:101794. [PMID: 34481092 PMCID: PMC9721532 DOI: 10.1016/j.clinre.2021.101794] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023]
Abstract
Food intake and energy expenditure are key regulators of body weight. To regulate food intake, the brain must integrate physiological signals and hedonic cues. The brain plays an essential role in modulating the appropriate responses to the continuous update of the body energy-status by the peripheral signals and the neuronal pathways that generate the gut-brain axis. This regulation encompasses various steps involved in food consumption, include satiation, satiety, and hunger. It is important to have a comprehensive understanding of the mechanisms that regulate food consumption as well as to standardize the vocabulary for the steps involved. This review discusses the current knowledge of the regulation and the contribution peripheral and central signals at each step of the cycle to control appetite. We also highlight how food intake has been measured. The increasingly complex understanding of regulation and action mechanisms intervening in the gut-brain axis offers ambitious targets for new strategies to control appetite.
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Zhou Y, Chen M, Liu L, Chen Z. Difference in Gastrointestinal Risk Associated with Use of GLP-1 Receptor Agonists: A Real-World Pharmacovigilance Study. Diabetes Metab Syndr Obes 2022; 15:155-163. [PMID: 35046686 PMCID: PMC8763271 DOI: 10.2147/dmso.s348025] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 12/22/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are promising weight-loss drugs, but real-world data concerning the liability of GLP-1RAs in gastrointestinal safety are lacking. We examined the differences in gastrointestinal safety between semaglutide and liraglutide. MATERIALS AND METHODS We used the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and retrieved data during the first three years of semaglutide and liraglutide approved by the FDA. Thirteen main gastrointestinal adverse drug reactions (GADRs) were evaluated. Patient demographics, treatment information, and outcome of events were summarized. Disproportionality analyses were conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals (CIs). RESULTS In the reported cases of semaglutide (n = 2047) and liraglutide (n = 4175), semaglutide had a higher pooled ROR and later pooled time-to-onset median of GADRs compared with those of liraglutide (5.53, 95% CI 5.23-5.85 vs 3.95, 95% CI 3.81-4.10; 7 days, Q1-Q3: 0-48 vs 4 days, Q1-Q3: 0-34.5). The thirteen GADRs associated with these two GLP-1RAs showed a significant difference in the profile of reporting risk and time-to-onset. CONCLUSION GLP-1RAs produce a spectrum of distinct classes of GADRs. The individual properties of GADRs between semaglutide and liraglutide might enable incretin-based treatment of obesity to be "tailored" to the needs of each patient.
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Affiliation(s)
- Yu Zhou
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Mingyu Chen
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Libin Liu
- Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China
| | - Zhou Chen
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, People’s Republic of China
- Correspondence: Zhou Chen; Libin Liu Tel +86-591-22862587; +86-591-86218562 Email ;
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Li H, Donelan W, Wang F, Zhang P, Yang L, Ding Y, Tang D, Li S. GLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions. Front Cell Dev Biol 2021; 9:777026. [PMID: 34869379 PMCID: PMC8636013 DOI: 10.3389/fcell.2021.777026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/25/2021] [Indexed: 01/14/2023] Open
Abstract
Multiple GLP-1-derived therapeutics are clinically used to treat type 2 diabetes and obesity. However, the underlying mechanism of how these drugs regulate the body weight of obese patients remains incompletely understood. Here, we report that the lipolysis effects of GLP-1 on β cells can depend on its induced expression of fibronectin type III domain containing 5 (FNDC5). The transmembrane FNDC5 is a precursor of the recently identified hormone irisin that possesses a range of bioactivities, including anti-obesity and anti-diabetes. We revealed that GLP-1 upregulates the expression and secretion of FNDC5 in β cells, while GLP-1 itself fails to activate the lipolysis genes in FNDC5-knockout β cells. In addition, liraglutide, a clinically used GLP-1 receptor agonist, induced the expression of FNDC5 in mouse pancreas and brain tissues and increased the serum level of secreted FNDC5. Furthermore, we observed the expression of the well-known membrane-associated FNDC5 and a novel, secretable FNDC5 (sFNDC5) isoform in β cells and multiple rat tissues. Recombinant sFNDC5 stimulated lipolysis of wild type and FNDC5-knockout β cells. This new isoform further induced lipolysis and browning of adipocytes, and similar to irisin, executed potent anti-obesity activities in an obese mouse model. Overall, our studies provided new mechanistic insights into GLP-1’s anti-obesity actions in which GLP-1 induces the secretion of FNDC5 derivatives from its responsive organs that then mediate its anti-obesity activities.
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Affiliation(s)
- Hui Li
- Center for Gene and Immunotherapy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
| | - William Donelan
- Department of Urology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Fang Wang
- Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Peilan Zhang
- Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery, and Development, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Lijun Yang
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Yousong Ding
- Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery, and Development, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Dongqi Tang
- Center for Gene and Immunotherapy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shiwu Li
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
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Albaker W, Al Sheikh M, Albakr A, Alkhafaji D, Al Besher E, Al-Hariri M. The Efficacy and Safety of Liraglutide 3.0 mg for Weight Management in Obese Non-Diabetic Saudi Outpatients. Int J Gen Med 2021; 14:8643-8650. [PMID: 34849008 PMCID: PMC8627262 DOI: 10.2147/ijgm.s336904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/08/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Unmanaged cases of obesity might lead to serious conditions and complications, which impair patients' lives. The aim of this study was to assess the effectiveness and safety of daily 3 mg subcutaneous (s/c) Liraglutide amongst obese non-diabetic patients in Eastern Province, Saudi Arabia. METHODS A retrospective cohort study of obese non-diabetic Saudi patients with obesity managed with s/c Liraglutide 3.0 mg who visited the outpatient clinic in Al Mashfa Hospital, Al Khobar, KSA during 2019-2021. We collected patient data from the electronic reporting system for different parameters. Body weight, hemoglobin A1c %, systolic and diastolic blood pressure mmHg were obtained at baseline and after the intervention. RESULTS Records of 258 patients who were using a daily dose of Liraglutide 3.0 mg s/c for at least four months have been reviewed. The body weight loss of patients who used Liraglutide for four months was 8.1±0.8 kg. Moreover, around 204 patients continued for up to six months. Meanwhile, the mean body weight loss was 13 kg. There was a significant reduction of hemoglobin A1c (HbA1c) % by 0.43%. The majority of patients (94.5%) reported satisfaction with the treatment, while adverse events were mainly nausea, vomiting and constipation. CONCLUSION Daily s/c Liraglutide of 3.0 mg is effective in producing significant body weight reduction in obese non-diabetic Saudi patients with tolerable minimal side effects and may provide health benefits in terms of reduced risk of obesity and its related outcomes.
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Affiliation(s)
- Waleed Albaker
- Department of Internal Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Mona Al Sheikh
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Aishah Albakr
- Department of Neurology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Dania Alkhafaji
- Department of Internal Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Eman Al Besher
- Department of Family Medicine, Ministry of Health, Dammam, Saudi Arabia
| | - Mohammed Al-Hariri
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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Cominato L, Franco R, Damiani D. Adolescent obesity treatments: news, views, and evidence. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:527-536. [PMID: 34591402 PMCID: PMC10528567 DOI: 10.20945/2359-3997000000393] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/18/2021] [Indexed: 11/23/2022]
Abstract
Obesity is a complex and multifactorial disease that is influenced by physiological, environmental, socioeconomic, and genetic factors. In recent decades, this serious disease has impacted a large number of adolescents as a result of lifestyle factors. A lack of exercise and the consumption of excessive calories from an inadequate diet are the main contributors to adolescent obesity. However, genetic and hormonal factors might also play a role. The short- and long-term consequences of this disease include chronic issues such as type 2 diabetes and cardiovascular disorders and an increase in early mortality rates. Although it is a serious disease, obesity in adolescents can be controlled with diet and exercise. When these lifestyle changes do not obtain the expected results, we can intensify the treatment by adding medication to the practice of diet and exercise. Additionally, for more severe cases, bariatric surgery can be an option. The purpose of this review is to clarify the current epidemiology, risks, and comorbidities and discuss news about the main treatments and the necessary improvements in this context.
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Affiliation(s)
- Louise Cominato
- Unidade de Endocrinologia Pediátrica, Universidade de São Paulo, São Paulo, Brasil,
| | - Ruth Franco
- Unidade de Endocrinologia Pediátrica, Universidade de São Paulo, São Paulo, Brasil
| | - Durval Damiani
- Unidade de Endocrinologia Pediátrica, Universidade de São Paulo, São Paulo, Brasil
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Kakouri A, Kanti G, Kapantais E, Kokkinos A, Lanaras L, Farajian P, Galanakis C, Georgantopoulos G, Vlahos NF, Mastorakos G, Bargiota A, Valsamakis G. New Incretin Combination Treatments under Investigation in Obesity and Metabolism: A Systematic Review. Pharmaceuticals (Basel) 2021; 14:869. [PMID: 34577569 PMCID: PMC8468399 DOI: 10.3390/ph14090869] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/18/2021] [Accepted: 08/23/2021] [Indexed: 12/25/2022] Open
Abstract
The worldwide upward trend in obesity in adults and the increased incidence of overweight children suggests that the future risk of obesity-related illnesses will be increased. The existing anti-obesity drugs act either in the central nervous system (CNS) or in the peripheral tissues, controlling the appetite and metabolism. However, weight regain is a common homeostatic response; current anti-obesity medications show limited effectiveness in achieving long-term weight loss maintenance; in addition to being linked to various side effects. Combined anti-obesity medications (per os or injectable) target more than one of the molecular pathways involved in weight regulation, as well as structures in the CNS. In this systematic review, we conducted a search of PubMed and The ClinicalTrials.gov up to February 2021. We summarized the Food and Drug Administration (FDA)-approved medications, and we focused on the combined pharmacological treatments, related to the incretin hormones, currently in a clinical trial phase. We also assessed the mechanism of action and therapeutic utility of these novel hybrid peptides and potential interactions with other regulatory hormones that may have beneficial effects on obesity. As we improve our understanding of the pathophysiology of obesity, we hope to identify more novel treatment strategies.
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Affiliation(s)
- Agni Kakouri
- Athens Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
- Department of Ophthalmology & Visual Sciences, University of Illinois, Chicago, IL 60607, USA
| | - Georgia Kanti
- Endocrinology and Diabetes Center, Athens General Hospital “G. Gennimatas”, 115 27 Athens, Greece;
| | - Efthymios Kapantais
- Hellenic Medical Association for Obesity, 115 27 Athens, Greece; (E.K.); (A.K.); (L.L.); (P.F.); (C.G.); (G.G.)
| | - Alexandros Kokkinos
- Hellenic Medical Association for Obesity, 115 27 Athens, Greece; (E.K.); (A.K.); (L.L.); (P.F.); (C.G.); (G.G.)
| | - Leonidas Lanaras
- Hellenic Medical Association for Obesity, 115 27 Athens, Greece; (E.K.); (A.K.); (L.L.); (P.F.); (C.G.); (G.G.)
| | - Paul Farajian
- Hellenic Medical Association for Obesity, 115 27 Athens, Greece; (E.K.); (A.K.); (L.L.); (P.F.); (C.G.); (G.G.)
| | - Christos Galanakis
- Hellenic Medical Association for Obesity, 115 27 Athens, Greece; (E.K.); (A.K.); (L.L.); (P.F.); (C.G.); (G.G.)
| | - Georgios Georgantopoulos
- Hellenic Medical Association for Obesity, 115 27 Athens, Greece; (E.K.); (A.K.); (L.L.); (P.F.); (C.G.); (G.G.)
| | - Nikos F. Vlahos
- Assisted Reproduction Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 115 28 Athens, Greece;
| | - George Mastorakos
- Department of Endocrinology, Diabetes Mellitus and Metabolism, 2nd Department of Obstetrics and Gynecology, Aretaieion University Hospital, 115 28 Athens, Greece;
| | - Alexandra Bargiota
- University Department of Endocrinology and Metabolic Disorders, University Hospital of Larissa, University of Thessaly, 413 34 Larissa, Greece;
| | - Georgios Valsamakis
- Assisted Reproduction Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 115 28 Athens, Greece;
- Department of Endocrinology, Diabetes Mellitus and Metabolism, 2nd Department of Obstetrics and Gynecology, Aretaieion University Hospital, 115 28 Athens, Greece;
- University Department of Endocrinology and Metabolic Disorders, University Hospital of Larissa, University of Thessaly, 413 34 Larissa, Greece;
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Shi Y, Guo S, Liang Y, Liu L, Wang A, Sun K, Li Y. Construction and evaluation of liraglutide delivery system based on milk exosomes: a new idea for oral peptide delivery. Curr Pharm Biotechnol 2021; 23:1072-1079. [PMID: 34414872 DOI: 10.2174/1389201022666210820114236] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 05/13/2021] [Accepted: 05/23/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Increasing the bioavailability of peptide or protein drugs has always been an essential topic in pharmacy. Milk exosomes as a carrier for oral drug delivery systems have begun to attract attention in recent years. The application of oral milk exosomes carriers to peptide drugs such as liraglutide is worth trying. OBJECTIVE Milk-derived exosomes are used in this study to encapsulate the GLP-1 receptor agonist liraglutide. It also explored the feasibility of using this drug delivery system for oral biomolecules delivery in the future. METHODS The size and morphology of milk exosomes were characterized. The gastrointestinal stability of milk exosomes was evaluated in a dialysis bag. The cellular uptake of milk exosomes in an intestinal cell was observed. Six drug loading methods have been evaluated and compared preliminarily, and they are the incubation method, sonication method, extrusion method, freeze-thaw cycles method, saponin-assisted method, and electroporation method. RESULTS As demonstrated in this study, milk exosomes showed significant stability in the gastrointestinal environment and excellent affinity with intestinal cells, indicating their unique benefits used for oral drug delivery. Effective drug loading method for exosomes is challenging. Among the six drug loading methods used in this study, the liraglutide-Exo prepared by the extrusion method obtained the most significant drug load, which was 2.45 times the direct incubation method. The liraglutide-Exo obtained by the freeze-thaw cycles method has the slightest morphological change. CONCLUSION The study showed milk exosome-based oral drug delivery systems are promising.
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Affiliation(s)
- Yanan Shi
- College of Life Science, Yantai University, Yantai, 264005. China
| | - Shiqi Guo
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005. China
| | - Yanzi Liang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005. China
| | - Lanze Liu
- College of Life Science, Yantai University, Yantai, 264005. China
| | - Aiping Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005. China
| | - Kaoxiang Sun
- College of Life Science, Yantai University, Yantai, 264005. China
| | - Youxin Li
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005. China
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45
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Wang Y, He W, Wei W, Mei X, Yang M, Wang Y. Exenatide Attenuates Obesity-Induced Mitochondrial Dysfunction by Activating SIRT1 in Renal Tubular Cells. Front Endocrinol (Lausanne) 2021; 12:622737. [PMID: 34434166 PMCID: PMC8380782 DOI: 10.3389/fendo.2021.622737] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 07/21/2021] [Indexed: 11/13/2022] Open
Abstract
Saturated free fatty acid (FFA)-induced lipotoxicity plays an important role in obesity-induced kidney injury. Exenatide, a Glucagon-like peptide-1 receptor agonist(GLP-1RA), protects against high-fat diet (HFD)-induced kidney injury. The precise mechanism needs to be further explored. This study investigated whether exenatide protects against FFA-induced tubular epithelial cells (TECs) lipotoxicity and elucidated its underlying mechanisms. Here, we show that exenatide treatment reversed HFD induced TECs injuries, including TECs apoptosis and SIRT1 downregulation. The efficacy of exenatide was better than simvastatin. In palmitate (PA)-stimulated HK2 cells, exenatide treatment reversed the downregulation of SIRT1 and prevented an increase in reactive oxygen species (ROS) production, a decrease in mitochondrial membrane potential, and mitochondrial apoptosis. The renal-protective effects of exenatide on the generation of mitochondrial ROS and mitochondrial apoptosis were blocked by inhibiting SIRT1 activation. Collectively, these findings show that exenatide was superior to simvastatin in the treatment of obesity-TECs injuries, the mechanism is partially through SIRT1 restoration, which directly reverses mitochondrial dysfunction and apoptosis.
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Affiliation(s)
- Yao Wang
- Department of Nephrology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Wei He
- Department of Endocrinology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Wei Wei
- Department of Nephrology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Xiaoxue Mei
- Department of Endocrinology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Ming Yang
- Department of Nephrology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Ying Wang
- Department of Endocrinology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
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Lazzaroni E, Ben Nasr M, Loretelli C, Pastore I, Plebani L, Lunati ME, Vallone L, Bolla AM, Rossi A, Montefusco L, Ippolito E, Berra C, D'Addio F, Zuccotti GV, Fiorina P. Anti-diabetic drugs and weight loss in patients with type 2 diabetes. Pharmacol Res 2021; 171:105782. [PMID: 34302978 DOI: 10.1016/j.phrs.2021.105782] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/17/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Obesity is frequently a comorbidity of type 2 diabetes. Even modest weight loss can significantly improve glucose homeostasis and lessen cardiometabolic risk factors in patients with type 2 diabetes, but lifestyle-based weight loss strategies are not long-term effective. There is an increasing need to consider pharmacological approaches to assist weight loss in the so called diabesity syndrome. Aim of this review is to analyze the weight-loss effect of non-insulin glucose lowering drugs in patients with type 2 diabetes. MATERIAL AND METHODS A systematic analysis of the literature on the effect of non-insulin glucose lowering drugs on weight loss in patients with type 2 diabetes was performed. For each class of drugs, the following parameters were analyzed: kilograms lost on average, effect on body mass index and body composition. RESULTS Our results suggested that anti-diabetic drugs can be stratified into 3 groups based on their efficacy in weight loss: metformin, acarbose, empagliflozin and exenatide resulted in a in a mild weight loss (less than 3.2% of initial weight); canagliflozin, ertugliflozin, dapagliflozin and dulaglutide induces a moderate weight loss (between 3.2% and 5%); liraglutide, semaglutide and tirzepatide resulted in a strong weight loss (greater than 5%). CONCLUSIONS This study shows that new anti-diabetic drugs, particularly GLP1-RA and Tirzepatide, are the most effective in inducing weight loss in patients with type 2 diabetes. Interestingly, exenatide appears to be the only GLP1-RA that induces a mild weight loss.
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Affiliation(s)
- Elisa Lazzaroni
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università Degli Studi Milano, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università Degli Studi Milano, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Laura Plebani
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Luciana Vallone
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Antonio Rossi
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Laura Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Elio Ippolito
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università Degli Studi Milano, Milan, Italy
| | - Cesare Berra
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS Multimedica, Milan, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università Degli Studi Milano, Milan, Italy
| | - Gian Vincenzo Zuccotti
- Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Dept. Biomedical and Clinical Sciences "L. Sacco", Università di Milano and Pediatric Department, Buzzi Children's Hospital, Milan, Italy
| | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università Degli Studi Milano, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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47
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Sweeney P, Bedenbaugh MN, Maldonado J, Pan P, Fowler K, Williams SY, Gimenez LE, Ghamari-Langroudi M, Downing G, Gui Y, Hadley CK, Joy ST, Mapp AK, Simerly RB, Cone RD. The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia. Sci Transl Med 2021; 13:13/590/eabd6434. [PMID: 33883274 DOI: 10.1126/scitranslmed.abd6434] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 11/19/2020] [Accepted: 03/25/2021] [Indexed: 12/14/2022]
Abstract
Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.
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Affiliation(s)
- Patrick Sweeney
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Michelle N Bedenbaugh
- Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37240, USA
| | - Jose Maldonado
- Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37240, USA
| | - Pauline Pan
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Katelyn Fowler
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Luis E Gimenez
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Masoud Ghamari-Langroudi
- Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37240, USA
| | - Griffin Downing
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.,Department of Molecular, Cellular, and Developmental Biology, School of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yijun Gui
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.,Department of Molecular, Cellular, and Developmental Biology, School of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - Colleen K Hadley
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Stephen T Joy
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Anna K Mapp
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.,Department of Chemistry, School of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - Richard B Simerly
- Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37240, USA.
| | - Roger D Cone
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA. .,Department of Molecular, Cellular, and Developmental Biology, School of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA.,Department of Molecular and Integrative Physiology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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Han C, Sun Y, Yang Q, Zhou F, Chen X, Wu L, Sun L, Han J. Stapled, Long-Acting Xenopus GLP-1-Based Dual GLP-1/Glucagon Receptor Agonists with Potent Therapeutic Efficacy for Metabolic Disease. Mol Pharm 2021; 18:2906-2923. [PMID: 34240881 DOI: 10.1021/acs.molpharmaceut.0c00995] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Novel peptidic glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have increased efficacy over GLP-1R monoagonists for the treatment of diabetes and obesity. We identified a novel Xenopus GLP-1-based dual GLP-1R/GCGR agonist (xGLP/GCG-13) designed with a proper activity ratio favoring the GLP-1R versus the GCGR. However, the clinical utility of xGLP/GCG-13 is limited by its short in vivo half-life. Starting from xGLP/GCG-13, dual Cys mutation was performed, followed by covalent side-chain stapling and serum albumin binder incorporation, resulting in a stabilized secondary structure, enhanced agonist potency at GLP-1R and GCGR, and improved stability. The lead peptide 2c (stapled xGLP/GCG-13 analogue with a palmitic acid albumin binder) exhibits balanced GLP-1R and GCGR activations and potent, long-lasting effects on in vivo glucose control. 2c was further explored pharmacologically in diet-induced obesity and db/db rodent models. Chronic administration of 2c potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, increased energy expenditure, and normalized lipid metabolism and adiposity in relevant animal models. These results indicated that 2c has potential for development as a novel antidiabetic and/or antiobesity drug. Furthermore, we propose that the incorporation of a proper serum protein-binding motif into a di-Cys staple is an effective method for improving the stabilities and bioactivities of peptides. This approach is likely applicable to other therapeutic peptides, such as glucose-dependent insulin-tropic peptide receptor (GIPR) and GLP-1R dual agonists or GLP-1R/GCGR/GIPR triagonists.
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Affiliation(s)
- Chun Han
- Department of Chemistry, Changzhi University, Changzhi 046011, PR China
| | - Yuqing Sun
- Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314001, PR China
| | - Qimeng Yang
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Feng Zhou
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Xinyu Chen
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Lintao Wu
- Department of Chemistry, Changzhi University, Changzhi 046011, PR China
| | - Lidan Sun
- Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314001, PR China
| | - Jing Han
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
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49
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Shah H, Khan MSH, Dhurandhar NV, Hegde V. The triumvirate: why hypertension, obesity, and diabetes are risk factors for adverse effects in patients with COVID-19. Acta Diabetol 2021; 58:831-843. [PMID: 33587177 PMCID: PMC7882857 DOI: 10.1007/s00592-020-01636-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/07/2020] [Indexed: 02/06/2023]
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic. The cellular receptor for SARS-CoV-2 entry is the angiotensin-converting enzyme 2, a membrane-bound homolog of angiotensin-converting enzyme. Henceforth, this has brought the attention of the scientific community to study the interaction between COVID-19 and the renin-angiotensin system (RAS), as well as RAS inhibitors. However, these inhibitors are commonly used to treat hypertension, chronic kidney disorder, and diabetes. Obesity is a known risk factor for heart disease, diabetes, and hypertension, whereas diabetes and hypertension may be indirectly related to each other through the effects of obesity. Furthermore, people with hypertension, obesity, diabetes, and other related complications like cardiovascular and kidney diseases have a higher risk of severe COVID-19 infection than the general population and usually exhibit poor prognosis. This severity could be due to systemic inflammation and compromised immune response and RAS associated with these comorbid conditions. Therefore, there is an urgent need to develop evidence-based treatment methods that do not affect the severity of COVID-19 infection and effectively manage these chronic diseases in people with COVID-19.
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Affiliation(s)
- Harsh Shah
- Obesity and Metabolic Health Laboratory, Department of Nutritional Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX, 79409, USA
| | - Md Shahjalal Hossain Khan
- Obesity and Metabolic Health Laboratory, Department of Nutritional Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX, 79409, USA
| | - Nikhil V Dhurandhar
- Obesity and Metabolic Health Laboratory, Department of Nutritional Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX, 79409, USA
| | - Vijay Hegde
- Obesity and Metabolic Health Laboratory, Department of Nutritional Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX, 79409, USA.
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50
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Whicher CA, Price HC, Phiri P, Rathod S, Barnard-Kelly K, Ngianga K, Thorne K, Asher C, Peveler RC, McCarthy J, Holt RIG. The use of liraglutide 3.0 mg daily in the management of overweight and obesity in people with schizophrenia, schizoaffective disorder and first episode psychosis: Results of a pilot randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 2021; 23:1262-1271. [PMID: 33528914 DOI: 10.1111/dom.14334] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 02/05/2023]
Abstract
AIM To investigate the feasibility and acceptability of using liraglutide 3.0 mg daily in the management of overweight and obesity in people with schizophrenia, schizoaffective disorder and first episode psychosis. MATERIALS AND METHODS A double-blind, randomized, placebo-controlled pilot trial took place in mental health centres and primary care within Southern Health NHS Foundation Trust. The participants were adults with schizophrenia, schizoaffective or first-episode psychosis prescribed antipsychotic medication who were overweight or obese. The intervention was once-daily subcutaneous liraglutide or placebo, titrated to 3.0 mg daily, for 6 months. The primary outcomes were recruitment, consent, retention and adherence. The secondary exploratory outcomes were weight, HbA1c and Brief Psychiatric Rating Scale. RESULTS Seven hundred and ninety-nine individuals were screened for eligibility. The most common reasons for exclusion were ineligibility (44%) and inability to make contact (28%). The acceptance rate, as a proportion of all eligible participants, was 12.2%. The most commonly stated reason why eligible candidates declined to participate related to the study-specific medication and protocol (n = 50). Forty-seven participants were randomized, with 79% completing the trial. Participants in the liraglutide arm lost a mean 5.7 ± 7.9 kg compared with no significant weight change in the placebo group (treatment difference -6.0 kg, p = .015). Body mass index, waist circumference and HbA1c were reduced in the intervention group. CONCLUSIONS This study supports the need for a larger randomized controlled trial to evaluate the use of liraglutide (maximum dose 3.0 mg daily) in the management of obesity in people with severe mental illness.
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Affiliation(s)
- Clare A Whicher
- Southern Health NHS Foundation Trust, Research & Development Dept. Tom Rudd Unit, Moorgreen Hospital, West End Southampton, UK
| | - Hermione C Price
- Southern Health NHS Foundation Trust, Research & Development Dept. Tom Rudd Unit, Moorgreen Hospital, West End Southampton, UK
| | - Peter Phiri
- Southern Health NHS Foundation Trust, Research & Development Dept. Tom Rudd Unit, Moorgreen Hospital, West End Southampton, UK
- Primary Care, Population Sciences and Medical Education, Faculty of Medicine, University of Southampton, Aldermoor Health Centre, Southampton, UK
| | - Shanaya Rathod
- Southern Health NHS Foundation Trust, Research & Development Dept. Tom Rudd Unit, Moorgreen Hospital, West End Southampton, UK
| | | | - Kandala Ngianga
- Faculty of Science and Health, School of Health and Care Professions, Portsmouth, UK
| | - Kerensa Thorne
- Southern Health NHS Foundation Trust, Research & Development Dept. Tom Rudd Unit, Moorgreen Hospital, West End Southampton, UK
| | - Carolyn Asher
- Southern Health NHS Foundation Trust, Research & Development Dept. Tom Rudd Unit, Moorgreen Hospital, West End Southampton, UK
| | - Robert C Peveler
- Academic Department of Psychiatry, College Keep, Southampton, UK
| | - Joanne McCarthy
- Southern Health NHS Foundation Trust, Research & Development Dept. Tom Rudd Unit, Moorgreen Hospital, West End Southampton, UK
| | - Richard I G Holt
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
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