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Kelly CA, Sipos JA. Approach to the Patient With Thyroid Nodules: Considering GLP-1 Receptor Agonists. J Clin Endocrinol Metab 2025; 110:e2080-e2087. [PMID: 39400117 DOI: 10.1210/clinem/dgae722] [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: 06/17/2024] [Revised: 08/28/2024] [Accepted: 10/11/2024] [Indexed: 10/15/2024]
Abstract
Glucagon-like peptide 1 receptor agonists (GLP1RAs) have rapidly changed the landscape of diabetes and obesity treatment. Enthusiasm for their use is tempered with concerns regarding their risk for inducing C-cell tumors based on preclinical studies in rodents. A black-box warning from the US Food and Drug Administration recommends against using GLP1RA in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2), providing clear guidance regarding this cohort of patients. However, emerging data also suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with these agents. Other studies, though, have not confirmed an association between GLP1RAs and DTC. With conflicting results concerning thyroid cancer risk, there is no clear consensus regarding the optimal approach to screening patients prior to initiating the medications and/or evaluating for thyroid cancer during GLP1RA treatment. Within the context of patient cases, this review will summarize the existing data, describe ongoing controversies, and outline future areas for research regarding thyroid cancer risk with GLP1RA use.
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Affiliation(s)
- Clare A Kelly
- Division of Endocrinology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106 USA
| | - Jennifer A Sipos
- Division of Endocrinology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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2
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Tarasiuk-Zawadzka A, Fichna J. Interaction between nutritional factors and the enteric nervous system in inflammatory bowel diseases. J Nutr Biochem 2025:109959. [PMID: 40354831 DOI: 10.1016/j.jnutbio.2025.109959] [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: 04/17/2024] [Revised: 01/30/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025]
Abstract
The enteric nervous system (ENS) is a highly conserved, yet complicated network of neurons and glial cells located throughout the gut wall that controls digestive processes and gastrointestinal (GI) homeostasis. The intestinal epithelium, the immune system, and the gut microbiota are just a few examples of the cellular networks that the ENS interacts with on a variety of levels to maintain GI function. The presence or absence of nutrients in the intestinal lumen may cause short- and/or long-term changes in neurotransmitter expression, excitability, and neuronal survival, which ultimately affect gut motility, secretion, and permeability. Hence, the ENS should be identified as a key factor in initiating coordinated responses to nutrients. In this review we summarize current knowledge on nutrient-dependent ENS activity and how ENS secondary to nutrition may affect likelihood of developing inflammatory bowel disease. Our findings highlight that nutrients interact with enteroendocrine cells in the gut, triggering hormone secretion that plays a crucial role in signaling food-related information to the brain and regulating metabolic processes such as feeding behavior, insulin secretion, and energy balance; however, the complex interactions between nutrients, the ENS, and the immune system require further research to understand their contributions to GI disorders and potential therapeutic applications in treating obesity and metabolic diseases. Lay Summary: The enteric nervous system (ENS) controls digestion and interacts with nutrients in the gut to regulate processes like gut movement and hormone release, affecting metabolism and overall gut health. This review highlights the need for further research on how nutrient-ENS interactions contribute to conditions like inflammatory bowel disease, obesity, and metabolic disorders.
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Affiliation(s)
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland
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3
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Müller TD, Adriaenssens A, Ahrén B, Blüher M, Birkenfeld AL, Campbell JE, Coghlan MP, D'Alessio D, Deacon CF, DelPrato S, Douros JD, Drucker DJ, Figueredo Burgos NS, Flatt PR, Finan B, Gimeno RE, Gribble FM, Hayes MR, Hölscher C, Holst JJ, Knerr PJ, Knop FK, Kusminski CM, Liskiewicz A, Mabilleau G, Mowery SA, Nauck MA, Novikoff A, Reimann F, Roberts AG, Rosenkilde MM, Samms RJ, Scherer PE, Seeley RJ, Sloop KW, Wolfrum C, Wootten D, DiMarchi RD, Tschöp MH. Glucose-dependent insulinotropic polypeptide (GIP). Mol Metab 2025; 95:102118. [PMID: 40024571 PMCID: PMC11931254 DOI: 10.1016/j.molmet.2025.102118] [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: 12/06/2024] [Revised: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP. SCOPE OF REVIEW In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases. MAJOR CONCLUSIONS Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.
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Affiliation(s)
- Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany.
| | - Alice Adriaenssens
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Bo Ahrén
- Department of Clinical Sciences, Lund, Lund University, Lund, Sweden
| | - Matthias Blüher
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen 72076, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Matthew P Coghlan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - David D'Alessio
- Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - Carolyn F Deacon
- School of Biomedical Sciences, Ulster University, Coleraine, UK; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefano DelPrato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | | | - Daniel J Drucker
- The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Natalie S Figueredo Burgos
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Brian Finan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Ruth E Gimeno
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Fiona M Gribble
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Matthew R Hayes
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christian Hölscher
- Neurodegeneration Research Group, Henan Academy of Innovations in Medical Science, Xinzheng, China
| | - Jens J Holst
- Department of Biomedical Sciences and the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Patrick J Knerr
- Indianapolis Biosciences Research Institute, Indianapolis, IN, USA
| | - Filip K Knop
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christine M Kusminski
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Arkadiusz Liskiewicz
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France; CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France
| | | | - Michael A Nauck
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany
| | - Frank Reimann
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Anna G Roberts
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark
| | - Ricardo J Samms
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Philip E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kyle W Sloop
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Christian Wolfrum
- Institute of Food, Nutrition and Health, ETH Zurich, 8092, Schwerzenbach, Switzerland
| | - Denise Wootten
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | | | - Matthias H Tschöp
- Helmholtz Munich, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany
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Zandvakili I, Perez-Tilve D. The unexpected role of GIP in transforming obesity treatment. Trends Endocrinol Metab 2025; 36:330-338. [PMID: 39198118 DOI: 10.1016/j.tem.2024.07.022] [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: 06/03/2024] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 09/01/2024]
Abstract
Despite sharing incretin activity with glucagon-like peptide 1 (GLP-1), the development of gastric inhibitory polypeptide (GIP)-based drugs has been hindered by the minor effects of native GIP on appetite and body weight and genetic studies associating loss-of-function with reduced obesity. Yet, pharmacologically optimized GIP-based molecules have demonstrated profound weight lowering benefits of GIPR agonism when combined with GLP-1-based therapies, which has re-energized deeper exploration of the molecular mechanisms and downstream signaling of GIPR. Interestingly, both GIPR agonism and antagonism offer metabolic benefits, leading to differing viewpoints on how to target GIPR therapeutically. Here we summarize the emerging evidence about the tissue-specific mechanisms that positions GIP-based therapies as important targets for the next generation of anti-obesity and metabolic therapies.
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Affiliation(s)
- Inuk Zandvakili
- Division of Digestive Diseases, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Diego Perez-Tilve
- Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
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5
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Al-Zaid B, Al-Sabah S. The C-terminal regions of the GLP-1 and GIP receptors are not the key determinants of their differential arrestin recruitment but modulate the rate of receptor endocytosis. Front Pharmacol 2025; 16:1528295. [PMID: 40201698 PMCID: PMC11975949 DOI: 10.3389/fphar.2025.1528295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/28/2025] [Indexed: 04/10/2025] Open
Abstract
Introduction: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of metabolism and mediate the incretin effect. This glucose-dependent potentiation of insulin secretion is severely impaired in patients with type-2 diabetes mellitus. While pharmacological doses of GLP-1 can overcome this impairment, the same is not true for GIP. The reasons for this are unclear. However, differences in the signalling profiles of the GLP-1 and GIP receptors (GLP-1R and GIPR) may contribute. GLP-1R and GIPR are closely related G protein-coupled receptors but differ in their ability to recruit arrestin, GIPR being relatively poorer. Furthermore, these receptors have been reported to utilize different mechanisms to undergo agonist-induced internalization. Methods: This study aimed to identify the role of the C-terminal region of the two receptors in their differing signalling behaviour using chimeric receptors where the C-terminal tail of one receptor was replaced with that of the other. Results: Replacement of the C-terminal tail had only limited effects on G protein and arrestin recruitment to either receptor. GIP-stimulated internalisation of GIPR occurred at a significantly (P < 0.001) slower rate than GLP-1-stimulated internalisation of GLP-1R. Replacement of the C-terminal tail of GIPR with that of GLP-1R significantly (P < 0.05) increased the internalization rate but not to the rate of wild-type GLP-1R. The reciprocal substitution significantly (P < 0.005) decreased internalization rate. Conclusion: These data show that the C-terminal region of GLP-1R and GIPR is not the critical determinant of their differing ability to recruit arrestin but modulates receptor endocytosis.
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Affiliation(s)
| | - Suleiman Al-Sabah
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
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6
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Guzman H, Hasan LZ, Reid TJ. Treatment of Type 2 Diabetes in Patients with Obesity: A Review. Endocrinol Metab Clin North Am 2025; 54:163-173. [PMID: 39919872 DOI: 10.1016/j.ecl.2024.10.004] [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] [Indexed: 02/09/2025]
Abstract
Type 2 diabetes and obesity have some overlapping pathophysiology. This has allowed for the creation of therapies which are highly effective in treating both conditions. Weekly subcutaneous incretin agonists are preferred agents as they provide significant improvement in glycemic parameters, weight, and other comorbidities, like heart failure and reduce major adverse cardiovascular event. Bariatric surgery continues to show the most durable benefits for patients with both type 2 diabetes mellitus and obesity and should be considered in patients who are unable to meet goals with pharmacotherapy and lifestyle.
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Affiliation(s)
- Heidi Guzman
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Columbia University College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Leen Z Hasan
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Columbia University College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Tirissa J Reid
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Columbia University College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
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7
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Liu X, Liu X, Hu Y, Wang X, Yang X, Yan B, Zhou Y, Zhou L, Fan G, Yang J. Secretagogin Is Highly Expressed in Enteroendocrine K Cells and Plays a Critical Role in Nutrient-Induced GIP Secretion. J Endocr Soc 2025; 9:bvaf022. [PMID: 40012909 PMCID: PMC11859952 DOI: 10.1210/jendso/bvaf022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Indexed: 02/28/2025] Open
Abstract
Context Incretin hormones, primarily composed of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are secreted by enteroendocrine cells (EECs) and play crucial roles in maintaining blood glucose homeostasis. Notably, GIP accounts for two-thirds of the entire incretin effect. However, the secretion and function of GIP are impaired in individuals with type 2 diabetes mellitus (T2DM), and the regulatory mechanisms governing GIP secretion remain unclear. Objective Our study aims to explore the role of an EEC-enriched protein, Secretagogin (SCGN), in the regulation of GIP secretion. Methods We collected duodenal tissues from both humans and mice to observe the colocalization of SCGN and GIP in EECs. Additionally, we utilized human cohorts and gene-edited mouse models to investigate the effect of SCGN on GIP secretion. Our study included 128 subjects, comprising 64 individuals diagnosed with newly onset diabetes and 64 age- and sex-matched nondiabetic healthy controls. At the animal level, we employed leptin receptor-deficient (db/db) mice and Scgn knockout mice for our investigations. Results Our findings indicate that SCGN is abundantly expressed in GIP-producing K cells within the intestinal epithelium of both humans and mice. We observed a positive correlation between SCGN and GIP levels in postprandial states among patients with T2DM, db/db mice, and their healthy controls. Notably, Scgn knockout mice exhibited decreased GIP and insulin secretion. However, SCGN deficiency did not affect K-cell number, GIP mRNA expression, or intestinal morphology. Conclusion Collectively, these findings demonstrate that SCGN is a key regulator of nutrient-induced GIP secretion.
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Affiliation(s)
- Xinyu Liu
- Department of Endocrinology, The Sixth Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Nanshan People's Hospital, Shenzhen 518052, Guangdong, China
| | - Xuan Liu
- Department of Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
- Department of Endocrinology, The Central Hospital of Shaoyang City, Shaoyang 422000, Hunan, China
| | - Yuanyuan Hu
- Department of Endocrinology, The Sixth Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Nanshan People's Hospital, Shenzhen 518052, Guangdong, China
| | - Xin Wang
- Department of Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Xin Yang
- Department of Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Bin Yan
- Department of Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Yiting Zhou
- Department of Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Lingzhi Zhou
- Department of Pediatrics, The Sixth Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Nanshan People's Hospital, Shenzhen 518052, Guangdong, China
| | - Gang Fan
- Department of Urology, The Sixth Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Nanshan People's Hospital, Shenzhen 518052, Guangdong, China
| | - Jing Yang
- Department of Endocrinology, The Sixth Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Nanshan People's Hospital, Shenzhen 518052, Guangdong, China
- Department of Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
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8
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Douros JD, Flak JN, Knerr PJ. The agony and the efficacy: central mechanisms of GLP-1 induced adverse events and their mitigation by GIP. Front Endocrinol (Lausanne) 2025; 16:1530985. [PMID: 39963285 PMCID: PMC11830610 DOI: 10.3389/fendo.2025.1530985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 01/02/2025] [Indexed: 02/20/2025] Open
Affiliation(s)
| | - Jonathan N. Flak
- Indiana Biosciences Research Institute, Indianapolis, IN, United States
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Patrick J. Knerr
- Indiana Biosciences Research Institute, Indianapolis, IN, United States
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9
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Kacena C. Effects of the Curcuminoid and Non-Curcuminoid Compounds of Turmeric on the Gut Microbiome and Inflammation: Potential Use in the Treatment and Prevention of Disease. Nutr Rev 2025:nuae221. [PMID: 39873671 DOI: 10.1093/nutrit/nuae221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2025] Open
Abstract
The gut microbiome is a complex system that directly interacts with and influences many systems in the body. This delicate balance of microbiota plays an important role in health and disease and is highly influenced by lifestyle factors and the surrounding environment. As further research emerges, understanding the full potential of the gut microbiome and the impact of using nutraceuticals to positively influence its function may open the door to greater therapeutic outcomes in the treatment and prevention of disease. Curcumin, a bioactive compound derived from the turmeric rhizome, has been studied in depth for its influence on human health as a potent anti-inflammatory and antioxidant properties. However, the therapeutic activity of curcumin is limited by its low oral bioavailability. While most available research has primarily focused on the curcuminoid compounds of turmeric, the non-curcuminoid compounds hold promise to offer therapeutic benefits while synergistically enhancing the bioavailability of curcumin and supporting the gut microbiome. This review summarizes current knowledge of the relationship between the gut and the various systems within the body, and how dysbiosis, or disruption in the gut microbial balance, leads to inflammation and increased risk of chronic disease. The review also summarizes recent research that focuses on the bioactivity of both the curcuminoid and non-curcuminoid compounds that comprise the whole turmeric root and their synergistic role in enhancing bioavailability to support a healthy gut microbiome and promising use in the treatment and prevention of disease.
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Kokkorakis M, Chakhtoura M, Rhayem C, Al Rifai J, Ghezzawi M, Valenzuela-Vallejo L, Mantzoros CS. Emerging pharmacotherapies for obesity: A systematic review. Pharmacol Rev 2025; 77:100002. [PMID: 39952695 DOI: 10.1124/pharmrev.123.001045] [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: 12/29/2023] [Revised: 09/03/2024] [Accepted: 09/04/2024] [Indexed: 09/22/2024] Open
Abstract
The history of antiobesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the prevailing conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or US Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging antiobesity drugs or combinations thereof and 4 withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, and TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide and survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4% to 24.2%. Almost half of the drugs undergoing phase 2 trials are incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on underrepresented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. SIGNIFICANCE STATEMENT: Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium for weight management. However, emerging alternatives of novel agents and combinations populate the current obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.
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Affiliation(s)
- Michail Kokkorakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marlene Chakhtoura
- Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
| | - Caline Rhayem
- Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Jana Al Rifai
- Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Malak Ghezzawi
- Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Laura Valenzuela-Vallejo
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts.
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11
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Park S, Jain R, Mirfakhraee S. Glucagon-like-peptide-1 agonist therapy in adults with cystic fibrosis. J Cyst Fibros 2025; 24:40-46. [PMID: 39214747 DOI: 10.1016/j.jcf.2024.08.005] [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: 05/27/2024] [Revised: 07/23/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Glucagon-like-peptide-1 (GLP-1) agonists are commonly used to improve glycemic control and promote weight loss in individuals with type 2 diabetes mellitus (T2DM) and/or obesity. However, there is a paucity of evidence regarding GLP-1 agonist use in people with cystic fibrosis (pwCF). We present 11 people with CF (males: 3, females: 7; age range 24-47; BMI range 25.7-43.7) treated with GLP-1 agonists (semaglutide: 9,tirzepatide: 2) for variable duration (1-50 months). All experienced weight loss on GLP- 1 agonist therapy (median change in weight = -7.2 kg; change in BMI [kg/m2] = -0.9 to -8.1). Eight pwCF showed improvement in percent predicted forced expiratory volume in 1 second (ppFEV1) [change = -5 to + 18] and nine pwCF showed improvement in percent predicted forced vital capacity (ppFVC) [change= +1 to + 26]. Of the 7 pwCF with CFRD, all reduced their insulin quantity (mean, 31.5 % decrease in total daily insulin dose), and glucose time in range improved for most (mean, +11 % increase from baseline). Four pwCF stopped using GLP-1 agonists: 2 due to severe nausea/vomiting, 1 due to lack of perceived benefit, and 1 due to change in insurance coverage. This report is the largest published series to date of pwCF treated with GLP-1 agonist therapy. With the addition of GLP-1 agonists, all individuals experienced weight loss and a reduction in daily insulin dose, and most had improvement in pulmonary function. Future multi-center studies are needed to corroborate the efficacy and safety of these agents in the CF population.
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Affiliation(s)
- Sanghoon Park
- University of Texas Southwestern Medical Center, Department of Internal Medicine, Dallas, TX, United States
| | - Raksha Jain
- University of Texas Southwestern Medical Center, Division of Pulmonary and Clinical Care Medicine, Dallas, TX, United States
| | - Sasan Mirfakhraee
- University of Texas Southwestern Medical Center, Division of Endocrinology and Metabolism, Dallas, TX, United States.
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12
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Samanta A, Bordbar DD, Weng CY, Chancellor JR. Glucagon-like Peptide-1 Receptor Agonists in the Management of Diabetic Retinopathy. Int Ophthalmol Clin 2025; 65:23-26. [PMID: 39710901 DOI: 10.1097/iio.0000000000000541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are a family of drugs, most well known by the third-generation once-weekly subcutaneous semaglutide, that act on the incretin pathway of metabolic, hormonal signaling to modulate pancreatic insulin release, gastric emptying, energy intake, and subjective feelings of satiety. This class of drugs' efficacy and safety in the treatment of type 2 diabetes and obesity have been demonstrated across multiple large randomized controlled trials. These data have propelled GLP-1 receptor agonists to ubiquity in diabetic management and weight loss therapy, leading them to be frequently encountered in ophthalmic practice. The effect of GLP-1 receptor agonists like semaglutide on diabetic retinopathy (DR) is at this point unclear; some studies indicate a worsening of DR with the initiation of GLP-1 agonists, especially semaglutide. Overall, the macrovascular reduction of cardiovascular and stroke risks from GLP-1 receptor agonists should be prioritized over the potential microvascular progression of DR, as long as the patient is regularly followed by ophthalmology.
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Affiliation(s)
- Anindya Samanta
- Cullen Eye Institute, Baylor College of Medicine, Houston, TX
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13
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Rabbani N, Thornalley PJ. Unraveling the impaired incretin effect in obesity and type 2 diabetes: Key role of hyperglycemia-induced unscheduled glycolysis and glycolytic overload. Diabetes Res Clin Pract 2024; 217:111905. [PMID: 39447679 DOI: 10.1016/j.diabres.2024.111905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/01/2024] [Accepted: 10/21/2024] [Indexed: 10/26/2024]
Abstract
Glucagon-like peptide-1 (GLP-1) agonists and GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) co-agonists are major treatment options for subjects with obesity and patients with type 2 diabetes mellitus (T2DM). They counter without addressing the mechanistic cause of the impaired incretin effect associated with obesity and T2DM. Incretin effect impairment is characterized by decreased secretion of incretins from enteroendocrine cells and incretin resistance of pancreatic β-cells. It is linked to hyperglycemia. We present evidence that subversion of the gating of glucose entry into glycolysis, mainly by glucokinase (hexokinase-4), during persistent hyperglycemia in enteroendocrine cells, pancreatic β- and α-cells and appetite-regulating neurons contributes to the biochemical mechanism of the impaired incretin effect. Unscheduled glycolysis and glycolytic overload thereby produced decreases cell signalling of incretin secretion to glucose and other secretion stimuli and incretin receptor responses. This mechanism provides a guide for development of alternative therapies targeting recovery of the impaired incretin effect.
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Affiliation(s)
- Naila Rabbani
- QU Health, Qatar University, University Street, PO Box 2713, Doha, Qatar
| | - Paul J Thornalley
- College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, PO Box 34110, Doha, Qatar.
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14
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Rabbani SA, El-Tanani M, Matalka II, Rangraze IR, Aljabali AAA, Khan MA, Tambuwala MM. Tirzepatide: unveiling a new dawn in dual-targeted diabetes and obesity management. Expert Rev Endocrinol Metab 2024; 19:487-505. [PMID: 39194153 DOI: 10.1080/17446651.2024.2395540] [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: 05/05/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024]
Abstract
INTRODUCTION Incretin-based therapies have emerged as effective treatments for type 2 diabetes (T2D) and obesity. However, not all patients achieve optimal outcomes with existing treatments, highlighting the need for more effective solutions. AREAS COVERED We present a comprehensive evaluation of Tirzepatide (TZP), a novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonist, for managing obesity and T2D. We conducted a systematic search of Cochrane, PubMed, Scopus, and Web of Science databases from inception to April 2024. The focus of the review is on the development and therapeutic potential of TZP, with detailed exploration on pharmacodynamics, pharmacokinetics, clinical efficacy, and safety. Furthermore, it reviews TZP's impacts on glycemic control, weight management, and its potential cardiovascular (CV) benefits. EXPERT OPINION TZP represents a significant advancement in the dual-targeted approach to treating T2D and obesity. Its unique mechanism of action offers superior efficacy in reducing glycemic levels and body weight compared to existing therapies. New data suggesting improvements in CV outcomes indicate that TZP could set a new standard in the treatment paradigm. While long-term data on efficacy and safety are still forthcoming, current evidence positions TZP as a promising option for patients who have not reached their therapeutic goals with existing treatments.
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Affiliation(s)
- Syed Arman Rabbani
- RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Mohamed El-Tanani
- RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Ismail I Matalka
- RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
- Department of Pathology and Microbiology, Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Imran Rashid Rangraze
- Internal Medicine Department, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Alaa A A Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, Jordan
| | - Mohammad Ahmed Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
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15
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Ansari S, Khoo B, Tan T. Targeting the incretin system in obesity and type 2 diabetes mellitus. Nat Rev Endocrinol 2024; 20:447-459. [PMID: 38632474 DOI: 10.1038/s41574-024-00979-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/12/2024] [Indexed: 04/19/2024]
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are widespread, non-communicable diseases that are responsible for considerable levels of morbidity and mortality globally, primarily in the form of cardiovascular disease (CVD). Changes to lifestyle and behaviour have insufficient long-term efficacy in most patients with these diseases; metabolic surgery, although effective, is not practically deliverable on the scale that is required. Over the past two decades, therapies based on incretin hormones, spearheaded by glucagon-like peptide 1 (GLP1) receptor agonists (GLP1RAs), have become the treatment of choice for obesity and T2DM, and clinical evidence now suggests that these agents have benefits for CVD. We review the latest advances in incretin-based pharmacotherapy. These include 'GLP1 plus' agents, which combine the known advantages of GLP1RAs with the activity of additional hormones, such as glucose-dependent insulinotropic peptide, glucagon and amylin, to achieve desired therapeutic goals. Second-generation non-peptidic oral GLP1RAs promise to extend the benefits of GLP1 therapy to those who do not want, or cannot have, subcutaneous injection therapy. We conclude with a discussion of the knowledge gaps that must be addressed before incretin-based therapies can be properly deployed for maximum benefit in the treatment of obesity and T2DM.
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Affiliation(s)
- Saleem Ansari
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - Bernard Khoo
- Department of Endocrinology, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Tricia Tan
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK.
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16
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Wang R, Mijiti S, Xu Q, Liu Y, Deng C, Huang J, Yasheng A, Tian Y, Cao Y, Su Y. The Potential Mechanism of Remission in Type 2 Diabetes Mellitus After Vertical Sleeve Gastrectomy. Obes Surg 2024; 34:3071-3083. [PMID: 38951388 DOI: 10.1007/s11695-024-07378-z] [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: 03/03/2024] [Revised: 06/13/2024] [Accepted: 06/19/2024] [Indexed: 07/03/2024]
Abstract
In recent years, there has been a gradual increase in the prevalence of obesity and type 2 diabetes mellitus (T2DM), with bariatric surgery remaining the most effective treatment strategy for these conditions. Vertical sleeve gastrectomy (VSG) has emerged as the most popular surgical procedure for bariatric/metabolic surgeries, effectively promoting weight loss and improving or curing T2DM. The alterations in the gastrointestinal tract following VSG may improve insulin secretion and resistance by increasing incretin secretion (especially GLP-1), modifying the gut microbiota composition, and through mechanisms dependent on weight loss. This review focuses on the potential mechanisms through which the enhanced action of incretin and metabolic changes in the digestive system after VSG may contribute to the remission of T2DM.
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Affiliation(s)
- Rongfei Wang
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No.57 Mei Hua East Road, Xiang Zhou District, Zhuhai, 519000, Guangdong, China
| | - Salamu Mijiti
- Department of General Surgery, The First People's Hospital of Kashi, Autonomous Region, Kashi, 844000, Xinjiang Uygur, China
| | - Qilin Xu
- Department of General Surgery, The First People's Hospital of Kashi, Autonomous Region, Kashi, 844000, Xinjiang Uygur, China
| | - Yile Liu
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No.57 Mei Hua East Road, Xiang Zhou District, Zhuhai, 519000, Guangdong, China
| | - Chaolun Deng
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No.57 Mei Hua East Road, Xiang Zhou District, Zhuhai, 519000, Guangdong, China
| | - Jiangtao Huang
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No.57 Mei Hua East Road, Xiang Zhou District, Zhuhai, 519000, Guangdong, China
| | - Abudoukeyimu Yasheng
- Department of General Surgery, The First People's Hospital of Kashi, Autonomous Region, Kashi, 844000, Xinjiang Uygur, China
| | - Yunping Tian
- Department of General Surgery, The First People's Hospital of Kashi, Autonomous Region, Kashi, 844000, Xinjiang Uygur, China.
| | - Yanlong Cao
- Department of General Surgery, The First People's Hospital of Kashi, Autonomous Region, Kashi, 844000, Xinjiang Uygur, China.
| | - Yonghui Su
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No.57 Mei Hua East Road, Xiang Zhou District, Zhuhai, 519000, Guangdong, China.
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17
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Kusminski CM, Perez-Tilve D, Müller TD, DiMarchi RD, Tschöp MH, Scherer PE. Transforming obesity: The advancement of multi-receptor drugs. Cell 2024; 187:3829-3853. [PMID: 39059360 PMCID: PMC11286204 DOI: 10.1016/j.cell.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 07/28/2024]
Abstract
For more than a century, physicians have searched for ways to pharmacologically reduce excess body fat. The tide has finally turned with recent advances in biochemically engineered agonists for the receptor of glucagon-like peptide-1 (GLP-1) and their use in GLP-1-based polyagonists. These polyagonists reduce body weight through complementary pharmacology by incorporating the receptors for glucagon and/or the glucose-dependent insulinotropic polypeptide (GIP). In their most advanced forms, gut-hormone polyagonists achieve an unprecedented weight reduction of up to ∼20%-30%, offering a pharmacological alternative to bariatric surgery. Along with favorable effects on glycemia, fatty liver, and kidney disease, they also offer beneficial effects on the cardiovascular system and adipose tissue. These new interventions, therefore, hold great promise for the future of anti-obesity medications.
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Affiliation(s)
- Christine M Kusminski
- Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Diego Perez-Tilve
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Munich, Germany; German Center for Diabetes Research (DZD) and Walther-Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
| | | | - Matthias H Tschöp
- Helmholtz Munich, Munich, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität, Munich, Germany
| | - Philipp E Scherer
- Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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18
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Nielsen ST, Kweka B, Praygod G, Filteau S, Olsen MF, Friis H, Faurholt-Jepsen D, Krogh-Madsen R. The incretin effect in type 2 diabetes in a Sub-Saharan African population. Clin Diabetes Endocrinol 2024; 10:20. [PMID: 39049087 PMCID: PMC11271029 DOI: 10.1186/s40842-024-00178-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 03/01/2024] [Indexed: 07/27/2024] Open
Abstract
AIM Type 2 diabetes is increasing in Sub-Saharan Africa, but the pathophysiology in this population is poorly investigated. In Western populations, the incretin effect is reduced in type 2 diabetes, leading to lowered insulin secretion. The aim of this study was to investigate the incretin effect in a group of Sub-Saharan Africans with type 2 diabetes. METHODS Twenty adults diagnosed with type 2 diabetes, based on either an oral glucose tolerance test (n = 10) or on glycated hemoglobin A1c (n = 10), and 10 non-diabetic controls were included in an interventional study in Tanzania. We investigated the incretin effect as the difference between the plasma insulin area under the curve during an oral glucose tolerance test and that obtained during an intravenous glucose infusion. Differences between diabetes groups were analyzed by Kruskal-Wallis one-way analysis of variance. RESULTS The incretin effect did not differ between groups (p = 0.45), and there was no difference in plasma concentrations of the incretin hormones during the OGTT. CONCLUSION A reduced incretin effect appears not to contribute to hyperglycemia in type 2 diabetes in this Tanzanian population. More research is needed to explain the diabetes phenotype often seen in Sub-Saharan Africa. TRIAL REGISTRATION Clinicaltrials.gov: NCT03106480 , date of registration: 04/10/2017.
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Affiliation(s)
- Signe Tellerup Nielsen
- Department of Anesthesia Surgery and Intensive Care, Copenhagen University Hospital - Herlev, Herlev, Denmark.
- Department of Anesthesiology and Intensive Care, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark.
| | - Belinda Kweka
- National Institute for Medical Research, Mwanza, Tanzania
| | - George Praygod
- National Institute for Medical Research, Mwanza, Tanzania
| | - Suzanne Filteau
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Mette Frahm Olsen
- Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Henrik Friis
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Daniel Faurholt-Jepsen
- Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Rikke Krogh-Madsen
- Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Infectious Diseases, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark
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19
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Perez PA, Wiley MB, Makriyannis A, DiPatrizio NV. Cannabinoids Block Fat-induced Incretin Release via CB 1-dependent and CB 1-independent Pathways in Intestinal Epithelium. GASTRO HEP ADVANCES 2024; 3:931-941. [PMID: 39318720 PMCID: PMC11419882 DOI: 10.1016/j.gastha.2024.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 07/11/2024] [Indexed: 09/26/2024]
Abstract
Background and Aims Glucose homeostasis is regulated by a dynamic interplay between hormones along the gastro-insular axis. For example, enteroendocrine L- and K- cells that line the intestine produce the incretins glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), respectively, which are secreted following a meal. Broadly, incretin signaling enhances insulin release from the endocrine pancreas and participates in the control of food intake, and therapeutics that mimic their activity have recently been developed for the treatment of type-2 diabetes and obesity. Notably, genes for cannabinoid subtype-1 receptor (CB1R) are expressed in these cell subpopulations; however, roles for CB1Rs in controlling fat-induced incretin release are unclear. To address this gap in our understanding, we tested the hypothesis that intestinal epithelial CB1Rs control fat-induced incretin secretion. Methods We treated mice with conditional deletion of CB1Rs in the intestinal epithelium (IntCB1-/-) or controls (IntCB1+/+) with oil gavage to stimulate incretin release in the presence of the cannabinoid receptor agonists, WIN55,212-2 or Δ9 tetrahydrocannabinol (THC), and the peripherally-restricted CB1R antagonist AM6545. Circulating incretin levels were measured in plasma. Results Oral gavage of corn oil increased levels of bioactive GLP1 and GIP in IntCB1+/+ mouse plasma. Pretreatment with the WIN55,212-2 or THC blocked this response, which was largely reversed by coadministration with AM6545. WIN55,212-2 failed to inhibit fat-induced GIP release, but not GLP1, in IntCB1-/- mice. In contrast, THC inhibited the secretion of incretins irrespective of CB1R expression in intestinal epithelial cells. Conclusion These results indicate that cannabinoid receptor agonists can differentially inhibit incretin release via mechanisms that include intestinal epithelial CB1R-dependent and CB1R-independent mechanisms.
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Affiliation(s)
- Pedro Antonio Perez
- Center for Cannabinoid Research (UCRCCR), School of Medicine, University of California, Riverside, Riverside, California
- Department of Neuroscience and The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California
| | - Mark Benjamin Wiley
- Center for Cannabinoid Research (UCRCCR), School of Medicine, University of California, Riverside, Riverside, California
| | | | - Nicholas Vincent DiPatrizio
- Center for Cannabinoid Research (UCRCCR), School of Medicine, University of California, Riverside, Riverside, California
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20
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Helsted MM, Schaltz NL, Gasbjerg LS, Christensen MB, Vilsbøll T, Knop FK. Safety of native glucose-dependent insulinotropic polypeptide in humans. Peptides 2024; 177:171214. [PMID: 38615716 DOI: 10.1016/j.peptides.2024.171214] [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: 01/23/2024] [Revised: 04/04/2024] [Accepted: 04/09/2024] [Indexed: 04/16/2024]
Abstract
In this systematic review, we assessed the safety and possible safety events of native glucose-dependent insulinotropic polypeptide (GIP)(1-42) in human studies with administration of synthetic human GIP. We searched the PubMed database for all trials investigating synthetic human GIP(1-42) administration. A total of 67 studies were included. Study duration ranged from 30 min to 6 days. In addition to healthy individuals, the studies included individuals with impaired glucose tolerance, type 2 diabetes, type 1 diabetes, chronic pancreatitis and secondary diabetes, latent autoimmune diabetes in adults, diabetes caused by a mutation in the hepatocyte nuclear factor 1-alpha gene, end-stage renal disease, chronic renal insufficiency, critical illness, hypoparathyroidism, or cystic fibrosis-related diabetes. Of the included studies, 78% did not mention safety events, 10% of the studies reported that no safety events were observed in relation to GIP administration, and 15% of the studies reported safety events in relation to GIP administration with most frequently reported event being a moderate and transient increased heart rate. Gastrointestinal safety events, and changes in blood pressure were also reported. Plasma concentration of active GIP(1-42) increased linearly with dose independent of participant phenotype. There was no significant correlation between achieved maximal concentration of GIP(1-42) and reported safety events. Clearance rates of GIP(1-42) were similar between participant groups. In conclusion, the available data indicate that GIP(1-42) in short-term (up to 6 days) infusion studies is generally well-tolerated. The long-term safety of continuous GIP(1-42) administration is unknown.
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Affiliation(s)
- Mads M Helsted
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Nina L Schaltz
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Herlev, Denmark.
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21
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Kizilkaya HS, Sørensen KV, Madsen JS, Lindquist P, Douros JD, Bork-Jensen J, Berghella A, Gerlach PA, Gasbjerg LS, Mokrosiński J, Mowery SA, Knerr PJ, Finan B, Campbell JE, D'Alessio DA, Perez-Tilve D, Faas F, Mathiasen S, Rungby J, Sørensen HT, Vaag A, Nielsen JS, Holm JC, Lauenborg J, Damm P, Pedersen O, Linneberg A, Hartmann B, Holst JJ, Hansen T, Wright SC, Lauschke VM, Grarup N, Hauser AS, Rosenkilde MM. Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes. Nat Metab 2024; 6:1268-1281. [PMID: 38871982 PMCID: PMC11272584 DOI: 10.1038/s42255-024-01061-4] [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: 04/18/2023] [Accepted: 05/02/2024] [Indexed: 06/15/2024]
Abstract
Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.
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Affiliation(s)
- Hüsün S Kizilkaya
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kimmie V Sørensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jakob S Madsen
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Peter Lindquist
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jonathan D Douros
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
- Indiana Biosciences Research Institute Indianapolis, Indianapolis, IN, USA
| | - Jette Bork-Jensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alessandro Berghella
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
- Department of Bioscience and Agro-Food and Environmental Technology, University of Teramo, Teramo, Italy
| | - Peter A Gerlach
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lærke S Gasbjerg
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Stephanie A Mowery
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
- Indiana Biosciences Research Institute Indianapolis, Indianapolis, IN, USA
| | - Patrick J Knerr
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
- Indiana Biosciences Research Institute Indianapolis, Indianapolis, IN, USA
| | - Brian Finan
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University Durham, Durham, NC, USA
| | - David A D'Alessio
- Duke Molecular Physiology Institute, Duke University Durham, Durham, NC, USA
| | - Diego Perez-Tilve
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Felix Faas
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Signe Mathiasen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen Rungby
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Henrik T Sørensen
- Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
- Department of Epidemiology, Boston University, Boston, MA, USA
| | - Allan Vaag
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Sciences, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Jens S Nielsen
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Jens-Christian Holm
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- The Children's Obesity Clinic, accredited European Centre for Obesity Management, Department of Pediatrics, Holbæk Hospital, Holbæk, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jeannet Lauenborg
- Department of Obstetrics and Gynecology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Peter Damm
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark
- Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark
| | - Oluf Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Metabolic Research, Department of Medicine, Gentofte Hospital, Copenhagen, Denmark
| | - Allan Linneberg
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Shane C Wright
- Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Volker M Lauschke
- Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Alexander S Hauser
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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22
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Xie C, Iroga P, Bound MJ, Grivell J, Huang W, Jones KL, Horowitz M, Rayner CK, Wu T. Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study. Diabetologia 2024; 67:1260-1270. [PMID: 38561463 PMCID: PMC11153273 DOI: 10.1007/s00125-024-06131-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 02/14/2024] [Indexed: 04/04/2024]
Abstract
AIMS/HYPOTHESIS Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. METHODS Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min. RESULTS There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. CONCLUSIONS/INTERPRETATION In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. TRIAL REGISTRATION www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant.
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Affiliation(s)
- Cong Xie
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Peter Iroga
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Michelle J Bound
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Jacqueline Grivell
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Weikun Huang
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Karen L Jones
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Michael Horowitz
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Christopher K Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia.
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia.
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23
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Modvig IM, Smits MM, Galsgaard KD, Hjørne AP, Drzazga AK, Rosenkilde MM, Holst JJ. L-valine is a powerful stimulator of GLP-1 secretion in rodents and stimulates secretion through ATP-sensitive potassium channels and voltage-gated calcium channels. Nutr Diabetes 2024; 14:43. [PMID: 38862477 PMCID: PMC11166632 DOI: 10.1038/s41387-024-00303-4] [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: 01/23/2024] [Revised: 05/30/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND We previously reported that, among all the naturally occurring amino acids, L-valine is the most powerful luminal stimulator of glucagon-like peptide 1 (GLP-1) release from the upper part of the rat small intestine. This makes L-valine an interesting target for nutritional-based modulation of GLP-1 secretion. However, the molecular mechanism of L-valine-induced secretion remains unknown. METHODS We aimed to investigate the effect of orally given L-valine in mice and to identify the molecular details of L-valine stimulated GLP-1 release using the isolated perfused rat small intestine and GLUTag cells. In addition, the effect of L-valine on hormone secretion from the distal intestine was investigated using a perfused rat colon. RESULTS Orally given L-valine (1 g/kg) increased plasma levels of active GLP-1 comparably to orally given glucose (2 g/kg) in male mice, supporting that L-valine is a powerful stimulator of GLP-1 release in vivo (P > 0.05). Luminal L-valine (50 mM) strongly stimulated GLP-1 release from the perfused rat small intestine (P < 0.0001), and inhibition of voltage-gated Ca2+-channels with nifedipine (10 μM) inhibited the GLP-1 response (P < 0.01). Depletion of luminal Na+ did not affect L-valine-induced GLP-1 secretion (P > 0.05), suggesting that co-transport of L-valine and Na+ is not important for the depolarization necessary to activate the voltage-gated Ca2+-channels. Administration of the KATP-channel opener diazoxide (250 μM) completely blocked the L-valine induced GLP-1 response (P < 0.05), suggesting that L-valine induced depolarization arises from metabolism and opening of KATP-channels. Similar to the perfused rat small intestine, L-valine tended to stimulate peptide tyrosine-tyrosine (PYY) and GLP-1 release from the perfused rat colon. CONCLUSIONS L-valine is a powerful stimulator of GLP-1 release in rodents. We propose that intracellular metabolism of L-valine leading to closure of KATP-channels and opening of voltage-gated Ca2+-channels are involved in L-valine induced GLP-1 secretion.
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Affiliation(s)
- Ida Marie Modvig
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mark M Smits
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Katrine Douglas Galsgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anna Pii Hjørne
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anna Katarzyna Drzazga
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Łódź, Poland
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
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Das S, Ravi H, Babu A, Banerjee M, Kanagavalli R, Dhanasekaran S, Devi Rajeswari V, Venkatraman G, Ramanathan G. Therapeutic potentials of glucose-dependent insulinotropic polypeptide (GIP) in T2DM: Past, present, and future. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 142:293-328. [PMID: 39059989 DOI: 10.1016/bs.apcsb.2023.12.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a worldwide health problem that has raised major concerns to the public health community. This chronic condition typically results from the cell's inability to respond to normal insulin levels. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the primary incretin hormones secreted from the intestinal tract. While clinical research has extensively explored the therapeutic potential of GLP-1R in addressing various T2DM-related abnormalities, the possibility of GIPR playing an important role in T2DM treatment is still under investigation. Evidence suggests that GIP is involved in the pathophysiology of T2DM. This chapter focuses on examining the role of GIP as a therapeutic molecule in combating T2DM, comparing the past, present, and future scenarios. Our goal is to delve into how GIP may impact pancreatic β-cell function, adipose tissue uptake, and lipid metabolism. Furthermore, we will elucidate the mechanistic functions of GIP and its receptors in relation to other clinical conditions like cardiovascular diseases, non-alcoholic fatty liver diseases, neurodegenerative diseases, and renal disorders. Additionally, this chapter will shed light on the latest advancements in pharmacological management for T2DM, highlighting potential structural modifications of GIP and the repurposing of drugs, while also addressing the challenges involved in bringing GIP-based treatments into clinical practice.
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Affiliation(s)
- Soumik Das
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Harini Ravi
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Achsha Babu
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Manosi Banerjee
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - R Kanagavalli
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Sivaraman Dhanasekaran
- School of Energy Technology, Pandit Deendayal Energy University, Knowledge Corridor, Gandhinagar, Gujarat, India
| | - V Devi Rajeswari
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Ganesh Venkatraman
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Gnanasambandan Ramanathan
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
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25
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Solinas G, Becattini B. An adipoincretin effect links adipostasis with insulin secretion. Trends Endocrinol Metab 2024; 35:466-477. [PMID: 38861922 DOI: 10.1016/j.tem.2023.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 10/20/2023] [Accepted: 10/24/2023] [Indexed: 06/13/2024]
Abstract
The current paradigm for the insulin system focuses on the phenomenon of glucose-stimulated insulin secretion and insulin action on blood glucose control. This historical glucose-centric perspective may have introduced a conceptual bias in our understanding of insulin regulation. A body of evidence demonstrating that in vivo variations in blood glucose and insulin secretion can be largely dissociated motivated us to reconsider the fundamental design of the insulin system as a control system for metabolic homeostasis. Here, we propose that a minimal glucose-centric model does not accurately describe the physiological behavior of the insulin system and propose a new paradigm focusing on the effects of incretins, arguing that under fasting conditions, insulin is regulated by an adipoincretin effect.
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Affiliation(s)
- Giovanni Solinas
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
| | - Barbara Becattini
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
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26
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Mittendorfer B, Johnson JD, Solinas G, Jansson PA. Insulin Hypersecretion as Promoter of Body Fat Gain and Hyperglycemia. Diabetes 2024; 73:837-843. [PMID: 38768368 PMCID: PMC11109786 DOI: 10.2337/dbi23-0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/26/2024] [Indexed: 05/22/2024]
Affiliation(s)
- Bettina Mittendorfer
- Departments of Medicine and Nutrition & Exercise Physiology, School of Medicine, University of Missouri, Columbia, MO
| | - James D. Johnson
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Giovanni Solinas
- Department of Molecular and Clinical Medicine, School of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Per-Anders Jansson
- Department of Molecular and Clinical Medicine, School of Medicine, University of Gothenburg, Gothenburg, Sweden
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27
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Becattini B, Molinaro A, Henricsson M, Borén J, Solinas G. Adipocyte PI3K links adipostasis with baseline insulin secretion at fasting through an adipoincretin effect. Cell Rep 2024; 43:114132. [PMID: 38656871 DOI: 10.1016/j.celrep.2024.114132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 03/06/2024] [Accepted: 04/04/2024] [Indexed: 04/26/2024] Open
Abstract
Insulin-PI3K signaling controls insulin secretion. Understanding this feedback mechanism is crucial for comprehending how insulin functions. However, the role of adipocyte insulin-PI3K signaling in controlling insulin secretion in vivo remains unclear. Using adipocyte-specific PI3Kα knockout mice (PI3KαAdQ) and a panel of isoform-selective PI3K inhibitors, we show that PI3Kα and PI3Kβ activities are functionally redundant in adipocyte insulin signaling. PI3Kβ-selective inhibitors have no effect on adipocyte AKT phosphorylation in control mice but blunt it in adipocytes of PI3KαAdQ mice, demonstrating adipocyte-selective pharmacological PI3K inhibition in the latter. Acute adipocyte-selective PI3K inhibition increases serum free fatty acid (FFA) and potently induces insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect operates in fasted mice with increasing FFA and decreasing glycemia, indicating that it is not primarily a control system for blood glucose. This feedback control system defines the rates of adipose tissue lipolysis and chiefly controls basal insulin secretion during fasting.
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Affiliation(s)
- Barbara Becattini
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Angela Molinaro
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Marcus Henricsson
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Jan Borén
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Giovanni Solinas
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
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28
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Shilleh AH, Viloria K, Broichhagen J, Campbell JE, Hodson DJ. GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells. Peptides 2024; 175:171179. [PMID: 38360354 DOI: 10.1016/j.peptides.2024.171179] [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: 01/12/2024] [Revised: 02/09/2024] [Accepted: 02/13/2024] [Indexed: 02/17/2024]
Abstract
Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are transmembrane receptors involved in insulin, glucagon and somatostatin secretion from the pancreatic islet. Therapeutic targeting of GLP1R and GIPR restores blood glucose levels in part by influencing beta cell, alpha cell and delta cell function. Despite the importance of the incretin-mimetics for diabetes therapy, our understanding of GLP1R and GIPR expression patterns and signaling within the islet remain incomplete. Here, we present the evidence for GLP1R and GIPR expression in the major islet cell types, before addressing signaling pathway(s) engaged, as well as their influence on cell survival and function. While GLP1R is largely a beta cell-specific marker within the islet, GIPR is expressed in alpha cells, beta cells, and (possibly) delta cells. GLP1R and GIPR engage Gs-coupled pathways in most settings, although the exact outcome on hormone release depends on paracrine communication and promiscuous signaling. Biased agonism away from beta-arrestin is an emerging concept for improving therapeutic efficacy, and is also relevant for GLP1R/GIPR dual agonism. Lastly, dual agonists exert multiple effects on islet function through GIPR > GLP1R imbalance, increased GLP1R surface expression and cAMP signaling, as well as beneficial alpha cell-beta cell-delta cell crosstalk.
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Affiliation(s)
- Ali H Shilleh
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Katrina Viloria
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | | | - Jonathan E Campbell
- Duke Molecular Physiology Institute, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
| | - David J Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
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29
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Novikoff A, Müller TD. Pharmacological Advances in Incretin-Based Polyagonism: What We Know and What We Don't. Physiology (Bethesda) 2024; 39:142-156. [PMID: 38353610 PMCID: PMC11368522 DOI: 10.1152/physiol.00032.2023] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/08/2024] [Accepted: 02/08/2024] [Indexed: 02/21/2024] Open
Abstract
The prevalence of obesity continues to rise in both adolescents and adults, in parallel obesity is strongly associated with the increased incidence of type 2 diabetes, heart failure, certain types of cancer, and all-cause mortality. In relation to obesity, many pharmacological approaches of the past have tried and failed to combat the rising obesity epidemic, particularly due to insufficient efficacy or unacceptable side effects. However, while the history of antiobesity medication is plagued by failures and disappointments, we have witnessed over the last 10 years substantial progress, particularly in regard to biochemically optimized agonists at the receptor for glucagon-like peptide-1 (GLP-1R) and unimolecular coagonists at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Although the GIP receptor:GLP-1R coagonists are being heralded as premier pharmacological tools for the treatment of obesity and diabetes, uncertainty remains as to why these drugs testify superiority over best-in-class GLP-1R monoagonists. Particularly with regard to GIP, there remains great uncertainty if and how GIP acts on systems metabolism and if the GIP system should be activated or inhibited to improve metabolic outcome in adjunct to GLP-1R agonism. In this review, we summarize recent advances in GLP-1- and GIP-based pharmacology and discuss recent findings and open questions related to how the GIP system affects systemic energy and glucose metabolism.
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Affiliation(s)
- Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
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30
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Huber H, Schieren A, Holst JJ, Simon MC. Dietary impact on fasting and stimulated GLP-1 secretion in different metabolic conditions - a narrative review. Am J Clin Nutr 2024; 119:599-627. [PMID: 38218319 PMCID: PMC10972717 DOI: 10.1016/j.ajcnut.2024.01.007] [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: 09/07/2023] [Revised: 01/03/2024] [Accepted: 01/09/2024] [Indexed: 01/15/2024] Open
Abstract
Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide and central mediator of glucose metabolism, is secreted by L cells in the intestine in response to food intake. Postprandial secretion of GLP-1 is triggered by nutrient-sensing via transporters and G-protein-coupled receptors (GPCRs). GLP-1 secretion may be lower in adults with obesity/overweight (OW) or type 2 diabetes mellitus (T2DM) than in those with normal glucose tolerance (NGT), but these findings are inconsistent. Because of the actions of GLP-1 on stimulating insulin secretion and promoting weight loss, GLP-1 and its analogs are used in pharmacologic preparations for the treatment of T2DM. However, physiologically stimulated GLP-1 secretion through the diet might be a preventive or synergistic method for improving glucose metabolism in individuals who are OW, or have impaired glucose tolerance (IGT) or T2DM. This narrative review focuses on fasting and postprandial GLP-1 secretion in individuals with different metabolic conditions and degrees of glucose intolerance. Further, the influence of relevant diet-related factors (e.g., specific diets, meal composition, and size, phytochemical content, and gut microbiome) that could affect fasting and postprandial GLP-1 secretion are discussed. Some studies showed diminished glucose- or meal-stimulated GLP-1 response in participants with T2DM, IGT, or OW compared with those with NGT, whereas other studies have reported an elevated or unchanged GLP-1 response in T2DM or IGT. Meal composition, especially the relationship between macronutrients and interventions targeting the microbiome can impact postprandial GLP-1 secretion, although it is not clear which macronutrients are strong stimulants of GLP-1. Moreover, glucose tolerance, antidiabetic treatment, grade of overweight/obesity, and sex were important factors influencing GLP-1 secretion. The results presented in this review highlight the potential of nutritional and physiologic stimulation of GLP-1 secretion. Further research on fasting and postprandial GLP-1 concentrations and the resulting metabolic consequences under different metabolic conditions is needed.
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Affiliation(s)
- Hanna Huber
- Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Institute of Neuroscience and Physiology, Mölndal, Sweden; Department Nutrition and Microbiota, University of Bonn, Institute of Nutrition and Food Science, Bonn, Germany
| | - Alina Schieren
- Department Nutrition and Microbiota, University of Bonn, Institute of Nutrition and Food Science, Bonn, Germany
| | - Jens Juul Holst
- Department of Biomedical Sciences, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | - Marie-Christine Simon
- Department Nutrition and Microbiota, University of Bonn, Institute of Nutrition and Food Science, Bonn, Germany.
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31
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Arte PA, Tungare K, Bhori M, Jobby R, Aich J. Treatment of type 2 diabetes mellitus with stem cells and antidiabetic drugs: a dualistic and future-focused approach. Hum Cell 2024; 37:54-84. [PMID: 38038863 DOI: 10.1007/s13577-023-01007-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023]
Abstract
Type 2 Diabetes Mellitus (T2DM) accounts for more than 90% of total diabetes mellitus cases all over the world. Obesity and lack of balance between energy intake and energy expenditure are closely linked to T2DM. Initial pharmaceutical treatment and lifestyle interventions can at times lead to remission but usually help alleviate it to a certain extent and the condition remains, thus, recurrent with the patient being permanently pharmaco-dependent. Mesenchymal stromal cells (MSCs) are multipotent, self-renewing cells with the ability to secrete a variety of biological factors that can help restore and repair injured tissues. MSC-derived exosomes possess these properties of the original stem cells and are potentially able to confer superior effects due to advanced cell-to-cell signaling and the presence of stem cell-specific miRNAs. On the other hand, the repository of antidiabetic agents is constantly updated with novel T2DM disease-modifying drugs, with higher efficacy and increasingly convenient delivery protocols. Delving deeply, this review details the latest progress and ongoing studies related to the amalgamation of stem cells and antidiabetic drugs, establishing how this harmonized approach can exert superior effects in the management and potential reversal of T2DM.
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Affiliation(s)
- Priyamvada Amol Arte
- School of Biotechnology and Bioinformatics, DY Patil Deemed to Be University, CBD Belapur, Navi Mumbai, Maharashtra, 400614, India.
- Anatek Services PVT LTD, Sai Chamber, 10, Near Santacruz Railway Bridge, Sen Nagar, Santacruz East, Mumbai, Maharashtra, 400055, India.
| | - Kanchanlata Tungare
- School of Biotechnology and Bioinformatics, DY Patil Deemed to Be University, CBD Belapur, Navi Mumbai, Maharashtra, 400614, India
| | - Mustansir Bhori
- Inveniolife Technology PVT LTD, Office No.118, Grow More Tower, Plot No.5, Sector 2, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Renitta Jobby
- Amity Institute of Biotechnology, Amity University Maharashtra, Mumbai-Pune Expressway, Bhatan, Panvel, Navi Mumbai, Maharashtra, 410206, India
- Amity Centre of Excellence in Astrobiology, Amity University Maharashtra, Mumbai-Pune Expressway, Bhatan, Panvel, Navi Mumbai, Maharashtra, 410206, India
| | - Jyotirmoi Aich
- School of Biotechnology and Bioinformatics, DY Patil Deemed to Be University, CBD Belapur, Navi Mumbai, Maharashtra, 400614, India
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Galderisi A, Tricò D, Lat J, Samuels S, Weiss R, Van Name M, Pierpont B, Santoro N, Caprio S. Incretin effect determines glucose trajectory and insulin sensitivity in youths with obesity. JCI Insight 2023; 8:e165709. [PMID: 37847560 PMCID: PMC10721315 DOI: 10.1172/jci.insight.165709] [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: 10/03/2022] [Accepted: 10/11/2023] [Indexed: 10/18/2023] Open
Abstract
In youths with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on β cell function and insulin sensitivity. Youths with obesity and 2-hour glucose level ≥ 120 mg/dL underwent a 3-hour oral glucose-tolerance test (OGTT) and an isoglycemic i.v. glucose infusion to quantify the incretin effect. After 2 years, 30 of 39 participants had a repeated OGTT and were stratified into 3 tertiles according to the baseline incretin effect. The high-incretin effect group demonstrated a longitudinal increase in β cell function (disposition index, minimal model [DIMM]), with greater insulin sensitivity at follow-up and stable insulin secretion (φtotal). A lower incretin effect at baseline was associated with higher 1-hour and 2-hour glucose level at follow-up. The high-incretin effect group displayed a greater increase of GLP-17-36 than the moderate- and low-incretin group at baseline, while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin in respect to the high-incretin group. The incretin effect during pubertal transition affected the longitudinal trajectory of β cell function and weight in youths with obesity.
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Affiliation(s)
- Alfonso Galderisi
- Yale University, Department of Pediatrics, New Haven, Connecticut, USA
| | - Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Jessica Lat
- Yale University, Department of Pediatrics, New Haven, Connecticut, USA
| | - Stephanie Samuels
- Yale University, Department of Pediatrics, New Haven, Connecticut, USA
| | - Ram Weiss
- Department of Pediatrics, Ruth Rappaport Childrens’ Hospital, Rambam Medical Center, Haifa, Israel
| | - Michelle Van Name
- Yale University, Department of Pediatrics, New Haven, Connecticut, USA
| | - Bridget Pierpont
- Yale University, Department of Pediatrics, New Haven, Connecticut, USA
| | - Nicola Santoro
- Yale University, Department of Pediatrics, New Haven, Connecticut, USA
- Department of Medicine and Health Sciences University of Molise, Campobasso, Italy
| | - Sonia Caprio
- Yale University, Department of Pediatrics, New Haven, Connecticut, USA
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Aulinger BA, D'Alessio DA. Assessment of the incretin effect in healthy subjects: concordance between clamp and OGTT methods. Am J Physiol Endocrinol Metab 2023; 325:E412-E420. [PMID: 37702736 PMCID: PMC10642988 DOI: 10.1152/ajpendo.00104.2022] [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: 04/21/2022] [Revised: 07/11/2023] [Accepted: 08/31/2023] [Indexed: 09/14/2023]
Abstract
The incretin effect describes the insulin response to nutrient ingestion that exceeds the response to glycemia per se. It is mediated by gastrointestinal factors and is necessary to maintain postprandial glucose homeostasis. The incretin effect results in a more than twofold increase of the insulin response to a meal in healthy people and two different techniques have been used in the past to measure its magnitude. Most studies employ an OGTT on 1 day, followed by a matching glucose infusion on a separate day. Another study design employs a hyperglycemic glucose clamp that is maintained after oral ingestion of glucose. Both protocols allow quantification of the incretin effect by comparing the insulin response to an identical glycemic stimulus. Here we performed a within-subject comparison of both techniques to quantify the incretin effect and suggest different calculation methods to interpret the results derived from the clamp experiment in a cohort of healthy young adults (n = 10, age 33 ± 4 yr). All subjects participated on four different study days: 1) OGTT, 2) isoglycemic glucose infusion (Iso-IV), 3) hyperglycemic clamp with oral glucose ingestion (clamp-OGTT), and 4) hyperglycemic clamp (clamp). With the classic OGTT/Iso-IV method, the insulin response to glucose ingestion increased more than twofold and was 60 ± 6% and 49 ± 5% for insulin and c-peptide. Different estimates of the incretin effect based on the clamp method ranged from 58% to 79% for insulin and 38% to 61% for c-peptide, both significantly higher than values derived from the OGTT/isoglycemic infusion method. However, when the effect of continuous hyperglycemia on insulin secretion was accounted for, using extrapolation from early time points of the clamp, good agreement was noted between the two methods. Based on these results, both techniques seem to be equally suited to measure the incretin effect and should be employed according to the scientific questions, experimental contingencies, and investigator experience.NEW & NOTEWORTHY This proof-of-concept study shows that the incretin effect can be reliably assessed by two different methods with similar quantitative results. A single-day hyperglycemic clamp with oral glucose ingestion allows the determination of the incretin effect with fewer study days and less day-to-day variability.
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Affiliation(s)
- Benedikt A Aulinger
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
- Clinical Research Unit, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, United States
| | - David A D'Alessio
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Duke University, Durham, North Carolina, United States
- Clinical Research Unit, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, United States
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Drucker DJ, Holst JJ. The expanding incretin universe: from basic biology to clinical translation. Diabetologia 2023; 66:1765-1779. [PMID: 36976349 DOI: 10.1007/s00125-023-05906-7] [Citation(s) in RCA: 100] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/20/2023] [Indexed: 03/29/2023]
Abstract
Incretin hormones, principally glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1), potentiate meal-stimulated insulin secretion through direct (GIP + GLP-1) and indirect (GLP-1) actions on islet β-cells. GIP and GLP-1 also regulate glucagon secretion, through direct and indirect pathways. The incretin hormone receptors (GIPR and GLP-1R) are widely distributed beyond the pancreas, principally in the brain, cardiovascular and immune systems, gut and kidney, consistent with a broad array of extrapancreatic incretin actions. Notably, the glucoregulatory and anorectic activities of GIP and GLP-1 have supported development of incretin-based therapies for the treatment of type 2 diabetes and obesity. Here we review evolving concepts of incretin action, focusing predominantly on GLP-1, from discovery, to clinical proof of concept, to therapeutic outcomes. We identify established vs uncertain mechanisms of action, highlighting biology conserved across species, while illuminating areas of active investigation and uncertainty that require additional clarification.
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Affiliation(s)
- Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
| | - Jens J Holst
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Ammann M, Santol J, Pereyra D, Kalchbrenner T, Wuerger T, Laengle J, Smoot RL, Hulla W, Laengle F, Starlinger P. Glucagon-like peptide-1 and glucagon-like peptide-2 regulation during human liver regeneration. Sci Rep 2023; 13:15980. [PMID: 37749369 PMCID: PMC10519971 DOI: 10.1038/s41598-023-43283-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 09/21/2023] [Indexed: 09/27/2023] Open
Abstract
Accumulating evidence suggests that metabolic demands of the regenerating liver are met via lipid metabolism and critical regulators of this process. As such, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) critically affect hepatic regeneration in rodent models. The present study aimed to evaluate potential alterations and dynamics of circulating GLP-1 and GLP-2 in patients undergoing liver resections, focusing on post-hepatectomy liver failure (PHLF). GLP-1, GLP-2, Interleukin-6 (IL-6) and parameters of lipid metabolism were determined perioperatively in fasting plasma of 46 patients, who underwent liver resection. GLP-1 and GLP-2 demonstrated a rapid and consistently inverse time course during hepatic regeneration with a significant decrease of GLP-1 and increase of GLP-2 on POD1. Importantly, these postoperative dynamics were significantly more pronounced when PHLF occurred. Of note, the extent of resection or development of complications were not associated with these alterations. IL-6 mirrored the time course of GLP-2. Assessing the main degradation protein dipeptidyl peptidase 4 (DPP4) no significant association with either GLP-1 or -2 could be found. Additionally, in PHLF distinct postoperative declines in plasma lipid parameters were present and correlated with GLP-2 dynamics. Our data suggest dynamic inverse regulation of GLP-1 and GLP-2 during liver regeneration, rather caused by an increase in expression/release than by changes in degradation capacity and might be associated with inflammatory responses. Their close association with circulating markers of lipid metabolism and insufficient hepatic regeneration after liver surgery suggest a critical involvement during these processes in humans.
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Affiliation(s)
- Markus Ammann
- Department of Surgery, State Hospital Wiener Neustadt, Wiener Neustadt, Austria
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Jonas Santol
- Department of Surgery, HPB Centre, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - David Pereyra
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Tamara Kalchbrenner
- Department of Pathology, State Hospital Wiener Neustadt, Wiener Neustadt, Austria
| | - Tanja Wuerger
- Department of Pathology, State Hospital Wiener Neustadt, Wiener Neustadt, Austria
| | - Johannes Laengle
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Rory L Smoot
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Wolfgang Hulla
- Department of Pathology, State Hospital Wiener Neustadt, Wiener Neustadt, Austria
| | - Friedrich Laengle
- Department of Surgery, State Hospital Wiener Neustadt, Wiener Neustadt, Austria
| | - Patrick Starlinger
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria.
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
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Vemulapalli HS, Vajje J, Rehman W, Virk GS, Shah K, Chaudhari SS, Mian IUD, Saleem F. Safety and Efficacy of Liraglutide on Cardiovascular Outcomes in Patients With Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials. Cureus 2023; 15:e45421. [PMID: 37854744 PMCID: PMC10581595 DOI: 10.7759/cureus.45421] [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] [Accepted: 09/17/2023] [Indexed: 10/20/2023] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disorder, with type 2 diabetes (T2DM) significantly impacting the cardiovascular (CV) system. Our comprehensive study on the cardiovascular effects of liraglutide, conducted concurrently with the formulation of diabetes treatment guidelines, aims to provide healthcare providers and patients with reassurance regarding the safety and effectiveness of liraglutide. From the beginning until August 20, 2023, we conducted searches in databases including PubMed, Web of Science, Embase, Cochrane Library, Scopus, and Google Scholar. These searches aimed to identify studies comparing liraglutide to control in terms of symptom resolution among patients with T2DM. For all relevant outcomes, we calculated risk ratios along with their corresponding 95% confidence intervals. Thirteen randomized controlled trials (RCTs) were included in this analysis. The results demonstrated a significant reduction in the risk of major adverse cardiovascular events (MACE), myocardial infarction, CV mortality, and all-cause mortality. No significant difference was found between the liraglutide and control groups for the outcome of stroke. However, sensitivity analysis revealed a significant reduction in the risk of stroke among patients taking liraglutide. Our comprehensive meta-analysis strongly supports the use of liraglutide for managing cardiovascular disease (CVD) due to its established safety and effectiveness. Further RCTs and meta-analyses are needed to more thoroughly evaluate liraglutide's therapeutic potential, with the aim of enhancing the quality of life for those with CVD.
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Affiliation(s)
| | - Jaahnavi Vajje
- Internal Medicine, Dr. Pinnamaneni Siddhartha Institute of Medical Sciences and Research Foundation, Vijayawada, IND
| | - Wajeeh Rehman
- Internal Medicine, United Health Services Hospitals, State University of New York Upstate Medical University Binghamton Campus, Johnson City, USA
| | - Ghazala S Virk
- Internal Medicine, Avalon University School of Medicine, Ohio, USA
| | - Krushi Shah
- Internal Medicine, Gujarat Medical Education and Research Society (GMERS) Medical College, Gandhinagar, IND
| | - Sandipkumar S Chaudhari
- General Physician, Lions General Hospital, Mehsana, IND
- General Practice, General Hospital, Vadnagar, IND
| | - Irfan-Ud-Din Mian
- Medicine, Combined Military Hospital (CMH) Lahore Medical College and Institute of Dentistry, Lahore, PAK
| | - Faraz Saleem
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
- Internal Medicine, Akhtar Saeed Medical and Dental College, Lahore, PAK
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Smedegaard S, Kampmann U, Ovesen PG, Støvring H, Rittig N. Whey Protein Premeal Lowers Postprandial Glucose Concentrations in Adults Compared with Water-The Effect of Timing, Dose, and Metabolic Status: a Systematic Review and Meta-analysis. Am J Clin Nutr 2023; 118:391-405. [PMID: 37536867 DOI: 10.1016/j.ajcnut.2023.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 04/19/2023] [Accepted: 05/02/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND Serving whey protein before a meal in order to lower postprandial blood glucose concentrations is known as a premeal. The underlying mechanisms are only partly understood but may involve stimulation of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and insulin secretion together with a slower gastric emptying rate. OBJECTIVES The objective of this systematic review and meta-analysis was to review all randomized clinical trials investigating premeals with whey protein in comparison with a nonactive comparator (control) that evaluated plasma glucose, GLP-1, GIP, insulin, and/or gastric emptying rate. Secondary aims included subgroup analyses on the timing and dose of the premeal together with the metabolic state of the participants [lean, obese, and type 2 diabetes mellitus (T2DM)]. METHODS We searched EMBASE, CENTRAL, PUBMED, and clinicaltrials.gov and found 16 randomized crossover trials with a total of 244 individuals. The last search was performed on 9 August, 2022. RESULTS Whey protein premeals lowered peak glucose concentration by -1.4 mmol/L [-1.9 mmol/L; -0.9 mmol/L], and the area under the curve for glucose was -0.9 standard deviation (SD) [-1.2 SD; -0.6 SD] compared with controls (high certainty). In association with these findings, whey protein premeals elevated GLP-1 (low certainty) and peak insulin (high certainty) concentrations and slowed gastric emptying rate (high certainty) compared with controls. Subgroup analyses showed a more pronounced and prolonged glucose-lowering effect in individuals with T2DM compared with participants without T2DM. The available evidence did not elucidate the role of GIP. The protein dose used varied between 4 and 55 g, and meta-regression analysis showed that the protein dose correlated with the glucose-lowering effects. CONCLUSIONS In conclusion, whey protein premeals lower postprandial blood glucose, reduce gastric emptying rate, and increase peak insulin. In addition, whey protein premeals may elevate plasma concentrations of GLP-1. Whey protein premeals may possess clinical potential, but the long-term effects await future clinical trials.
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Affiliation(s)
- Stine Smedegaard
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
| | - Ulla Kampmann
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Per G Ovesen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark
| | - Henrik Støvring
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Nikolaj Rittig
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
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Fadzeyeva E, Locatelli CA, Trzaskalski NA, Nguyen MA, Capozzi ME, Vulesevic B, Morrow NM, Ghorbani P, Hanson AA, Lorenzen-Schmidt I, Doyle MA, Seymour R, Varin EM, Fullerton MD, Campbell JE, Mulvihill EE. Pancreas-derived DPP4 is not essential for glucose homeostasis under metabolic stress. iScience 2023; 26:106748. [PMID: 37216093 PMCID: PMC10192926 DOI: 10.1016/j.isci.2023.106748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 03/09/2023] [Accepted: 04/21/2023] [Indexed: 05/24/2023] Open
Abstract
Mice systemically lacking dipeptidyl peptidase-4 (DPP4) have improved islet health, glucoregulation, and reduced obesity with high-fat diet (HFD) feeding compared to wild-type mice. Some, but not all, of this improvement can be linked to the loss of DPP4 in endothelial cells (ECs), pointing to the contribution of non-EC types. The importance of intra-islet signaling mediated by α to β cell communication is becoming increasingly clear; thus, our objective was to determine if β cell DPP4 regulates insulin secretion and glucose tolerance in HFD-fed mice by regulating the local concentrations of insulinotropic peptides. Using β cell double incretin receptor knockout mice, β cell- and pancreas-specific Dpp4-/- mice, we reveal that β cell incretin receptors are necessary for DPP4 inhibitor effects. However, although β cell DPP4 modestly contributes to high glucose (16.7 mM)-stimulated insulin secretion in isolated islets, it does not regulate whole-body glucose homeostasis.
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Affiliation(s)
- Evgenia Fadzeyeva
- The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
- The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
| | - Cassandra A.A. Locatelli
- The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
- The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
| | - Natasha A. Trzaskalski
- The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
- The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
| | - My-Anh Nguyen
- The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
- The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
| | - Megan E. Capozzi
- Duke Molecular Physiology Institute, 300 North Duke Street, Durham, NC 27701, USA
| | - Branka Vulesevic
- The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
- The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
| | - Nadya M. Morrow
- The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
- The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
| | - Peyman Ghorbani
- The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
| | - Antonio A. Hanson
- The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
- The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
| | - Ilka Lorenzen-Schmidt
- The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
| | - Mary-Anne Doyle
- Division of Endocrinology & Metabolism, Department of Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada
| | - Richard Seymour
- The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
| | - Elodie M. Varin
- Lunenfeld Tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada
| | - Morgan D. Fullerton
- The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
- Centre for Infection, Immunity and Inflammation, Ottawa, ON K1H 8M5, Canada
| | - Jonathan E. Campbell
- Duke Molecular Physiology Institute, 300 North Duke Street, Durham, NC 27701, USA
| | - Erin E. Mulvihill
- The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
- The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
- Centre for Infection, Immunity and Inflammation, Ottawa, ON K1H 8M5, Canada
- Montreal Diabetes Research Group, Montreal, QC H2X 0A9, Canada
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Dutta P, Kumar Y, Babu AT, Giri Ravindran S, Salam A, Rai B, Baskar A, Dhawan A, Jomy M. Tirzepatide: A Promising Drug for Type 2 Diabetes and Beyond. Cureus 2023; 15:e38379. [PMID: 37265914 PMCID: PMC10231274 DOI: 10.7759/cureus.38379] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2023] [Indexed: 06/03/2023] Open
Abstract
Tirzepatide is a promising drug with dual-acting glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor activation that has revolutionized the treatment of type 2 diabetes mellitus (T2DM) as an adjunct to diet and exercise. In phase 3 clinical trials (SURPASS 1-5), the dose-dependent efficacy and safety of tirzepatide were assessed by once-weekly subcutaneous injection (5 mg, 10 mg, and 15 mg), as monotherapy or combination therapy, in individuals with T2DM. Tirzepatide has been shown to achieve better glycemic control in terms of glycosylated hemoglobin reduction and improved fasting and postprandial glucose levels as compared to other diabetic medications. Moreover, the studies demonstrate a reduction in body weight (-6.2 to -12.9 kg), and other cardiovascular benefits by altering the lipid profile, reducing blood pressure, and visceral adiposity. Tirzepatide has acceptable side effects and is well tolerated, with a low risk of hypoglycemia. The SURPASS 4 clinical trial has shown positive cardiovascular outcomes in people with T2DM and elevated cardiovascular risk. Additionally, encouraging results from SURMOUNT trials and ongoing SURPASS-CVOT studies will shed more light on cardiovascular safety in the future. In this review, we have summarized the clinical trials and their respective outcomes and highlighted the potential future indications for tirzepatide in the management of obesity, heart failure, and nonalcoholic steatohepatitis.
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Affiliation(s)
- Palak Dutta
- General Medicine, Kyiv Medical University, Kyiv, UKR
| | | | - Alexis T Babu
- Medicine, Tbilisi State Medical University, Tbilisi, GEO
| | - Suganya Giri Ravindran
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ajal Salam
- Medicine and Surgery, Government Medical College, Kottayam, IND
| | - Bhumish Rai
- Medicine and Surgery, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences (PGIMS), Rohtak, IND
| | - Aakash Baskar
- Medicine and Surgery, K.A.P. Viswanatham Government Medical College, Tiruchirappalli, IND
| | - Ananya Dhawan
- Medicine and Surgery, Soochow University, Suzhou, CHN
| | - Manjima Jomy
- Medicine and Surgery, Southeast University, Nanjing, CHN
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RoyChaudhuri S, Majumder A, Sanyal D, Chakraborty S, Chuyan S. Early Insight Into the Retrospective Data of a Case Series on Type 2 Diabetes Mellitus on Alternate-Day Dosing of Oral Semaglutide: Utopia or Reality? Cureus 2023; 15:e37065. [PMID: 37153287 PMCID: PMC10155755 DOI: 10.7759/cureus.37065] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2023] [Indexed: 04/05/2023] Open
Abstract
Introduction Oral semaglutide, with a long half-life of seven days, is the first oral-based peptide drug and is used as an antidiabetic for the reduction of glycosylated hemoglobin (HbA1c). Oral semaglutide, like other glucagon-like peptide-1 receptor agonists (GLP1RAs), is costly and has gastrointestinal (GI) side effects, especially with a 14 mg dose. In the real world, some type 2 diabetes mellitus (T2DM) patients on 14 mg oral dose adopt an alternate-day strategy to minimize unwanted GI symptoms. In this study, we analyzed the ambulatory glucose profile (AGP) data of patients with T2DM who were on 14 mg alternate-day oral semaglutide therapy. Methods This retrospective observational study evaluated the AGP data of 10 patients on alternate-day dosing of 14 mg oral semaglutide. The AGP data over a period of 14 days on a single group of patients were analyzed without any control group or randomization and are presented as a case series. AGP monitoring, using Freestyle Libre Pro (Abbott, Illinois, United States), is a standard operating procedure of the endocrinology department for all T2DM patients who were put on oral semaglutide therapy. The AGP data of the glycemic parameters time-in-range (TIR), time-above-range (TAR), and time-below-range (TBR), were compared between the days when oral semaglutide was consumed (days-on-drug) versus the days when oral semaglutide was not consumed (days-off-drug). The statistical analysis was done with Statistical Package for Social Sciences (SPSS) version 21.0 (IBM Corp., Armonk, NY). Results We applied the Shapiro-Wilk test (sample size <50) for normality testing; the TIR values of days-on-drug and days-off-drug showed high p values (p =0.285 and 0.109), respectively. This indicated that TIR values days-on-drug and days-off-drug were normally distributed. Although, the distribution of TAR and TBR values days-on-drug and days-off-drug, were not normal as they had small p values (p< 0.05). Hence, further analysis of the paired set of data was done using the Wilcoxon signed-rank test. It revealed no difference in TIR, TAR, and TBR between the two groups (days-on-drug and days-off-drug). Conclusion Throughout the period of observation, the glycemic metrics (TIR, TAR, and TBR) remained steady with a 14 mg alternate-day oral semaglutide regimen.
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Nouri-Vaskeh M, Khalili N, Khalaji A, Behnam P, Alizadeh L, Ebrahimi S, Gilani N, Mohammadi M, Madinehzadeh SA, Zarei M. Circulating glucagon-like peptide-1 level in patients with liver cirrhosis. Arch Physiol Biochem 2023; 129:373-378. [PMID: 33043692 DOI: 10.1080/13813455.2020.1828479] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1), a gut-derived incretin hormone, plays a pivotal role in glucose-induced insulin secretion. Currently, the role of incretin hormones in the pathogenesis of cirrhosis is not clearly defined. This study aimed to investigate circulating levels of GLP-1 in liver cirrhosis and its association with the severity of liver disease. METHODS A total of 80 participants including 39 patients with a definite diagnosis of liver cirrhosis and 41 healthy controls recruited in this cross-sectional study. Circulating levels of GLP-1 were determined using the ELISA method. The severity of liver cirrhosis was assessed according to the Child-Pugh, MELD (i), MELD-Na, MELD New, and UK end-stage liver disease score (UKELD) criteria. RESULTS The mean age of patients and healthy subjects was 42.51 ± 12.80 and 42.07 ± 10.92 years, respectively (p value = .869). The mean MELD (i), MELD-Na, MELD New, UKELD, and Child-Pugh scores were 14.36 ± 4.26, 15.26 ± 4.81, 14.74 ± 4.66, 52.33 ± 3.82, and 7.28 ± 1.50, respectively. In this study, circulating levels of GLP-1 were statistically lower in cirrhotic patients compared with healthy controls (95.26 ± 17.15 vs 111.84 ± 38.14 pg/mL; p value = .017). CONCLUSION Larger prospective studies are needed to explore the incretin effect in cirrhosis patients compared with healthy individuals.
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Affiliation(s)
- Masoud Nouri-Vaskeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Neda Khalili
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirreza Khalaji
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pouya Behnam
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Alizadeh
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sara Ebrahimi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Gilani
- Department of Statistics and Epidemiology, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Mohammadi
- Department of Biological Science, University of Calgary, Calgary, Canada
- Center for Bioengineering Research and Education, University of Calgary, Calgary, Canada
| | | | - Mohammad Zarei
- Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Contribution of GIP and GLP-1 to the Insulin Response to Oral Administration of Glucose in Female Mice. Biomedicines 2023; 11:biomedicines11020591. [PMID: 36831127 PMCID: PMC9953110 DOI: 10.3390/biomedicines11020591] [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: 01/19/2023] [Revised: 02/09/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023] Open
Abstract
It has previously been shown that the incretin effect accounts for ≈50% of the insulin response to oral glucose in normal mice. Now, I have proceeded and studied the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) to the insulin response to oral glucose in female mice by using receptor antagonists. A specific GIP receptor antagonist (mGIP(3-30); 50 or 500 nmol/kg), a specific GLP-1 receptor antagonist (exendin(9-39); 3 or 30 nmol/kg), the combination of mGIP (500 nmol/kg) and exendin(9-39) (30 nmol/kg), or saline was given intravenously four minutes after administration of glucose (50 mg) through a gastric tube in anesthetized C57/BL6J mice (n = 95) with samples obtained before glucose administration and after 15, 30 and 60 min. The insulinogenic index, determined as the area under the 60 min curve for insulin (AUCinsulin) divided by the AUCglucose, was used to reflect the insulin response. It was found that the insulinogenic index was reduced by 67 ± 4% by mGIP(3-30) (p < 0.001), by 60 ± 14% by exendin(9-39) (p = 0.007) and by 61 ± 14% by the combination of mGIP(3-30) and exendin(9-39) (p = 0.043), both at their highest doses, compared to animals injected with glucose in the same experimental series. It is concluded that both GIP and GLP-1 are required for a normal incretin effect in female mice, that they contribute similarly to the insulin response, and that it is unlikely that there is another incretin hormone in this species.
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Targher G, Mantovani A, Byrne CD. Mechanisms and possible hepatoprotective effects of glucagon-like peptide-1 receptor agonists and other incretin receptor agonists in non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol 2023; 8:179-191. [PMID: 36620987 DOI: 10.1016/s2468-1253(22)00338-7] [Citation(s) in RCA: 65] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/22/2022] [Accepted: 09/29/2022] [Indexed: 01/07/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that stimulate insulin secretion from pancreatic β cells in response to food ingestion. Modified GLP-1 and GIP peptides are potent agonists for their incretin receptors, and some evidence shows that the dual GLP-1 and GIP receptor agonist tirzepatide is effective in promoting marked weight loss. GLP-1 receptor agonists signal in the CNS to suppress appetite, increase satiety, and thereby decrease calorie intake, but many other effects of incretin signalling have been recognised that are relevant to the treatment of non-alcoholic fatty liver disease (NAFLD). This Review provides an overview of the literature supporting the notion that endogenous incretins and incretin-receptor agonist treatments are important not only for decreasing risk of developing NAFLD, but also for treating NAFLD and NAFLD-related complications. We discuss incretin signalling and related incretin-receptor agonist treatments, mechanisms in key relevant tissues affecting liver disease, and clinical data from randomised controlled trials. Finally, we present future perspectives in this rapidly developing field of research and clinical medicine.
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Affiliation(s)
- Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, UK; Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
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Ahn CH, Oh TJ, Min SH, Cho YM. Incretin and Pancreatic β-Cell Function in Patients with Type 2 Diabetes. Endocrinol Metab (Seoul) 2023; 38:1-9. [PMID: 36781163 PMCID: PMC10008660 DOI: 10.3803/enm.2023.103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 01/30/2023] [Indexed: 02/15/2023] Open
Abstract
To maintain normal glucose homeostasis after a meal, it is essential to secrete an adequate amount of insulin from pancreatic β-cells. However, if pancreatic β-cells solely depended on the blood glucose level for insulin secretion, a surge in blood glucose levels would be inevitable after the ingestion of a large amount of carbohydrates. To avoid a deluge of glucose in the bloodstream after a large carbohydrate- rich meal, enteroendocrine cells detect the amount of nutrient absorption from the gut lumen and secrete incretin hormones at scale. Since insulin secretion in response to incretin hormones occurs only in a hyperglycemic milieu, pancreatic β-cells can secrete a "Goldilocks" amount of insulin (i.e., not too much and not too little) to keep the blood glucose level in the normal range. In this regard, pancreatic β-cell sensitivity to glucose and incretin hormones is crucial for maintaining normal glucose homeostasis. In this Namgok lecture 2022, we review the effects of current anti-diabetic medications on pancreatic β-cell sensitivity to glucose and incretin hormones.
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Affiliation(s)
- Chang Ho Ahn
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Tae Jung Oh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Se Hee Min
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Corresponding author: Young Min Cho. Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-1965, Fax: +82-2-2072-7246, E-mail:
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Wan W, Qin Q, Xie L, Zhang H, Wu F, Stevens RC, Liu Y. GLP-1R Signaling and Functional Molecules in Incretin Therapy. Molecules 2023; 28:751. [PMID: 36677809 PMCID: PMC9866634 DOI: 10.3390/molecules28020751] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/05/2023] [Accepted: 01/06/2023] [Indexed: 01/14/2023] Open
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). The GLP-1R cellular signaling mechanism relevant to insulin secretion and blood glucose regulation has been extensively studied. Numerous drugs targeting GLP-1R have entered clinical treatment. However, novel functional molecules with reduced side effects and enhanced therapeutic efficacy are still in high demand. In this review, we summarize the basis of GLP-1R cellular signaling, and how it is involved in the treatment of T2DM. We review the functional molecules of incretin therapy in various stages of clinical trials. We also outline the current strategies and emerging techniques that are furthering the development of novel therapeutic drugs for T2DM and other metabolic diseases.
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Affiliation(s)
- Wenwei Wan
- iHuman Institute, ShanghaiTech University, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Qikai Qin
- iHuman Institute, ShanghaiTech University, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Linshan Xie
- iHuman Institute, ShanghaiTech University, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Hanqing Zhang
- iHuman Institute, ShanghaiTech University, Shanghai 201210, China
| | - Fan Wu
- Structure Therapeutics, South San Francisco, CA 94080, USA
| | - Raymond C. Stevens
- iHuman Institute, ShanghaiTech University, Shanghai 201210, China
- Structure Therapeutics, South San Francisco, CA 94080, USA
| | - Yan Liu
- iHuman Institute, ShanghaiTech University, Shanghai 201210, China
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Kimita W, Bharmal SH, Ko J, Petrov MS. Identifying endotypes of individuals after an attack of pancreatitis based on unsupervised machine learning of multiplex cytokine profiles. Transl Res 2023; 251:54-62. [PMID: 35863673 DOI: 10.1016/j.trsl.2022.07.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/30/2022] [Accepted: 07/08/2022] [Indexed: 02/09/2023]
Abstract
After an attack of pancreatitis, individuals may develop metabolic sequelae (eg, new-onset diabetes) and/or pancreatic cancer. These new-onset morbidities are, at least in part, driven by low-grade inflammation. The aim was to study the profiles of cytokines/chemokines in individuals after an attack of pancreatitis. A commercially available panel including 31 cytokines/chemokines was investigated. Random forest classifier and unsupervised hierarchical clustering were applied to study participants (who had no persistent organ failure and did not require ICU admission) according to their cytokine/chemokine profiles. Pancreatitis-related characteristics, detailed body composition (determined using 3.0 T magnetic resonance imaging), markers of glucose, lipid, and iron metabolism, gut and pancreatic hormones, as well as liver and pancreatic enzymes, were compared between clusters. Bootstrap validation was employed. A total of 160 participants, including 107 postpancreatitis individuals (investigated at a median of 18 months after the last attack of pancreatitis) and 53 healthy volunteers, were studied. Twenty-two cytokines/chemokines were significantly different between postpancreatitis and health. Two distinct endotypes of individuals after an attack of pancreatitis were identified-‟inflammatory" and ‟noninflammatory." Sixteen cytokines/chemokines were significantly higher in the inflammatory endotype compared with the noninflammatory endotype. No cytokine/chemokine was significantly higher in the noninflammatory endotype. The inflammatory endotype was characterized by significantly elevated insulin (P= 0.001), glucose-dependent insulinotropic peptide (P = 0.001), peptide YY (P = 0.017), and ghrelin (P = 0.014). The noninflammatory endotype was characterized by significantly elevated hepcidin (P= 0.016). Pancreatitis-related factors, body composition, and other studied parameters did not differ significantly between the 2 endotypes. Individuals with a similar phenotype and clinical course of pancreatitis have differing cytokine/chemokine profiles after clinical resolution of the disease. People with the inflammatory endotype have distinct changes in the pancreatic and gut hormones known to be involved in the pathogenesis of new-onset morbidities after an attack of pancreatitis.
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Affiliation(s)
- Wandia Kimita
- School of Medicine, University of Auckland, Auckland, New Zealand
| | - Sakina H Bharmal
- School of Medicine, University of Auckland, Auckland, New Zealand
| | - Juyeon Ko
- School of Medicine, University of Auckland, Auckland, New Zealand
| | - Maxim S Petrov
- School of Medicine, University of Auckland, Auckland, New Zealand.
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Wong E, Cope R, Dima L, Nguyen T. Tirzepatide: A Dual Glucose-dependent Insulinotropic Polypeptide and Glucagon-Like Peptide-1 Agonist for the Management of Type 2 Diabetes Mellitus. Am J Ther 2023; 30:e26-e35. [PMID: 36516422 DOI: 10.1097/mjt.0000000000001588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 11/07/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Diabetes is a chronic disease that can lead to many complications, and controlling glucose balance is essential. Incretin hormones are produced in the gut and are essential to maintaining glucose homeostasis. Their effects range from increasing insulin synthesis, insulin secretion, and glucose sensing and decreasing glucagon secretion to promote satiety and suppressing appetite. Tirzepatide is a first in class dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP) analog approved for the management of adult patients with type 2 diabetes mellitus as an adjunct to diet and exercise. PHARMACODYNAMICS AND PHARMACOKINETICS Tirzepatide is a synthetic chemical structure based on the GIP sequence and consists of 39 amino acid peptides. Tirzepatide increases insulin secretion, reduces glucagon release in a glucose-dependent manner, decreases fasting and postprandial glucose levels, promotes satiety, decreases body weight, and delays gastric emptying. Pharmacodynamics and pharmacokinetics properties of tirzepatide were similar in patients with kidney and hepatic impairment, and its metabolites are excreting through urine and feces. CLINICAL TRIALS The SURPASS trials are pivotal phase 3 trials assessing the efficacy and safety of tirzepatide as monotherapy and as an add-on to different antihyperglycemic drugs for the management of T2DM. Tirzepatide consistently showed reductions in HbA1c, as well as benefits with weight loss, with common adverse events reported related to gastrointestinal issues. THERAPEUTIC ADVANCE Tirzepatide is a novel first in class dual GIP and glucagon-like peptide-1 agonist that improves overall glycemic control as an adjunct to diet and exercise. It has the potential benefits in other therapeutic areas such as obesity.
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Affiliation(s)
- Elaine Wong
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY; and
| | - Rebecca Cope
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY; and
| | - Lorena Dima
- Transilvania University of Brasov, Romania, Faculty of Medicine, Department of Fundamental Disciplines and Clinical Prevention, Brasov, Romania
| | - Timothy Nguyen
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY; and
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Luo P, Fan Y, Xiong Y, Feng H, Yang Z, Zhang C, Mei B. Genetic variants of the GLP-1R gene affect the susceptibility and glucose metabolism of gestational diabetes mellitus: a two-center nested case‒control study. Diabetol Metab Syndr 2022; 14:190. [PMID: 36528605 PMCID: PMC9759872 DOI: 10.1186/s13098-022-00963-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is the most common complication during pregnancy, occurring under the combined action of environmental and genetic factors. Genetic variants of glucagon-like peptide-1 receptor (GLP-1R) have been reported to affect insulin secretion and susceptibility to type 2 diabetes. This study aimed to explore the role of GLP-1R polymorphisms in GDM and glucose metabolism. METHODS A two-center nested case‒control study was designed, including 200 pregnant women with GDM and 200 pregnant women without GDM genotyped for five tag SNPs of GLP-1R using Sanger sequencing. Logistic regression was used to evaluate the relationship between GLP-1R polymorphisms and GDM risk. Glucose and insulin concentrations were measured based upon the 75 g oral glucose tolerance test (OGTT). Beta cell function of different genotypes was estimated with the 60 min insulinogenic index (IGI60) and OGTT-derived disposition index (DI). RESULTS Mutant genotype AG + GG of tag SNP rs6458093 nominally increased GDM risk (p = 0.049), especially among subjects younger than 35 years (p = 0.024) and with BMI no less than 24 (p = 0.041), after adjusting for confounders. Meanwhile, compared with subjects with wild genotype AA, subjects with genotype AG + GG of rs6458093 also showed nominally significantly lower IGI60 (p = 0.032) and DI (p = 0.029), as well as significantly higher 75 g OGTT-based 1 h glucose load plasma glucose levels (p = 0.045). Moreover, the mutant heterozygous genotype GA of tag SNP rs3765467 nominally decreased GDM risk among subjects older than 35 years (p = 0.037) but showed no association with insulin secretion and glucose homeostasis. CONCLUSIONS Tag SNP rs6458093 of GLP-1R was nominally associated with increased GDM risk and affected beta cell function and postprandial glucose metabolism, while tag SNP rs3765467 of GLP-1R was nominally associated with decreased GDM risk, providing evidence for molecular markers and etiological study of GDM.
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Affiliation(s)
- Ping Luo
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, 434020, China
| | - Ying Fan
- Gongan County Maternal and Child Health Care Hospital, Jingzhou, 434300, China
| | - Yusha Xiong
- Gongan County Maternal and Child Health Care Hospital, Jingzhou, 434300, China
| | - Hua Feng
- Gongan County Maternal and Child Health Care Hospital, Jingzhou, 434300, China
| | - Zhiping Yang
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, 434020, China
| | - Chunlin Zhang
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, 434020, China
| | - Bing Mei
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, 434020, China.
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Szoke D, Robbiano C, Dolcini R, Montefusco L, Aiello GB, Caruso S, Ottolenghi A, Birindelli S, Panteghini M. Incidence and status of insulin secretion in pregnant women with flat plasma glucose profiles during oral glucose tolerance test. Clin Biochem 2022; 109-110:23-27. [PMID: 36041500 DOI: 10.1016/j.clinbiochem.2022.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 06/30/2022] [Accepted: 08/25/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Flat shaped glucose curves (FC) during oral glucose tolerance test (OGTT) in pregnant women (PW) are a not uncommon finding. We aimed to define the FC incidence in a large PW cohort and to describe the status of insulin and C-peptide secretion in women with FC when compared with a well-matched control group. METHODS 1050 PW performing OGTT for gestational diabetes screening were enrolled. An increase <6 % in plasma glucose (PG) during OGTT defined a FC. Serum samples for measuring insulin and C-peptide were also obtained. RESULTS 61 (5.8 %) women showed a FC. 60 of them, paired to a group of 60 no-FC women matched for age, body mass index and gestational age, were further investigated. C-peptide and insulin concentrations were significantly lower (P < 0.001) in FC in both 1-h and 2-h OGTT samples. When incremental area under the curves (AUC) normalized to PG were estimated, only AUCinsulin remained however significantly lower. The insulin sensitivity index was higher in FC. CONCLUSIONS PW with FC showed a hypersensitivity to insulin with normal β-cell function. Moreover, a delayed glucose absorption could be hypothesised because of the slight but continuously increasing shape of insulin curve found in FC group. Both phenomena could occur in parallel and contribute to FC.
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Affiliation(s)
- Dominika Szoke
- UOC Patologia Clinica, ASST Fatebenefratelli-Sacco, Milano, Italy.
| | | | - Roberta Dolcini
- UOC Patologia Clinica, ASST Fatebenefratelli-Sacco, Milano, Italy
| | - Laura Montefusco
- UOC Endocrinologia e Diabetologia, ASST Fatebenefratelli-Sacco, Milano, Italy
| | | | - Simone Caruso
- UOC Patologia Clinica, ASST Fatebenefratelli-Sacco, Milano, Italy
| | - Anna Ottolenghi
- UOC Patologia Clinica, ASST Fatebenefratelli-Sacco, Milano, Italy
| | - Sarah Birindelli
- UOC Patologia Clinica, ASST Fatebenefratelli-Sacco, Milano, Italy
| | - Mauro Panteghini
- UOC Patologia Clinica, ASST Fatebenefratelli-Sacco, Milano, Italy; Dipartimento di Scienze Biomediche e Cliniche "Luigi Sacco", Università degli Studi, Milano, Italy
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Shah A, Prasad M, Mark V, Holst JJ, Laferrère B. Glucagon-like peptide-1 effect on β-cell function varies according to diabetes remission status after Roux-en-Y gastric bypass. Diabetes Obes Metab 2022; 24:2081-2089. [PMID: 35676799 PMCID: PMC9595602 DOI: 10.1111/dom.14793] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/20/2022] [Accepted: 06/01/2022] [Indexed: 11/30/2022]
Abstract
AIMS The contribution of endogenous glucagon-like peptide (GLP)-1 to β-cell function after Roux-en-Y gastric bypass surgery (RYGB) is well established in normoglycaemic individuals, but not in those with postoperative hyperglycaemia. We, therefore, studied the effect of GLP-1 on β-cell function in individuals with varying degrees of type 2 diabetes mellitus (T2D) control after RYGB. MATERIALS AND METHODS Glucose, insulin secretion rates, β-cell glucose sensitivity and glucagon were measured during an oral glucose tolerance test before (saline only) and at 3, 12 and 24 months after RYGB with and without infusion of the GLP-1 receptor blocker exendin9-39 (EX9). The cohort was retrospectively classified based on T2D remission (REM) status at the latest study time point: REM (n = 5), persistent T2D (n = 8), or impaired glucose tolerance (n = 16). RESULTS EX9 blunted the increase in β-cell glucose sensitivity at 3 months (-44.1%, p < .001) and 12 months (-43.3%, p < .001), but not at 24 months (-12.4%, p = .243). EX9 enhanced postprandial glucagon concentrations by 62.0% at 3 months (p = .008), 46.5% at 12 months (p = .055), and 30.4% at 24 months (p = .017). EX9 counterintuitively decreased glucose concentrations at 3 months in the entire cohort (p < .001) but had no effect on glycaemia at 12 and 24 months in persistent T2D and impaired glucose tolerance; it minimally worsened glycaemia in REM at 12 months. CONCLUSIONS GLP-1 blockade reversed the improvement in β-cell function observed after RYGB, but this effect varied temporally and by REM status. GLP-1 blockade transiently and minimally worsened glycaemia only in REM, and lowered postprandial glucose values at 3 months, regardless of REM status.
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Affiliation(s)
- Ankit Shah
- Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA
| | - Malini Prasad
- New York Obesity Nutrition Research Center, Division of Endocrinology. Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Victoria Mark
- New York Obesity Nutrition Research Center, Division of Endocrinology. Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Blandine Laferrère
- Division of Endocrinology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
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