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Ninomiya K, Yamaguchi Y, Matsubara N, Kumagai H. Effects of Cereal-Derived Proteins and Peptides on Blood Glucose Levels. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025. [PMID: 40381191 DOI: 10.1021/acs.jafc.4c13168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
Some cereal proteins and their digestive peptides exhibit the potential to regulate blood glucose levels, which is important for the management of diabetes and its complications. Proteins in common grains, such as wheat and buckwheat, and in legumes, such as kidney beans and soybeans, contain proteinaceous α-amylase inhibitors (α-AIs) that inhibit the breakdown of starch into reducing sugars, thereby mitigating postprandial glucose spikes. Indigestible cereal proteins function similarly to dietary fibers by adsorbing glucose and facilitating its excretion and stabilizing blood glucose levels. Moreover, peptides derived from these proteins can suppress glucose transporter expression in the intestine, thereby reducing glucose absorption. They also promote insulin secretion by inhibiting dipeptidyl peptidase-IV (DPP-IV), an enzyme that breaks down incretin hormones. Collectively, these properties highlight the potential of cereal proteins and peptides in functional foods for blood glucose management.
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Affiliation(s)
- Kazumi Ninomiya
- Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan
| | - Yusuke Yamaguchi
- College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880, Japan
| | - Nao Matsubara
- College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880, Japan
| | - Hitomi Kumagai
- College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880, Japan
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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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Qu Y, An K, Wang D, Yu H, Li J, Min Z, Xiong Y, Xue Z, Mao Z. Short-Chain Fatty Acid Aggregates Alpha-Synuclein Accumulation and Neuroinflammation via GPR43-NLRP3 Signaling Pathway in a Model Parkinson's Disease. Mol Neurobiol 2025; 62:6612-6625. [PMID: 39904963 DOI: 10.1007/s12035-025-04726-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 01/27/2025] [Indexed: 02/06/2025]
Abstract
Parkinson's disease (PD) is characterized by the aggregation of α-synuclein (α-syn) and the loss of dopaminergic (DA) neurons, with growing evidence suggesting a significant role of gut microbiota and their metabolites in the disease's pathogenesis. This study explores the effects of short-chain fatty acids (SCFAs) on PD progression, focusing on the G protein-coupled receptor 43 (GPR43) and the NLRP3 signaling pathway in both in vitro and in vivo models. Employing the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model and SH-SY5Y cells with SCFAs-treated, this study investigated the impact of SCFAs on α-syn deposition, DA loss, and neuroinflammation. In vitro, supernatant from STC-1 cells was administered to SH-SY5Y cells, and the effects were assessed following the knockdown of NLRP3 or GPR43. In vivo, mice were treated with NLRP3 or GPR43 inhibitors after feeding with SCFAs, and the motor deficits, α-syn pathology, DA neuronal loss, and inflammatory responses were observed. SCFAs were found to exacerbate motor and gastrointestinal dysfunctions in PD models, intensifying α-syn pathology and neuroinflammation. The activation of the NLRP3 inflammasome through GPR43 emerged as a key pathological mechanism, with inhibition of these molecules mitigating the observed effects. Such interventions reduced α-syn accumulation, DA loss, and inflammatory responses, highlighting the pivotal role of the SCFA/GPR43-NLRP3 pathway in PD. The findings from this study elucidate a critical link between gut-derived metabolic changes and neuroinflammatory processes in PD via the SCFA/GPR43-NLRP3 pathway. Targeting this pathway offers a promising therapeutic strategy and enriches our understanding of the gut-brain axis' role in PD progression.
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Affiliation(s)
- Yi Qu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ke An
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Danlei Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Haoheng Yu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jingyi Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhe Min
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yongjie Xiong
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zheng Xue
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhijuan Mao
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Vaezijoze S, Irani S, Siadat SD, Zali M. Modulation of satiety hormones by Bacteroides thetaiotaomicron, Bacteroides fragilis and their derivatives. AMB Express 2025; 15:41. [PMID: 40044987 PMCID: PMC11883081 DOI: 10.1186/s13568-025-01852-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/18/2025] [Indexed: 03/09/2025] Open
Abstract
Obesity is a complex disorder influenced by various factors, including gut microbiota, which play a crucial role in metabolic regulation. This study is aimed to investigate the effects of Bacteroides thetaiotaomicron and Bacteroides fragilis, along with their derivatives-outer membrane vesicles (OMVs) and cell-free supernatant (CFS)-on the expression and secretion of satiety hormones in the murine intestinal secretin tumor cell line (STC-1). We examined the expression of peptide YY (PYY), glucagon-like peptide-1 and -2 (GLP-1 and GLP-2, encoded by the GCG gene), the enzyme prohormone convertase-1 (PC1/PCSK1 gene), and the receptors G protein-coupled receptor 119 and 120 (GPR119 and GPR120), and G-protein-coupled bile acid receptor (TGR5). Our results demonstrate that live B. fragilis significantly increased PYY expression and secretion. B. thetaiotaomicron CFS notably upregulated GCG, PCSK1, GPR119, GPR120, and TGR5 expression, leading to elevated GLP-1 secretion. B. fragilis CFS decreased GPR119, GPR120, and GCG expression. OMVs from B. thetaiotaomicron at 50 µg/ml significantly enhanced GCG and PCSK1 expression, while B. fragilis OMVs generally decreased gene expression, except for PYY protein abundance. Inactive B. thetaiotaomicron and B. fragilis increased GCG mRNA levels and GLP-1 concentration, with inactive B. fragilis also elevating GLP-2 protein levels.This study suggests that B. thetaiotaomicron and its derivatives, particularly CFS and OMVs, have potential as next-generation probiotics, postbiotics, and paraprobiotics for modulating satiety hormones and managing obesity. Further research is warranted to explore their mechanisms and therapeutic applications in vivo.
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Affiliation(s)
- Somayeh Vaezijoze
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Shiva Irani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Seyed Davar Siadat
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran.
| | - Mohammadreza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Gorecki AM, Anyaegbu CC, Fitzgerald M, Fuller KA, Anderton RS. Imaging flow cytometry reveals LPS-induced changes to intracellular intensity and distribution of α-synuclein in a TLR4-dependent manner in STC-1 cells. Methods 2025; 234:93-111. [PMID: 39486562 DOI: 10.1016/j.ymeth.2024.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 10/15/2024] [Accepted: 10/18/2024] [Indexed: 11/04/2024] Open
Abstract
BACKGROUND Parkinson's disease is a chronic neurodegenerative disorder, where pathological protein aggregates largely composed of phosphorylated α-synuclein are implicated in disease pathogenesis and progression. Emerging evidence suggests that the interaction between pro-inflammatory microbial factors and the gut epithelium contributes to α-synuclein aggregation in the enteric nervous system. However, the cellular sources and mechanisms for α-synuclein pathology in the gut are still unclear. METHODS The STC-1 cell line, which models an enteroendocrine population capable of communicating with the gut microbiota, immune and nervous systems, was treated with a TLR4 inhibitor (TAK-242) prior to microbial lipopolysaccharide (LPS) exposure to investigate the role of TLR4 signalling in α-synuclein alterations. Antibodies targeting the full-length protein (α-synuclein) and the Serine-129 phosphorylated form (pS129) were used. Complex, multi-parametric image analysis was conducted through confocal microscopy (with Zen 3.8 analysis) and imaging flow cytometry (with IDEAS® analysis). RESULTS Confocal microscopy revealed heterogenous distribution of α-synuclein and pS129 in STC-1 cells, with prominent pS129 staining along cytoplasmic processes. Imaging flow cytometry further quantified the relationship between various α-synuclein morphometric features. Thereafter, imaging flow cytometry demonstrated a dose-specific effect of LPS, where the low (8 μg/mL), but not high dose (32 μg/mL), significantly altered measures related to α-synuclein intensity, distribution, and localisation. Pre-treatment with a TLR4 inhibitor TAK-242 alleviated some of these significant alterations. CONCLUSION This study demonstrates that LPS-TLR4 signalling alters the intracellular localisation of α-synuclein in enteroendocrine cells in vitro and showcases the utility of combining imaging flow cytometry to investigate subtle protein changes that may not be apparent through confocal microscopy alone. Further investigation is required to understand the apparent dose-dependent effects of LPS on α-synuclein in the gut epithelium in healthy states as well as conditions such as Parkinson's disease.
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Affiliation(s)
- Anastazja M Gorecki
- School of Health Sciences, University of Notre Dame Australia, Fremantle, WA, Australia; Curtin Health Innovation Research Institute, Curtin University, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia; Perron Institute for Neurological and Translational Science, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia; School of Biological Sciences, University of Western Australia, Crawley, WA, Australia.
| | - Chidozie C Anyaegbu
- Curtin Health Innovation Research Institute, Curtin University, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia; Perron Institute for Neurological and Translational Science, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia
| | - Melinda Fitzgerald
- Curtin Health Innovation Research Institute, Curtin University, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia; Perron Institute for Neurological and Translational Science, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia
| | - Kathryn A Fuller
- Translational Cancer Pathology Laboratory, School of Biomedical Sciences (M504), The University of Western Australia, Crawley, WA, Australia
| | - Ryan S Anderton
- School of Health Sciences, University of Notre Dame Australia, Fremantle, WA, Australia
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Yang K, Wu YT, He Y, Dai JX, Luo YL, Xie JH, Ding WJ. GLP-1 and IL-6 regulates obesity in the gut and brain. Life Sci 2025; 362:123339. [PMID: 39730038 DOI: 10.1016/j.lfs.2024.123339] [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: 09/17/2024] [Revised: 11/06/2024] [Accepted: 12/23/2024] [Indexed: 12/29/2024]
Abstract
Obesity is a chronic metabolic disease characterized by excessive nutrient intake leading to increased subcutaneous or visceral fat, resulting in pathological and physiological changes. The incidence rate of obesity, an important form of metabolic syndrome, is increasing worldwide. Excess appetite is a key pathogenesis of obesity, and the inflammatory response induced by obesity has received increasing attention. This review focuses on the role of appetite-regulating factor (Glucogan-like peptide 1) and inflammatory factor (Interleukin-6) in the gut and brain in individuals with obesity and draws insights from the current literature.
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Affiliation(s)
- Kun Yang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yu-Ting Wu
- Chengdu University of Traditional Chinese Medicine, 1166 Luitai Avenue, Chengdu, Sichuan 611137, China
| | - Yan He
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jin-Xiu Dai
- Chengdu University of Traditional Chinese Medicine, 1166 Luitai Avenue, Chengdu, Sichuan 611137, China
| | - Yu-Lu Luo
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jing-Hui Xie
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Wei-Jun Ding
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Chen X, Chu F, Sunchen S, Li J, Zhang M, Xu F, Dong H. TRPV4 couples with NCX1 to mediate glucose-dependent glucagon-like peptide-1 release and improve glucose homeostasis. J Physiol 2024; 602:6827-6847. [PMID: 39573816 DOI: 10.1113/jp287092] [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: 06/12/2024] [Accepted: 10/30/2024] [Indexed: 12/18/2024] Open
Abstract
Although glucose, as a secretagogue of intestinal hormone, can stimulate glucagon-like peptide 1 (GLP-1) release, it has not been fully elucidated how glucose triggers GLP-1 release from enteroendocrine cells (EECs). Here, we investigated the regulatory mechanisms of glucose-induced Ca2+-dependent GLP-1 release from EECs. STC-1 cells that possess many features of native intestinal EECs were used. The expression of TRPV4 channels and Na+/Ca2+ exchanger 1 (NCX1) in STC-1 was analysed by immunocytochemistry. Calcium and sodium imaging, and patch clamp were applied, and GLP-1 was detected using quantitative PCR, western blot and enzyme-linked immunosorbent assays. Glucose markedly induced Na+ and Ca2+ signalling in STC-1 cells. The glucose-induced Ca2+ signalling was significantly attenuated by selective blockers of the voltage-gated Ca2+ channels (VGCC), ryanodine receptors and InsP3 receptors. Most importantly, glucose-induced Ca2+ signalling was significantly attenuated by the selective blockers of TRPV4 and NCX1. Moreover, the physical and functional couplings of TRPV4 and NCX1 were demonstrated in STC-1 cells, and they promoted glucose-mediated Ca2+ signalling to upregulate expression and release of GLP-1 via Ca2+-sensitive PKCα. Finally, the selective TRPV4 activator improved glucose tolerance in an oral glucose tolerance test in mice, but the selective blockers of TRPV4 and NCX1 attenuated glucose-induced intestinal GLP-1 release. We demonstrate a coupling of TRPV4 and NCX1 in EECs to regulate glucose-stimulated intestinal GLP-1 release via a novel TRPV4/NCX1/Ca2+/PKCα axis. Targeting this axis may provide new therapeutic potentials for glycometabolic diseases. KEY POINTS: Glucagon-like peptide 1 (GLP-1) secreted primarily from intestinal L cells in response to meals plays a critical role in maintaining glucose homeostasis. Physical and functional couplings of TRPV4 and NCX1 are pivotal in glucose-stimulated GLP-1 release via a novel TRPV4/NCX1/Ca2+/PKCα axis. Since this axis is involved in glucose homeostasis, our findings may provide new potential drug targets for prevention/treatment of glycometabolic diseases.
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Affiliation(s)
- Xiongying Chen
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Fenglan Chu
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Sijin Sunchen
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China
| | - Junhui Li
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Mengting Zhang
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China
| | - Feng Xu
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Hui Dong
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China
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Ryu GR, Bae D, Uddin S, Meah MS, Ahmad W, Silvano KJ, Ahn G, Cha JY, Lee E, Song KH, Kim WY, Kim MG. Effect of transcription factor MEOX on insulin gene expression in glucagon-like peptide 1-secreting cells. In Vitro Cell Dev Biol Anim 2024; 60:1099-1108. [PMID: 39138833 DOI: 10.1007/s11626-024-00964-6] [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: 06/07/2024] [Accepted: 07/31/2024] [Indexed: 08/15/2024]
Abstract
Currently, the supply of beta cells for islet transplantation in the treatment of type 1 diabetes is limited. Enteroendocrine cells (EECs) are believed to have high potential as stem cells because they share significant developmental similarities with beta cells. In a previous study, we derived EEC cells that secrete individual gut hormones from STC-1 cells. This study aimed to examine intestinal hormone secretion and expression, investigate the expression of developmental-related transcription factors, and analyze the effect of MEOX on insulin gene expression in isolated EECs. The expression and secretion of enteroendocrine hormones were evaluated in L6 and K34 cells from STC-1 cells. Expression patterns of beta cell- and development-related genes in L6 and K34 cells were compared with beta cells. Comparisons of the MEOX-induced expression of Ins in beta cells and GLP-1-secreting cells were investigated. Both L6 and K34 cells predominantly expressed Glp1 and Gip, respectively. The secretion pattern of GLP-1 in L6 cells was similar to that of GLUTag cells. Previous microarray analysis confirmed MEOX as developmentally relevant transcription factors expressed in beta cells. Overexpression of MEOX showed a tendency to increase Ins expression in L6 and GLUTag cells, but not in MIN6 cells. However, when PDX1 and MEOX were co-expressed in GLUTag cells, insulin expression was suppressed, similar to that observed in MIN6 cells. These findings suggest a potential role for MEOX in regulating the expression of the Ins gene in both beta cells and GLP-1-secreting cells. Further studies are warranted to elucidate the underlying mechanism.
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Affiliation(s)
- Gyeong Ryul Ryu
- College of Pharmacy and Research Institute of Pharmaceutical Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Dongryeoul Bae
- College of Pharmacy and Research Institute of Pharmaceutical Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Shahab Uddin
- College of Pharmacy and Research Institute of Pharmaceutical Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
- Division of Applied Life Science (BK21 Four), Institute of Agricultural and Life Science, Plant Molecular Biology and Biotechnology Research Center, Plant Biological Rhythm Research Center, Research Institute of Life Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Mohammed Sohel Meah
- College of Pharmacy and Research Institute of Pharmaceutical Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Waqas Ahmad
- College of Pharmacy and Research Institute of Pharmaceutical Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Kris John Silvano
- College of Pharmacy and Research Institute of Pharmaceutical Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Gyeongik Ahn
- Division of Applied Life Science (BK21 Four), Institute of Agricultural and Life Science, Plant Molecular Biology and Biotechnology Research Center, Plant Biological Rhythm Research Center, Research Institute of Life Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Joon-Yung Cha
- Division of Applied Life Science (BK21 Four), Institute of Agricultural and Life Science, Plant Molecular Biology and Biotechnology Research Center, Plant Biological Rhythm Research Center, Research Institute of Life Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Esder Lee
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ki-Ho Song
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Woe-Yeon Kim
- Division of Applied Life Science (BK21 Four), Institute of Agricultural and Life Science, Plant Molecular Biology and Biotechnology Research Center, Plant Biological Rhythm Research Center, Research Institute of Life Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Min Gab Kim
- College of Pharmacy and Research Institute of Pharmaceutical Science, Gyeongsang National University, Jinju, 52828, Republic of Korea.
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Sharma R, Raza GS, Sodum N, Walkowiak J, Herzig KH. Effect of hypoxia on GLP-1 secretion - an in vitro study using enteroendocrine STC-1 -cells as a model. Pflugers Arch 2024; 476:1613-1621. [PMID: 39075239 PMCID: PMC11381484 DOI: 10.1007/s00424-024-02996-z] [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: 05/22/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 07/31/2024]
Abstract
Glucagon-like peptide (GLP)-1 is a hormone released by enteroendocrine L-cells after food ingestion. L-cells express various receptors for nutrient sensing including G protein-coupled receptors (GPRs). Intestinal epithelial cells near the lumen have a lower O2 tension than at the base of the crypts, which leads to hypoxia in L-cells. We hypothesized that hypoxia affects nutrient-stimulated GLP-1 secretion from the enteroendocrine cell line STC-1, the most commonly used model. In this study, we investigated the effect of hypoxia (1% O2) on alpha-linolenic acid (αLA) stimulated GLP-1 secretion and their receptor expressions. STC-1 cells were incubated for 12 h under hypoxia (1% O2) and treated with αLA to stimulate GLP-1 secretion. 12 h of hypoxia did not change basal GLP-1 secretion, but significantly reduced nutrient (αLA) stimulated GLP-1 secretion. In normoxia, αLA (12.5 μM) significantly stimulated (~ 5 times) GLP-1 secretion compared to control, but under hypoxia, GLP-1 secretion was reduced by 45% compared to normoxia. αLA upregulated GPR120, also termed free fatty acid receptor 4 (FFAR4), expressions under normoxia as well as hypoxia. Hypoxia downregulated GPR120 and GPR40 expression by 50% and 60%, respectively, compared to normoxia. These findings demonstrate that hypoxia does not affect the basal GLP-1 secretion but decreases nutrient-stimulated GLP-1 secretion. The decrease in nutrient-stimulated GLP-1 secretion was due to decreased GPR120 and GPR40 receptors expression. Changes in the gut environment and inflammation might contribute to the hypoxia of the epithelial and L-cells.
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Affiliation(s)
- Ravikant Sharma
- Research Unit of Biomedicine and Internal Medicine, Biocenter of Oulu, Medical Research Center, University of Oulu, Aapistie 5, 90220, Oulu, Finland
| | - Ghulam Shere Raza
- Research Unit of Biomedicine and Internal Medicine, Biocenter of Oulu, Medical Research Center, University of Oulu, Aapistie 5, 90220, Oulu, Finland
| | - Nalini Sodum
- Research Unit of Biomedicine and Internal Medicine, Biocenter of Oulu, Medical Research Center, University of Oulu, Aapistie 5, 90220, Oulu, Finland
| | - Jaroslaw Walkowiak
- Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, 60572, Poznań, Poland
| | - Karl-Heinz Herzig
- Research Unit of Biomedicine and Internal Medicine, Biocenter of Oulu, Medical Research Center, University of Oulu, Aapistie 5, 90220, Oulu, Finland.
- Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, 60572, Poznań, Poland.
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Yuan YC, Wang H, Jiang ZJ, Liu C, Li Q, Zhou SR, Yang JK. Potassium voltage-gated channel subfamily H member 2 (KCNH2) is a promising target for incretin secretagogue therapies. Signal Transduct Target Ther 2024; 9:207. [PMID: 39128897 PMCID: PMC11317495 DOI: 10.1038/s41392-024-01923-z] [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: 11/20/2023] [Revised: 06/16/2024] [Accepted: 07/14/2024] [Indexed: 08/13/2024] Open
Abstract
Derived from enteroendocrine cells (EECs), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are pivotal incretin hormones crucial for blood glucose regulation. Medications of GLP-1 analogs and GLP-1 receptor activators are extensively used in the treatment of type 2 diabetes (T2D) and obesity. However, there are currently no agents to stimulate endogenous incretin secretion. Here, we find the pivotal role of KCNH2 potassium channels in the regulation of incretin secretion. Co-localization of KCNH2 with incretin-secreting EECs in the intestinal epithelium of rodents highlights its significance. Gut epithelial cell-specific KCNH2 knockout in mice improves glucose tolerance and increases oral glucose-triggered GLP-1 and GIP secretion, particularly GIP. Furthermore, KCNH2-deficient primary intestinal epithelial cells exhibit heightened incretin, especially GIP secretion upon nutrient stimulation. Mechanistically, KCNH2 knockdown in EECs leads to reduced K+ currents, prolonged action potential duration, and elevated intracellular calcium levels. Finally, we found that dofetilide, a KCNH2-specific inhibitor, could promote incretin secretion in enteroendocrine STC-1 cells in vitro and in hyperglycemic mice in vivo. These findings elucidate, for the first time, the mechanism and application of KCNH2 in regulating incretin secretion by EECs. Given the therapeutic promise of GLP-1 and GIP in diabetes and obesity management, this study advances our understanding of incretin regulation, paving the way for potential incretin secretagogue therapies in the treatment of diabetes and obesity.
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Affiliation(s)
- Ying-Chao Yuan
- Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China
| | - Hao Wang
- Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
| | - Ze-Ju Jiang
- Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China
| | - Chang Liu
- Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Qi Li
- Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China
| | - Si-Rui Zhou
- Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China
| | - Jin-Kui Yang
- Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
- Subcenter of State Key Laboratory of Kidney Disease, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
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11
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Bhattacharyya S, Borthakur A, Tobacman JK. Common food additive carrageenan inhibits proglucagon expression and GLP-1 secretion by human enteroendocrine L-cells. Nutr Diabetes 2024; 14:28. [PMID: 38755184 PMCID: PMC11099076 DOI: 10.1038/s41387-024-00284-4] [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: 08/07/2023] [Revised: 04/20/2024] [Accepted: 04/25/2024] [Indexed: 05/18/2024] Open
Abstract
Proglucagon mRNA expression and GLP-1 secretion by cultured human L-cells (NCI-H716) were inhibited following exposure to λ-carrageenan, a commonly used additive in processed foods. Carrageenan is composed of sulfated or unsulfated galactose residues linked in alternating alpha-1,3 and beta-1,4 bonds and resembles the endogenous sulfated glycosaminoglycans. However, carrageenan has unusual alpha-1,3-galactosidic bonds, which are not innate to human cells and are implicated in immune responses. Exposure to carrageenan predictably causes inflammation, and carrageenan impairs glucose tolerance and contributes to insulin resistance. When cultured human L-cells were deprived overnight of glucose and serum and then exposed to high glucose, 10% FBS, and λ-carrageenan (1 µg/ml) for 10 minutes, 1 h, and 24 h, mRNA expression of proglucagon and secretion of GLP-1 were significantly reduced, compared to control cells not exposed to carrageenan. mRNA expression of proglucagon by mouse L-cells (STC-1) was also significantly reduced and supports the findings in the human cells. Exposure of co-cultured human intestinal epithelial cells (LS174T) to the spent media of the carrageenan-treated L-cells led to a decline in mRNA expression of GLUT-2 at 24 h. These findings suggest that ingestion of carrageenan-containing processed foods may impair the production of GLP-1, counteract the effect of GLP-1 receptor agonists and induce secondary effects on intestinal epithelial cells.
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Affiliation(s)
- Sumit Bhattacharyya
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
- Research, Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Alip Borthakur
- Department of Clinical & Translational Sciences, Marshall University, Huntington, WV, USA
| | - Joanne K Tobacman
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
- Research, Jesse Brown VA Medical Center, Chicago, IL, USA.
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12
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Miskelly MG, Lindqvist A, Piccinin E, Hamilton A, Cowan E, Nergård BJ, Del Giudice R, Ngara M, Cataldo LR, Kryvokhyzha D, Volkov P, Engelking L, Artner I, Lagerstedt JO, Eliasson L, Ahlqvist E, Moschetta A, Hedenbro J, Wierup N. RNA sequencing unravels novel L cell constituents and mechanisms of GLP-1 secretion in human gastric bypass-operated intestine. Diabetologia 2024; 67:356-370. [PMID: 38032369 PMCID: PMC10789678 DOI: 10.1007/s00125-023-06046-8] [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: 05/22/2023] [Accepted: 09/15/2023] [Indexed: 12/01/2023]
Abstract
AIMS/HYPOTHESIS Roux-en-Y gastric bypass surgery (RYGB) frequently results in remission of type 2 diabetes as well as exaggerated secretion of glucagon-like peptide-1 (GLP-1). Here, we assessed RYGB-induced transcriptomic alterations in the small intestine and investigated how they were related to the regulation of GLP-1 production and secretion in vitro and in vivo. METHODS Human jejunal samples taken perisurgically and 1 year post RYGB (n=13) were analysed by RNA-seq. Guided by bioinformatics analysis we targeted four genes involved in cholesterol biosynthesis, which we confirmed to be expressed in human L cells, for potential involvement in GLP-1 regulation using siRNAs in GLUTag and STC-1 cells. Gene expression analyses, GLP-1 secretion measurements, intracellular calcium imaging and RNA-seq were performed in vitro. OGTTs were performed in C57BL/6j and iScd1-/- mice and immunohistochemistry and gene expression analyses were performed ex vivo. RESULTS Gene Ontology (GO) analysis identified cholesterol biosynthesis as being most affected by RYGB. Silencing or chemical inhibition of stearoyl-CoA desaturase 1 (SCD1), a key enzyme in the synthesis of monounsaturated fatty acids, was found to reduce Gcg expression and secretion of GLP-1 by GLUTag and STC-1 cells. Scd1 knockdown also reduced intracellular Ca2+ signalling and membrane depolarisation. Furthermore, Scd1 mRNA expression was found to be regulated by NEFAs but not glucose. RNA-seq of SCD1 inhibitor-treated GLUTag cells identified altered expression of genes implicated in ATP generation and glycolysis. Finally, gene expression and immunohistochemical analysis of the jejunum of the intestine-specific Scd1 knockout mouse model, iScd1-/-, revealed a twofold higher L cell density and a twofold increase in Gcg mRNA expression. CONCLUSIONS/INTERPRETATION RYGB caused robust alterations in the jejunal transcriptome, with genes involved in cholesterol biosynthesis being most affected. Our data highlight SCD as an RYGB-regulated L cell constituent that regulates the production and secretion of GLP-1.
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Affiliation(s)
- Michael G Miskelly
- Neuroendocrine Cell Biology, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Andreas Lindqvist
- Neuroendocrine Cell Biology, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Elena Piccinin
- Department of Translational Biomedicine and Neuroscience, University of Bari 'Aldo Moro', Bari, Italy
- Department of Interdisciplinary Medicine, University of Bari 'Aldo Moro', Bari, Italy
| | - Alexander Hamilton
- Molecular Metabolism, Lund University Diabetes Centre, Lund University, Malmö, Sweden
- Islet Cell Exocytosis, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Elaine Cowan
- Islet Cell Exocytosis, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | | | - Rita Del Giudice
- Department of Experimental Medical Science, Lund University, Lund, Sweden
- Department of Biomedical Science and Biofilms - Research Center for Biointerfaces, Malmö University, Malmö, Sweden
| | - Mtakai Ngara
- Neuroendocrine Cell Biology, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Luis R Cataldo
- Molecular Metabolism, Lund University Diabetes Centre, Lund University, Malmö, Sweden
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Dmytro Kryvokhyzha
- Bioinformatics Unit, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Petr Volkov
- Bioinformatics Unit, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Luke Engelking
- Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Isabella Artner
- Endocrine Cell Differentiation and Function, Stem Cell Centre, Lund University, Malmö, Sweden
| | - Jens O Lagerstedt
- Islet Cell Exocytosis, Lund University Diabetes Centre, Lund University, Malmö, Sweden
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Lena Eliasson
- Islet Cell Exocytosis, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Emma Ahlqvist
- Genomics, Diabetes and Endocrinology, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari 'Aldo Moro', Bari, Italy
- INBB National Institute for Biostructure and Biosystems, Rome, Italy
| | - Jan Hedenbro
- Department of Surgery, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Nils Wierup
- Neuroendocrine Cell Biology, Lund University Diabetes Centre, Lund University, Malmö, Sweden.
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13
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Noguchi H, Kohda N, Hara H, Hira T. Synergistic enhancement of glucagon-like peptide-1 release by γ-aminobutyric acid and L-phenylalanine in enteroendocrine cells-searching active ingredients in a water extract of corn zein protein. Biosci Biotechnol Biochem 2023; 87:1505-1513. [PMID: 37667511 DOI: 10.1093/bbb/zbad124] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/21/2023] [Indexed: 09/06/2023]
Abstract
This study investigated the glucagon-like peptide-1 (GLP-1)-releasing activity of an aqueous extract (ZeinS) from corn zein protein and aimed to identify the active compounds responsible for this activity. Glucagon-like peptide-1-releasing activity was evaluated using a murine enteroendocrine cell line (GLUTag). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed on purified fractions of ZeinS to identify active molecules. ZeinS stimulated more GLP-1 secretion from GLUTag cells compared to zein hydrolysate. Fractions displaying biological activity were determined by solid-phase extraction and high-performance liquid chromatography (HPLC) fractionation. Subsequent LC-MS/MS analysis identified several amino acids in the active fractions of ZeinS. In particular, γ-aminobutyric acid (GABA) exhibited significant GLP-1-releasing activity both alone and synergistically with L-phenylalanine (Phe). Moreover, ZeinS-induced GLP-1 secretion was attenuated by antagonists for the GABA receptor and calcium sensing receptor. These results demonstrate that GABA and Phe identified in ZeinS synergistically stimulate GLP-1 secretion in enteroendocrine cells.
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Affiliation(s)
- Hiroki Noguchi
- Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
- Otsu Nutraceuticals Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan
| | - Noriyuki Kohda
- Otsu Nutraceuticals Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan
| | - Hiroshi Hara
- Department of Food Science and Human Nutrition, Fuji Women's University, Ishikari, Japan
| | - Tohru Hira
- Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
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14
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Macedo MH, Dias Neto M, Pastrana L, Gonçalves C, Xavier M. Recent Advances in Cell-Based In Vitro Models to Recreate Human Intestinal Inflammation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301391. [PMID: 37736674 PMCID: PMC10625086 DOI: 10.1002/advs.202301391] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 07/03/2023] [Indexed: 09/23/2023]
Abstract
Inflammatory bowel disease causes a major burden to patients and healthcare systems, raising the need to develop effective therapies. Technological advances in cell culture, allied with ethical issues, have propelled in vitro models as essential tools to study disease aetiology, its progression, and possible therapies. Several cell-based in vitro models of intestinal inflammation have been used, varying in their complexity and methodology to induce inflammation. Immortalized cell lines are extensively used due to their long-term survival, in contrast to primary cultures that are short-lived but patient-specific. Recently, organoids and organ-chips have demonstrated great potential by being physiologically more relevant. This review aims to shed light on the intricate nature of intestinal inflammation and cover recent works that report cell-based in vitro models of human intestinal inflammation, encompassing diverse approaches and outcomes.
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Affiliation(s)
- Maria Helena Macedo
- INL – International Iberian Nanotechnology LaboratoryAvenida Mestre José VeigaBraga4715‐330Portugal
| | - Mafalda Dias Neto
- INL – International Iberian Nanotechnology LaboratoryAvenida Mestre José VeigaBraga4715‐330Portugal
| | - Lorenzo Pastrana
- INL – International Iberian Nanotechnology LaboratoryAvenida Mestre José VeigaBraga4715‐330Portugal
| | - Catarina Gonçalves
- INL – International Iberian Nanotechnology LaboratoryAvenida Mestre José VeigaBraga4715‐330Portugal
| | - Miguel Xavier
- INL – International Iberian Nanotechnology LaboratoryAvenida Mestre José VeigaBraga4715‐330Portugal
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15
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Zhang M, Zhu L, Wu G, Zhang H, Wang X, Qi X. The impacts and mechanisms of dietary proteins on glucose homeostasis and food intake: a pivotal role of gut hormones. Crit Rev Food Sci Nutr 2023; 64:12744-12758. [PMID: 37800337 DOI: 10.1080/10408398.2023.2256400] [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: 10/07/2023]
Abstract
Glucose and energy metabolism disorders are the main reasons induced type 2 diabetes (T2D) and obesity. Besides providing energy, dietary nutrients could regulate glucose homeostasis and food intake via intestinal nutrient sensing induced gut hormone secretion. However, reviews regarding intestinal protein sensing are very limited, and no accurate information is available on their underlying mechanisms. Through intestinal protein sensing, dietary proteins regulate glucose homeostasis and food intake by secreting gut hormones, such as glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), peptide YY (PYY) and glucose-dependent insulinotropic polypeptide (GIP). After activating the sensory receptors, such as calcium-sensing receptor (CaSR), peptide transporter-1 (PepT1), and taste 1 receptors (T1Rs), protein digests induced Ca2+ influx and thus triggered gut hormone release. Additionally, research models used to study intestinal protein sensing have been emphasized, especially several innovative models with excellent physiological relevance, such as co-culture cell models, intestinal organoids, and gut-on-a-chips. Lastly, protein-based dietary strategies that stimulate gut hormone secretion and inhibit gut hormone degradation are proposed for regulating glucose homeostasis and food intake.
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Affiliation(s)
- Mingkai Zhang
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Ling Zhu
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Gangcheng Wu
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Hui Zhang
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Xingguo Wang
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Xiguang Qi
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, Wuxi, China
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16
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Chattopadhyay A, Reddy ST, Fogelman AM. The multiple roles of lysophosphatidic acid in vascular disease and atherosclerosis. Curr Opin Lipidol 2023; 34:196-200. [PMID: 37497844 DOI: 10.1097/mol.0000000000000890] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
Abstract
PURPOSE OF REVIEW To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis. RECENT FINDINGS A high-fat high-cholesterol diet decreases antimicrobial activity in the small intestine, which leads to increased levels of bacterial lipopolysaccharide in the mucus of the small intestine and in plasma that increase systemic inflammation, and enhance dyslipidemia and aortic atherosclerosis. Decreasing LPA production in enterocytes reduces the impact of the diet. LPA signaling inhibits glucagon-like peptide 1 secretion, promotes atherosclerosis, increases vessel permeability and infarct volume in stroke, but protects against abdominal aortic aneurysm formation and rupture. Acting through the calpain system in lymphatic endothelial cells, LPA reduces the trafficking of anti-inflammatory Treg lymphocytes, which enhances atherosclerosis. Acting through LPA receptor 1 in cardiac lymphatic endothelial cells and fibroblasts, LPA enhances hypertrophic cardiomyopathy. SUMMARY LPA plays multiple roles in vascular disease and atherosclerosis that is cell and context dependent. In some settings LPA promotes these disease processes and in others it inhibits the disease process. Because LPA is so ubiquitous, therapeutic approaches targeting LPA must be as specific as possible for the cells and the context in which the disease process occurs.
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Affiliation(s)
| | - Srinivasa T Reddy
- Division of Cardiology, Department of Medicine
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Gorecki AM, Spencer H, Meloni BP, Anderton RS. The Poly-Arginine Peptide R18D Interferes with the Internalisation of α-Synuclein Pre-Formed Fibrils in STC-1 Enteroendocrine Cells. Biomedicines 2023; 11:2089. [PMID: 37626586 PMCID: PMC10452853 DOI: 10.3390/biomedicines11082089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023] Open
Abstract
In Parkinson's disease (PD), gut inflammation is hypothesised to contribute to α-synuclein aggregation, but gastrointestinal α-synuclein expression is poorly characterised. Cationic arginine-rich peptides (CARPs) are an emerging therapeutic option that exerts various neuroprotective effects and may target the transmission of protein aggregates. This study aimed to investigate endogenous α-synuclein expression in enteroendocrine STC-1 cells and the potential of the CARP, R18D (18-mer of D-arginine), to prevent internalisation of pre-formed α-synuclein fibrils (PFFs) in enteroendocrine cells in vitro. Through confocal microscopy, the immunoreactivity of full-length α-synuclein and the serine-129 phosphorylated form (pS129) was investigated in STC-1 (mouse enteroendocrine) cells. Thereafter, STC-1 cells were exposed to PFFs tagged with Alexa-Fluor 488 (PFF-488) for 2 and 24 h and R18D-FITC for 10 min. After confirming the uptake of both PFFs and R18D-FITC through fluorescent microscopy, STC-1 cells were pre-treated with R18D (5 or 10 μM) for 10 min prior to 2 h of PFF-488 exposure. Immunoreactivity for endogenous α-synuclein and pS129 was evident in STC-1 cells, with prominent pS129 staining along cytoplasmic processes and in perinuclear areas. STC-1 cells internalised PFFs, confirmed through co-localisation of PFF-488 and human-specific α-synuclein immunoreactivity. R18D-FITC entered STC-1 cells within 10 min and pre-treatment of STC-1 cells with R18D interfered with PFF uptake. The endogenous presence of α-synuclein in enteroendocrine cells, coupled with their rapid uptake of PFFs, demonstrates a potential for pathogenic spread of α-synuclein aggregates in the gut. R18D is a novel therapeutic approach to reduce the intercellular transmission of α-synuclein pathology.
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Affiliation(s)
- Anastazja M. Gorecki
- School of Health Sciences, University of Notre Dame Australia, Fremantle, WA 6160, Australia; (H.S.)
- School of Biological Sciences, University of Western Australia, Crawley, WA 6009, Australia
- Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Holly Spencer
- School of Health Sciences, University of Notre Dame Australia, Fremantle, WA 6160, Australia; (H.S.)
| | - Bruno P. Meloni
- Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
- Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA 6009, Australia
- Department of Neurosurgery, Sir Charles Gairdner Hospital, First Floor, G-Block, QEII Medical Centre, Nedlands, WA 6008, Australia
| | - Ryan S. Anderton
- School of Health Sciences, University of Notre Dame Australia, Fremantle, WA 6160, Australia; (H.S.)
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Duffet L, Williams ET, Gresch A, Chen S, Bhat MA, Benke D, Hartrampf N, Patriarchi T. Optical tools for visualizing and controlling human GLP-1 receptor activation with high spatiotemporal resolution. eLife 2023; 12:86628. [PMID: 37265064 DOI: 10.7554/elife.86628] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023] Open
Abstract
The glucagon-like peptide-1 receptor (GLP1R) is a broadly expressed target of peptide hormones with essential roles in energy and glucose homeostasis, as well as of the blockbuster weight-loss drugs semaglutide and liraglutide. Despite its large clinical relevance, tools to investigate the precise activation dynamics of this receptor with high spatiotemporal resolution are limited. Here, we introduce a novel genetically encoded sensor based on the engineering of a circularly permuted green fluorescent protein into the human GLP1R, named GLPLight1. We demonstrate that fluorescence signal from GLPLight1 accurately reports the expected receptor conformational activation in response to pharmacological ligands with high sensitivity (max ΔF/F0=528%) and temporal resolution (τON = 4.7 s). We further demonstrated that GLPLight1 shows comparable responses to glucagon-like peptide-1 (GLP-1) derivatives as observed for the native receptor. Using GLPLight1, we established an all-optical assay to characterize a novel photocaged GLP-1 derivative (photo-GLP1) and to demonstrate optical control of GLP1R activation. Thus, the new all-optical toolkit introduced here enhances our ability to study GLP1R activation with high spatiotemporal resolution.
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Affiliation(s)
- Loïc Duffet
- Institute of Pharmacology and Toxicology, University of Zürich, Zurich, Switzerland
| | - Elyse T Williams
- Department of Chemistry, University of Zürich, Zürich, Switzerland
| | - Andrea Gresch
- Institute of Pharmacology and Toxicology, University of Zürich, Zurich, Switzerland
| | - Simin Chen
- Department of Chemistry, University of Zürich, Zürich, Switzerland
| | - Musadiq A Bhat
- Institute of Pharmacology and Toxicology, University of Zürich, Zurich, Switzerland
| | - Dietmar Benke
- Institute of Pharmacology and Toxicology, University of Zürich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zürich, Zürich, Switzerland
| | - Nina Hartrampf
- Department of Chemistry, University of Zürich, Zürich, Switzerland
| | - Tommaso Patriarchi
- Institute of Pharmacology and Toxicology, University of Zürich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zürich, Zürich, Switzerland
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19
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Cuffaro B, Boutillier D, Desramaut J, Jablaoui A, Werkmeister E, Trottein F, Waligora-Dupriet AJ, Rhimi M, Maguin E, Grangette C. Characterization of Two Parabacteroides distasonis Candidate Strains as New Live Biotherapeutics against Obesity. Cells 2023; 12:cells12091260. [PMID: 37174660 PMCID: PMC10177344 DOI: 10.3390/cells12091260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 04/03/2023] [Accepted: 04/16/2023] [Indexed: 05/15/2023] Open
Abstract
The gut microbiota is now considered as a key player in the development of metabolic dysfunction. Therefore, targeting gut microbiota dysbiosis has emerged as a new therapeutic strategy, notably through the use of live gut microbiota-derived biotherapeutics. We previously highlighted the anti-inflammatory abilities of two Parabacteroides distasonis strains. We herein evaluate their potential anti-obesity abilities and show that the two strains induced the secretion of the incretin glucagon-like peptide 1 in vitro and limited weight gain and adiposity in obese mice. These beneficial effects are associated with reduced inflammation in adipose tissue and the improvement of lipid and bile acid metabolism markers. P. distasonis supplementation also modified the Actinomycetota, Bacillota and Bacteroidota taxa of the mice gut microbiota. These results provide better insight into the capacity of P. distasonis to positively influence host metabolism and to be used as novel source of live biotherapeutics in the treatment and prevention of metabolic-related diseases.
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Affiliation(s)
- Bernardo Cuffaro
- University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Centre d'Infection et d'Immunité de Lille, 59000 Lille, France
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, MIHA Team, 78350 Jouy-en-Josas, France
| | - Denise Boutillier
- University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Centre d'Infection et d'Immunité de Lille, 59000 Lille, France
| | - Jérémy Desramaut
- University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Centre d'Infection et d'Immunité de Lille, 59000 Lille, France
| | - Amin Jablaoui
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, MIHA Team, 78350 Jouy-en-Josas, France
| | - Elisabeth Werkmeister
- University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Centre d'Infection et d'Immunité de Lille, 59000 Lille, France
- UMR2014-US41-PLBS-Plateformes Lilloises de Biologie and Santé, 59000 Lille, France
| | - François Trottein
- University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Centre d'Infection et d'Immunité de Lille, 59000 Lille, France
| | | | - Moez Rhimi
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, MIHA Team, 78350 Jouy-en-Josas, France
| | - Emmanuelle Maguin
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, MIHA Team, 78350 Jouy-en-Josas, France
| | - Corinne Grangette
- University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Centre d'Infection et d'Immunité de Lille, 59000 Lille, France
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20
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Gerstenberg MK, Andersen DB, Torz L, Castorena CM, Bookout AL, Hartmann B, Rehfeld JF, Petersen N, Holst JJ, Kuhre RE. Weight loss by calorie restriction does not alter appetite-regulating gut hormone responses from perfused rat small intestine. Acta Physiol (Oxf) 2023; 238:e13947. [PMID: 36755506 DOI: 10.1111/apha.13947] [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: 07/27/2022] [Revised: 01/27/2023] [Accepted: 02/06/2023] [Indexed: 02/10/2023]
Abstract
AIM Postprandial secretion of the appetite-inhibiting hormones, glucagon-like peptide-1 (GLP-1), and peptide YY are reduced with obesity. It is unclear if the reduced secretion persists following weight loss (WL), if other appetite-inhibiting hormones are also reduced, and if so whether reduced secretion results from intrinsic changes in the gut. METHODS To address whether WL may restore secretion of GLP-1 and other appetite-inhibiting hormones, we performed a gut perfusion study of the small intestine in diet-induced obese (DIO) rats after WL. A 20% weight loss (means ± SEM (g): 916 ± 53 vs. 703 ± 35, p < 0.01, n = 7) was induced by calorie restriction, and maintained stable for ≥7 days prior to gut perfusion to allow for complete renewal of enteroendocrine cells. Age-matched DIO rats were used as comparator. Several gut hormones were analyzed from the venous effluent, and gene expression was performed on gut tissue along the entire length of the intestine. RESULTS Secretion of cholecystokinin, gastrin, glucose-dependent insulinotropic peptide, GLP-1, neurotensin, and somatostatin was not affected by WL during basal conditions (p ≥ 0.25) or in response to macronutrients and bile acids (p ≥ 0.14). Glucose absorption was indistinguishable following WL. The expression of genes encoding the studied peptides, macronutrient transporters (glucose, fructose, and di-/tripeptides) and bile acid receptors did also not differ between DIO and WL groups. CONCLUSIONS These data suggest that the attenuated postprandial responses of GLP-1, as well as reduced responses of other appetite-inhibiting gut hormones, in people living with obesity may persist after weight loss and may contribute to their susceptibility for weight regain.
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Affiliation(s)
| | - Daniel B Andersen
- Department of Biomedical Sciences, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Lola Torz
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | | | - Angie L Bookout
- Global Drug Discovery, Novo Nordisk A/S, Seattle, Washington, USA
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Rune E Kuhre
- Department of Biomedical Sciences, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.,Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
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21
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Odongo K, Hironao KY, Yamashita Y, Ashida H. Development of sandwich ELISAs for detecting glucagon-like peptide-1 secretion from intestinal L-cells and their application in STC-1 cells and mice. J Clin Biochem Nutr 2023; 72:28-38. [PMID: 36777078 PMCID: PMC9899920 DOI: 10.3164/jcbn.22-78] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 09/03/2022] [Indexed: 11/05/2022] Open
Abstract
Certain nutrients stimulate glucagon-like peptide-1 (GLP-1) secretion from the intestinal enteroendocrine L-cells, but due to rapid degradation by the DPP-4 enzyme, >90% is converted to inactive metabolite before reaching the target organs via circulation. Plants are a source of potent bioactive compounds that promote endogenous secretion of GLP-1 from L-cells. To search for the effective bioactive compound from a vast library of natural compounds, a reliable and low-cost assay is required considering the high cost of commercial assays. We developed a low-cost sandwich enzyme-linked immunosorbent assays (s-ELISAs) for detecting 'total', 'sensitive active', and 'wide-range active' GLP-1. The s-ELISAs exhibited high sensitivity with measurement ranges between 0.94~240, 0.98~62.5, and 4.8~4,480 pmol/L, respectively. High precision was observed; i.e., CVs within 5% and 20% for intra- and inter-assay variations, respectively, and excellent recovery of exogenous GLP-1 from assay buffer. The developed s-ELISAs had the same performance as the commercial kits and approximately 80% cheaper cost. For their application, cinnamtannin A2-induced GLP-1 secretion was confirmed in STC-1 cells consistent with our previous findings. The s-ELISAs were further validated by measuring plasma GLP-1 level in mice after oral administration of black soy bean seed coat extract containing cinnamtannin A2.
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Affiliation(s)
- Kevin Odongo
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Ken-yu Hironao
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Yoko Yamashita
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Hitoshi Ashida
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan,To whom correspondence should be addressed. E-mail:
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22
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Gautier T, Fahet N, Tamanai-Shacoori Z, Oliviero N, Blot M, Sauvager A, Burel A, Gall SDL, Tomasi S, Blat S, Bousarghin L. Roseburia intestinalis Modulates PYY Expression in a New a Multicellular Model including Enteroendocrine Cells. Microorganisms 2022; 10:2263. [PMID: 36422333 PMCID: PMC9694292 DOI: 10.3390/microorganisms10112263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 09/10/2024] Open
Abstract
The gut microbiota contributes to human health and disease; however, the mechanisms by which commensal bacteria interact with the host are still unclear. To date, a number of in vitro systems have been designed to investigate the host-microbe interactions. In most of the intestinal models, the enteroendocrine cells, considered as a potential link between gut bacteria and several human diseases, were missing. In the present study, we have generated a new model by adding enteroendocrine cells (ECC) of L-type (NCI-H716) to the one that we have previously described including enterocytes, mucus, and M cells. After 21 days of culture with the other cells, enteroendocrine-differentiated NCI-H716 cells showed neuropods at their basolateral side and expressed their specific genes encoding proglucagon (GCG) and chromogranin A (CHGA). We showed that this model could be stimulated by commensal bacteria playing a key role in health, Roseburia intestinalis and Bacteroides fragilis, but also by a pathogenic strain such as Salmonella Heidelberg. Moreover, using cell-free supernatants of B. fragilis and R. intestinalis, we have shown that R. intestinalis supernatant induced a significant increase in IL-8 and PYY but not in GCG gene expression, while B. fragilis had no impact. Our data indicated that R. intestinalis produced short chain fatty acids (SCFAs) such as butyrate whereas B. fragilis produced more propionate. However, these SCFAs were probably not the only metabolites implicated in PYY expression since butyrate alone had no effect. In conclusion, our new quadricellular model of gut epithelium could be an effective tool to highlight potential beneficial effects of bacteria or their metabolites, in order to develop new classes of probiotics.
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Affiliation(s)
- Thomas Gautier
- Institut NUMECAN, INSERM, Univ Rennes, INRAE, F-35000 Rennes, France
| | - Nelly Fahet
- Institut NUMECAN, INSERM, Univ Rennes, INRAE, F-35000 Rennes, France
| | | | - Nolwenn Oliviero
- Institut NUMECAN, INSERM, Univ Rennes, INRAE, F-35000 Rennes, France
| | - Marielle Blot
- ISCR (Institut des Sciences Chimiques de Rennes)-UMR CNRS 6226, Univ Rennes, CNRS, F-35000 Rennes, France
| | - Aurélie Sauvager
- ISCR (Institut des Sciences Chimiques de Rennes)-UMR CNRS 6226, Univ Rennes, CNRS, F-35000 Rennes, France
| | - Agnes Burel
- Plateforme Microscopie Electronique MRic/ISFR Biosit/Campus Santé, Univ Rennes, F-35000 Rennes, France
| | | | - Sophie Tomasi
- ISCR (Institut des Sciences Chimiques de Rennes)-UMR CNRS 6226, Univ Rennes, CNRS, F-35000 Rennes, France
| | - Sophie Blat
- Institut NUMECAN, INSERM, Univ Rennes, INRAE, F-35000 Rennes, France
| | - Latifa Bousarghin
- Institut NUMECAN, INSERM, Univ Rennes, INRAE, F-35000 Rennes, France
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23
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Miguéns-Gómez A, Sierra-Cruz M, Pérez-Vendrell AM, Rodríguez-Gallego E, Beltrán-Debón R, Terra X, Ardévol A, Pinent M. Differential effects of a cafeteria diet and GSPE preventive treatments on the enterohormone secretions of aged vs. young female rats. Food Funct 2022; 13:10491-10500. [PMID: 36148543 DOI: 10.1039/d2fo02111k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Grape seed derived procyanidins (GSPE) have been shown to effectively prevent intestinal disarrangements induced by a cafeteria diet in young rats. However, little is known about the effects of procyanidins and cafeteria diet on enterohormone secretion in aged rats, as the ageing processes modify these effects. To study these effects in aged rats, we subjected 21-month-old and young 2-month-old female rats to two sub-chronic preventive GSPE treatments. After three months of cafeteria diet administration, we analysed the basal and stimulated secretion and mRNA expression of CCK, PYY and GLP-1, caecal SCFA and intestinal sizes. We found that the effects of a cafeteria diet on the basal duodenal CCK secretion are age dependent. GLP-1 in the ileum was not modified regardless of the rat's age, and GSPE preventive effects differed in the two age groups. GSPE pre-treatment reduced GLP-1, PYY and ChgA in mRNA in aged ileum tissue, while the cafeteria diet increased these in aged colon. The GSPE treatments only modified low-abundance SCFAs. The cafeteria diet in aged rats increases the caecum size differently from that in young rats and GSPE pre-treatment prevents this increase. Therefore, ageing modifies nutrient sensing, and the cafeteria diet acts mainly on the duodenum and colon, while procyanidins have a larger effect on the ileum.
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Affiliation(s)
- Alba Miguéns-Gómez
- MoBioFood Research Group, Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, c/Marcel·lí Domingo n°1, 43007 Tarragona, Spain.
| | - Marta Sierra-Cruz
- MoBioFood Research Group, Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, c/Marcel·lí Domingo n°1, 43007 Tarragona, Spain.
| | - Anna Maria Pérez-Vendrell
- Monogastric Nutrition, Centre Mas de Bover, IRTA, Ctra. Reus-El Morell Km 3.8, 43120 Constantí, Spain
| | - Esther Rodríguez-Gallego
- MoBioFood Research Group, Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, c/Marcel·lí Domingo n°1, 43007 Tarragona, Spain.
| | - Raúl Beltrán-Debón
- MoBioFood Research Group, Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, c/Marcel·lí Domingo n°1, 43007 Tarragona, Spain.
| | - Ximena Terra
- MoBioFood Research Group, Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, c/Marcel·lí Domingo n°1, 43007 Tarragona, Spain.
| | - Anna Ardévol
- MoBioFood Research Group, Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, c/Marcel·lí Domingo n°1, 43007 Tarragona, Spain.
| | - Montserrat Pinent
- MoBioFood Research Group, Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, c/Marcel·lí Domingo n°1, 43007 Tarragona, Spain.
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24
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Villegas-Novoa C, Wang Y, Sims CE, Allbritton NL. Development of a Primary Human Intestinal Epithelium Enriched in L-Cells for Assay of GLP-1 Secretion. Anal Chem 2022; 94:9648-9655. [PMID: 35758929 DOI: 10.1021/acs.analchem.2c00912] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus is a chronic disease associated with obesity and dysregulated human feeding behavior. The hormone glucagon-like peptide 1 (GLP-1), a critical regulator of body weight, food intake, and blood glucose levels, is secreted by enteroendocrine L-cells. The paucity of L-cells in primary intestinal cell cultures including organoids and monolayers has made assays of GLP-1 secretion from primary human cells challenging. In the current paper, an analytical assay pipeline consisting of an optimized human intestinal tissue construct enriched in L-cells paired with standard antibody-based GLP-1 assays was developed to screen compounds for the development of pharmaceuticals to modulate L-cell signaling. The addition of the serotonin receptor agonist Bimu 8, optimization of R-spondin and Noggin concentrations, and utilization of vasoactive intestinal peptide (VIP) increased the density of L-cells in a primary human colonic epithelial monolayer. Additionally, the incorporation of an air-liquid interface culture format increased the L-cell number so that the signal-to-noise ratio of conventional enzyme-linked immunoassays could be used to monitor GLP-1 secretion in compound screens. To demonstrate the utility of the optimized analytical method, 21 types of beverage sweeteners were screened for their ability to stimulate GLP-1 secretion. Stevioside and cyclamate were found to be the most potent inducers of GLP-1 secretion. This platform enables the quantification of GLP-1 secretion from human primary L-cells and will have broad application in understanding L-cell formation and physiology and will improve the identification of modulators of human feeding behavior.
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Affiliation(s)
- Cecilia Villegas-Novoa
- Department of Bioengineering, University of Washington, Seattle, Washington 98195, United States
| | - Yuli Wang
- Department of Bioengineering, University of Washington, Seattle, Washington 98195, United States
| | | | - Nancy L Allbritton
- Department of Bioengineering, University of Washington, Seattle, Washington 98195, United States
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25
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Anghel SA, Badea RA, Chiritoiu G, Patriche DS, Alexandru PR, Pena F. Novel luciferase-based GLP-1 reporter assay reveals naturally-occurring secretagogues. Br J Pharmacol 2022; 179:4738-4753. [PMID: 35736785 DOI: 10.1111/bph.15896] [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: 10/07/2021] [Revised: 04/22/2022] [Accepted: 05/15/2022] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND AND PURPOSE Glucagon-like peptide 1 (GLP-1) is a hormone derived from preproglucagon. It is secreted by enteroendocrine cells in response to feeding, and, in turn, acts as a critical regulator of insulin release. Modulating GLP-1 secretion thus holds promise as a strategy for controlling blood glucose levels. EXPERIMENTAL APPROACH To dissect GLP-1 regulation and to discover specific secretagogues, we engineered a reporter cell line introducing a luciferase within proglucagon sequence in GLUTag cells. The assay was validated using western blotting and ELISA. A focused natural compounds library was screened. We measured luminescence, glucose uptake and ATP to investigate the mechanism by which newly found secretagogues potentiate GLP-1 secretion. KEY RESULTS The newly created reporter cell line is ideal for the rapid, sensitive and quantitative assessment of GLP-1 secretion. The small molecule screen identified non-toxic GLP-1 modulators. Quercetin is the most potent newly found GLP-1 secretagogue, while other flavonoids also potentiate GLP-1 secretion. Quercetin requires glucose and extracellular calcium to act as GLP-1 secretagogue. Our results support a mechanism whereby flavonoids cause GLUTag cells to utilize glucose more efficiently, leading to elevated ATP levels, followed by KATP channel blockade and GLP-1 exocytosis. CONCLUSION AND IMPLICATIONS Our methodology enables finding of new GLP-1 secretagogues. Quercetin is a potent, naturally occuring GLP-1 secretagogue. Mechanistic studies of newly found secretagogues are possible in newly created reporter cell line. Further validation in more physiological systems, such as primary L-cells or whole organisms is needed. GLP-1 secretagogues might serve as leads for developing alternative glucose-lowering therapies.
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Affiliation(s)
- Sorina Andreea Anghel
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Rodica Aura Badea
- Department of Enzymology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Gabriela Chiritoiu
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - David Sebastian Patriche
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Petruta Ramona Alexandru
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Florentina Pena
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
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26
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Lok KH, Wareham NJ, Nair RS, How CW, Chuah LH. Revisiting the concept of incretin and enteroendocrine L-cells as type 2 diabetes mellitus treatment. Pharmacol Res 2022; 180:106237. [PMID: 35487405 PMCID: PMC7614293 DOI: 10.1016/j.phrs.2022.106237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/08/2022] [Accepted: 04/22/2022] [Indexed: 12/19/2022]
Abstract
The significant growth in type 2 diabetes mellitus (T2DM) prevalence strikes a common threat to the healthcare and economic systems globally. Despite the availability of several anti-hyperglycaemic agents in the market, none can offer T2DM remission. These agents include the prominent incretin-based therapy such as glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 inhibitors that are designed primarily to promote GLP-1R activation. Recent interest in various therapeutically useful gastrointestinal hormones in T2DM and obesity has surged with the realisation that enteroendocrine L-cells modulate the different incretins secretion and glucose homeostasis, reflecting the original incretin definition. Targeting L-cells offers promising opportunities to mimic the benefits of bariatric surgery on glucose homeostasis, bodyweight management, and T2DM remission. Revising the fundamental incretin theory is an essential step for therapeutic development in this area. Therefore, the present review explores enteroendocrine L-cell hormone expression, the associated nutrient-sensing mechanisms, and other physiological characteristics. Subsequently, enteroendocrine L-cell line models and the latest L-cell targeted therapies are reviewed critically in this paper. Bariatric surgery, pharmacotherapy and new paradigm of L-cell targeted pharmaceutical formulation are discussed here, offering both clinician and scientist communities a new common interest to push the scientific boundary in T2DM therapy.
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Affiliation(s)
- Kok-Hou Lok
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia.
| | - Nicholas J Wareham
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia; MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Cambridge, UK.
| | - Rajesh Sreedharan Nair
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia.
| | - Chee Wun How
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia.
| | - Lay-Hong Chuah
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia.
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27
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Choi KJ, Hwang JW, Kim SH, Park HS. Ca 2+ entry through reverse Na+/Ca 2+ exchanger in NCI-H716, glucagon-like peptide-1 secreting cells. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY 2022; 26:219-225. [PMID: 35477549 PMCID: PMC9046890 DOI: 10.4196/kjpp.2022.26.3.219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/18/2022] [Accepted: 04/06/2022] [Indexed: 11/27/2022]
Abstract
Glucagon like peptide-1 (GLP-1) released from enteroendocine L-cells in the intestine has incretin effects due to its ability to amplify glucose-dependent insulin secretion. Promotion of an endogenous release of GLP-1 is one of therapeutic targets for type 2 diabetes mellitus. Although the secretion of GLP-1 in response to nutrient or neural stimuli can be triggered by cytosolic Ca2+ elevation, the stimulus-secretion pathway is not completely understood yet. Therefore, the aim of this study was to investigate the role of reverse Na+/Ca2+ exchanger (rNCX) in Ca2+ entry induced by muscarinic stimulation in NCI-H716 cells, a human enteroendocrine GLP-1 secreting cell line. Intracellular Ca2+ was repetitively oscillated by the perfusion of carbamylcholine (CCh), a muscarinic agonist. The oscillation of cytosolic Ca2+ was ceased by substituting extracellular Na+ with Li+ or NMG+. KB-R7943, a specific rNCX blocker, completely diminished CCh-induced cytosolic Ca2+ oscillation. Type 1 Na+/Ca2+ exchanger (NCX1) proteins were expressed in NCI-H716 cells. These results suggest that rNCX might play a crucial role in Ca2+ entry induced by cholinergic stimulation in NCI-H716 cells, a GLP-1 secreting cell line.
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Affiliation(s)
- Kyung Jin Choi
- Department of Physiology, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Jin Wook Hwang
- Department of Physiology, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Se Hoon Kim
- Department of Physiology, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Hyung Seo Park
- Department of Physiology, College of Medicine, Konyang University, Daejeon 35365, Korea
- Myunggok Medical Research Institute, Konyang University, Daejeon 35365, Korea
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Butt S, Gagnon J, Saleh M. A Protective Role for Glucagon-like Peptide-2 in Heat-stable Enterotoxin b (STb)-Induced L-Cell Toxicity. Endocrinology 2022; 163:6546206. [PMID: 35266539 DOI: 10.1210/endocr/bqac029] [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: 11/19/2021] [Indexed: 11/19/2022]
Abstract
Enterotoxigenic Escherichia coli (ETEC)-derived purified heat-stable enterotoxin b (STb) is responsible for secretory diarrhea in livestock and humans. STb disrupts intestinal fluid homeostasis, epithelial barrier function, and promotes cell death. Glucagon-like peptide-2 (GLP-2) is a potent intestinotrophic hormone secreted by enteroendocrine L cells. GLP-2 enhances crypt cell proliferation, epithelial barrier function, and inhibits enterocyte apoptosis. Whether STb can affect GLP-2 producing L cells remains to be elucidated. First, secreted-His-labeled STb from transformed E coli was collected and purified. When incubated with L-cell models (GLUTag, NCI-H716, and secretin tumor cell line [STC-1]), fluorescent immunocytochemistry revealed STb was internalized and was differentially localized in the cytoplasm and nucleus. Cell viability experiments with neutral red and resazurin revealed that STb was toxic in all but the GLUTag cells. STb stimulated 2-hour GLP-2 secretion in all cell models. Interestingly, GLUTag cells produced the highest amount of GLP-2 when treated with STb, demonstrating an inverse relationship in GLP-2 secretion and cell toxicity. To demonstrate a protective role for GLP-2, GLUTag-conditioned media (rich in GLP-2) blocked STb toxicity in STC-1 cells. Confirming a protective role of GLP-2, teduglutide was able to improve cell viability in cells treated with H2O2. In conclusion, STb interacts with the L cell, stimulates secretion, and may induce toxicity if GLP-2 is not produced at high levels. GLP-2 or receptor agonists have the ability to improve cell viability in response to toxins. These results suggest that GLP-2 secretion can play a protective role during STb intoxication. This work supports future investigation into the use of GLP-2 therapies in enterotoxigenic-related diseases.
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Affiliation(s)
- Shahnawaz Butt
- Laurentian University, School of Natural Sciences, Sudbury, Ontario P3E 2C6, Canada
| | - Jeffrey Gagnon
- Laurentian University, School of Natural Sciences, Sudbury, Ontario P3E 2C6, Canada
| | - Mazen Saleh
- Laurentian University, School of Natural Sciences, Sudbury, Ontario P3E 2C6, Canada
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29
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Enteroendocrine System and Gut Barrier in Metabolic Disorders. Int J Mol Sci 2022; 23:ijms23073732. [PMID: 35409092 PMCID: PMC8998765 DOI: 10.3390/ijms23073732] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
With the continuous rise in the worldwide prevalence of obesity and type 2 diabetes, developing therapies regulating body weight and glycemia has become a matter of great concern. Among the current treatments, evidence now shows that the use of intestinal hormone analogs (e.g., GLP1 analogs and others) helps to control glycemia and reduces body weight. Indeed, intestinal endocrine cells produce a large variety of hormones regulating metabolism, including appetite, digestion, and glucose homeostasis. Herein, we discuss how the enteroendocrine system is affected by local environmental and metabolic signals. These signals include those arising from unbalanced diet, gut microbiota, and the host metabolic organs and their complex cross-talk with the intestinal barrier integrity.
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30
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Huang TT, Gu PP, Zheng T, Gou LS, Liu YW. Piperine, as a TAS2R14 agonist, stimulates the secretion of glucagon-like peptide-1 in the human enteroendocrine cell line Caco-2. Food Funct 2022; 13:242-254. [PMID: 34881772 DOI: 10.1039/d1fo02932k] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Piperine is reported to ameliorate common metabolic diseases, however, its molecular mechanism is still unclear. In the present study, we examined whether piperine could stimulate glucagon-like peptide-1 (GLP-1) secretion in a human enteroendocrine cell line, Caco-2, and explored the potential mechanisms from the activation of human bitter taste receptors (TAS2Rs). It was found that TAS2R14 was highly expressed in Caco-2 cells, far more than TAS2R4 and TAS2R10. Piperine and flufenamic acid (FA, a known TAS2R14 agonist) markedly increased intracellular calcium mobilization and significantly enhanced the GLP-1 secretion, accompanied by elevated levels of proglucagon mRNA in Caco-2 cells compared with the control. Moreover, piperine and FA activated TAS2R14 signaling as evidenced by the increased mRNA and protein levels of TAS2R14, and the protein expression of its downstream key molecules including phospholipase C β2 (PLCβ2) and a transient receptor potential channel melastatin 5 (TRPM5). On the other hand, a G protein βγ subunit inhibitor Gallein or a PLC inhibitor U73122 alleviated piperine-stimulated GLP-1 secretion in Caco-2 cells. In the meantime, a flavanone hesperetin significantly attenuated piperine and FA induced the intracellular calcium mobilization and GLP-1 secretion. Furthermore, TAS2R14 knockdown reversed the piperine-triggered up-regulation of PLCβ2 and TRPM5 as well as increased the GLP-1 secretion in Caco-2 cells by TAS2R14 shRNA transfection. In summary, our findings demonstrated that piperine promoted the GLP-1 secretion from enteroendocrine cells through the activation of TAS2R14 signaling. Moreover, TAS2R14 was likely a target of piperine in the alleviation of metabolic diseases.
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Affiliation(s)
- Ting-Ting Huang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
| | - Pan-Pan Gu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
| | - Ting Zheng
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
| | - Ling-Shan Gou
- Center for Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital, Xuzhou 221009, Jiangsu, China
| | - Yao-Wu Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China. .,Department of Pharmacology, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
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31
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Murata Y, Harada N, Kishino S, Iwasaki K, Ikeguchi-Ogura E, Yamane S, Kato T, Kanemaru Y, Sankoda A, Hatoko T, Kiyobayashi S, Ogawa J, Hirasawa A, Inagaki N. Medium-chain triglycerides inhibit long-chain triglyceride-induced GIP secretion through GPR120-dependent inhibition of CCK. iScience 2021; 24:102963. [PMID: 34466786 PMCID: PMC8382997 DOI: 10.1016/j.isci.2021.102963] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 01/14/2021] [Accepted: 08/05/2021] [Indexed: 12/13/2022] Open
Abstract
Long-chain triglycerides (LCTs) intake strongly stimulates GIP secretion from enteroendocrine K cells and induces obesity and insulin resistance partly due to GIP hypersecretion. In this study, we found that medium-chain triglycerides (MCTs) inhibit GIP secretion after single LCT ingestion and clarified the mechanism underlying MCT-induced inhibition of GIP secretion. MCTs reduced the CCK effect after single LCT ingestion in wild-type (WT) mice, and a CCK agonist completely reversed MCT-induced inhibition of GIP secretion. In vitro studies showed that medium-chain fatty acids (MCFAs) inhibit long-chain fatty acid (LCFA)-stimulated CCK secretion and increase in intracellular Ca2+ concentrations through inhibition of GPR120 signaling. Long-term administration of MCTs reduced obesity and insulin resistance in high-LCT diet-fed WT mice, but not in high-LCT diet-fed GIP-knockout mice. Thus, MCT-induced inhibition of GIP hypersecretion reduces obesity and insulin resistance under high-LCT diet feeding condition.
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Affiliation(s)
- Yuki Murata
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shigenobu Kishino
- Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Kanako Iwasaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Eri Ikeguchi-Ogura
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shunsuke Yamane
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tomoko Kato
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yoshinori Kanemaru
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Akiko Sankoda
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tomonobu Hatoko
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Sakura Kiyobayashi
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Jun Ogawa
- Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Akira Hirasawa
- Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
- Corresponding author
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32
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Characteristics of Food Protein-Derived Antidiabetic Bioactive Peptides: A Literature Update. Int J Mol Sci 2021; 22:ijms22179508. [PMID: 34502417 PMCID: PMC8431147 DOI: 10.3390/ijms22179508] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 12/25/2022] Open
Abstract
Diabetes, a glucose metabolic disorder, is considered one of the biggest challenges associated with a complex complication of health crises in the modern lifestyle. Inhibition or reduction of the dipeptidyl peptidase IV (DPP-IV), alpha-glucosidase, and protein-tyrosine phosphatase 1B (PTP-1B) enzyme activities or expressions are notably considered as the promising therapeutic strategies for the management of type 2 diabetes (T2D). Various food protein-derived antidiabetic bioactive peptides have been isolated and verified. This review provides an overview of the DPP-IV, PTP-1B, and α-glucosidase inhibitors, and updates on the methods for the discovery of DPP-IV inhibitory peptides released from food-protein hydrolysate. The finding of novel bioactive peptides involves studies about the strategy of separation fractionation, the identification of peptide sequences, and the evaluation of peptide characteristics in vitro, in silico, in situ, and in vivo. The potential of bioactive peptides suggests useful applications in the prevention and management of diabetes. Furthermore, evidence of clinical studies is necessary for the validation of these peptides’ efficiencies before commercial applications.
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33
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Sun EW, Iepsen EW, Pezos N, Lumsden AL, Martin AM, Schober G, Isaacs NJ, Rayner CK, Nguyen NQ, de Fontgalland D, Rabbitt P, Hollington P, Wattchow DA, Hansen T, Holm JC, Liou AP, Jackson VM, Torekov SS, Young RL, Keating DJ. A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans. Gastroenterology 2021; 161:536-547.e2. [PMID: 33848536 DOI: 10.1053/j.gastro.2021.04.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/04/2021] [Accepted: 04/06/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. DESIGN GLP-1 and PYY levels were assessed in body mass index-matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. RESULTS Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. CONCLUSION Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders.
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Affiliation(s)
- Emily W Sun
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
| | - Eva W Iepsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Nektaria Pezos
- Nutrition, Diabetes and Metabolism, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, Australia; Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia
| | - Amanda L Lumsden
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
| | - Alyce M Martin
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
| | - Gudrun Schober
- Nutrition, Diabetes and Metabolism, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, Australia; Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia
| | - Nichole J Isaacs
- Nutrition, Diabetes and Metabolism, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, Australia; Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia
| | - Christopher K Rayner
- Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Nam Q Nguyen
- Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | | | - Philippa Rabbitt
- Department of Surgery, Flinders Medical Centre, Bedford Park, Australia
| | - Paul Hollington
- Department of Surgery, Flinders Medical Centre, Bedford Park, Australia
| | - David A Wattchow
- Department of Surgery, Flinders Medical Centre, Bedford Park, Australia
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Jens-Christian Holm
- The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Holbæk University Hospital, Holbæk, Denmark
| | - Alice P Liou
- Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts
| | - V Margaret Jackson
- Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts
| | - Signe S Torekov
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
| | - Richard L Young
- Nutrition, Diabetes and Metabolism, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, Australia; Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia.
| | - Damien J Keating
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, Australia.
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Zhou L, Wang F, Song X, Shi M, Liang G, Zhang L, Huang F, Jiang G. 3-Deoxyglucosone reduces glucagon-like peptide-1 secretion at low glucose levels through down-regulation of SGLT1 expression in STC-1 cells. Arch Physiol Biochem 2021; 127:311-317. [PMID: 31291135 DOI: 10.1080/13813455.2019.1638413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
CONTEXT Sodium glucose co-transporter 1 (SGLT1) triggers low glucose-induced glucagon-like peptide-1 (GLP-1) secretion. We reported that a two-week administration of 3-deoxyglucosone (3DG), an independent factor associated with the development of pre-diabetes, reduces basal GLP-1 secretion in rats. OBJECTIVE This study investigated the effects of 3DG on GLP-1 secretion and SGLT1 pathway under low-glucose conditions in STC-1 cells. METHODS STC-1 cells were incubated with phloridzin or 3DG at 5.6 mM glucose. SGLT1 expression (by western blotting), GLP-1 and cyclic adenosine monophosphate (cAMP) levels (by ELISA), and intracellular Ca2+ concentration (by Fluo-3/AM) were measured. RESULTS Phloridzin inhibited GLP-1 secretion. SGLT1 protein expression in STC-1 cells cultured in 5.6 mM glucose is higher than that in 25 mM glucose. Exposure to 3DG for 6 h reduced GLP-1 secretion, SGLT1 protein expression, and intracellular concentrations of cAMP and Ca2+. CONCLUSIONS 3DG reduces low glucose-induced GLP-1 secretion in part through reduction of SGLT1 expression.
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Affiliation(s)
- Liang Zhou
- Suzhou Academy of Wumen Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Fei Wang
- Suzhou Academy of Wumen Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Xiudao Song
- Suzhou Academy of Wumen Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Min Shi
- Suzhou Academy of Wumen Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Guoqiang Liang
- Suzhou Academy of Wumen Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Lurong Zhang
- Suzhou Academy of Wumen Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Fei Huang
- Suzhou Academy of Wumen Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Guorong Jiang
- Suzhou Academy of Wumen Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
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35
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Shannon E, Conlon M, Hayes M. Seaweed Components as Potential Modulators of the Gut Microbiota. Mar Drugs 2021; 19:358. [PMID: 34201794 PMCID: PMC8303941 DOI: 10.3390/md19070358] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/20/2021] [Accepted: 06/20/2021] [Indexed: 12/11/2022] Open
Abstract
Macroalgae, or seaweeds, are a rich source of components which may exert beneficial effects on the mammalian gut microbiota through the enhancement of bacterial diversity and abundance. An imbalance of gut bacteria has been linked to the development of disorders such as inflammatory bowel disease, immunodeficiency, hypertension, type-2-diabetes, obesity, and cancer. This review outlines current knowledge from in vitro and in vivo studies concerning the potential therapeutic application of seaweed-derived polysaccharides, polyphenols and peptides to modulate the gut microbiota through diet. Polysaccharides such as fucoidan, laminarin, alginate, ulvan and porphyran are unique to seaweeds. Several studies have shown their potential to act as prebiotics and to positively modulate the gut microbiota. Prebiotics enhance bacterial populations and often their production of short chain fatty acids, which are the energy source for gastrointestinal epithelial cells, provide protection against pathogens, influence immunomodulation, and induce apoptosis of colon cancer cells. The oral bioaccessibility and bioavailability of seaweed components is also discussed, including the advantages and limitations of static and dynamic in vitro gastrointestinal models versus ex vivo and in vivo methods. Seaweed bioactives show potential for use in prevention and, in some instances, treatment of human disease. However, it is also necessary to confirm these potential, therapeutic effects in large-scale clinical trials. Where possible, we have cited information concerning these trials.
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Affiliation(s)
- Emer Shannon
- Food Biosciences, Teagasc Food Research Centre, Ashtown, D15 KN3K Dublin, Ireland;
- CSIRO Health and Biosecurity, Kintore Avenue, Adelaide, SA 5000, Australia;
| | - Michael Conlon
- CSIRO Health and Biosecurity, Kintore Avenue, Adelaide, SA 5000, Australia;
| | - Maria Hayes
- Food Biosciences, Teagasc Food Research Centre, Ashtown, D15 KN3K Dublin, Ireland;
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36
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Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat Rev Nephrol 2021; 17:227-244. [PMID: 33219281 DOI: 10.1038/s41581-020-00367-2] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 01/30/2023]
Abstract
As the prevalence of diabetes continues to climb, the number of individuals living with diabetic complications will reach an unprecedented magnitude. The emergence of new glucose-lowering agents - sodium-glucose cotransporter 2 inhibitors and incretin therapies - has markedly changed the treatment landscape of type 2 diabetes mellitus. In addition to effectively lowering glucose, incretin drugs, which include glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, can also reduce blood pressure, body weight, the risk of developing or worsening chronic kidney disease and/or atherosclerotic cardiovascular events, and the risk of death. Although kidney disease events have thus far been secondary outcomes in clinical trials, an ongoing phase III trial in patients with diabetic kidney disease will test the effect of a GLP1R agonist on a primary kidney disease outcome. Experimental data have identified the modulation of innate immunity and inflammation as plausible biological mechanisms underpinning the kidney-protective effects of incretin-based agents. These drugs block the mechanisms involved in the pathogenesis of kidney damage, including the activation of resident mononuclear phagocytes, tissue infiltration by non-resident inflammatory cells, and the production of pro-inflammatory cytokines and adhesion molecules. GLP1R agonists and DPP4 inhibitors might also attenuate oxidative stress, fibrosis and cellular apoptosis in the kidney.
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Affiliation(s)
- Radica Z Alicic
- Providence Medical Research Center, Providence Health Care, Spokane, WA, USA.,Department of Medicine, University of Washington School of Medicine, Spokane and Seattle, WA, USA
| | - Emily J Cox
- Providence Medical Research Center, Providence Health Care, Spokane, WA, USA
| | - Joshua J Neumiller
- Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
| | - Katherine R Tuttle
- Providence Medical Research Center, Providence Health Care, Spokane, WA, USA. .,Nephrology Division, Kidney Research Institute and Institute of Translational Health Sciences, University of Washington, Spokane and Seattle, WA, USA.
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Abstract
Glucagon-Like Peptide-1 (GLP-1) is an important peptide hormone secreted by L-cells in the gastrointestinal tract in response to nutrients. It is produced by the differential cleavage of the proglucagon peptide. GLP-1 elicits a wide variety of physiological responses in many tissues that contribute to metabolic homeostasis. For these reasons, therapies designed to either increase endogenous GLP-1 levels or introduce exogenous peptide mimetics are now widely used in the management of diabetes. In addition to GLP-1 production from L-cells, recent reports suggest that pancreatic islet alpha cells may also synthesize and secrete GLP-1. Intra-islet GLP-1 may therefore play an unappreciated role in islet health and glucose regulation, suggesting a potential functional paracrine role for islet-derived GLP-1. In this review, we assess the current literature from an islet-centric point-of-view to better understand the production, degradation, and actions of GLP-1 within the endocrine pancreas in rodents and humans. The relevance of intra-islet GLP-1 in human physiology is discussed regarding the potential role of intra-islet GLP-1 in islet health and dysfunction.
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Affiliation(s)
- Scott A. Campbell
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal Diabetes Research Centre CRCHUM, Montréal, Canada
| | - Janyne Johnson
- Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - Peter E. Light
- Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
- CONTACT Peter E. Light Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AlbertaT6G 2E1, Canada
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Kuhre RE, Deacon CF, Holst JJ, Petersen N. What Is an L-Cell and How Do We Study the Secretory Mechanisms of the L-Cell? Front Endocrinol (Lausanne) 2021; 12:694284. [PMID: 34168620 PMCID: PMC8218725 DOI: 10.3389/fendo.2021.694284] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/11/2021] [Indexed: 12/14/2022] Open
Abstract
Synthetic glucagon-like peptide-1 (GLP-1) analogues are effective anti-obesity and anti-diabetes drugs. The beneficial actions of GLP-1 go far beyond insulin secretion and appetite, and include cardiovascular benefits and possibly also beneficial effects in neurodegenerative diseases. Considerable reserves of GLP-1 are stored in intestinal endocrine cells that potentially might be mobilized by pharmacological means to improve the body's metabolic state. In recognition of this, the interest in understanding basic L-cell physiology and the mechanisms controlling GLP-1 secretion, has increased considerably. With a view to home in on what an L-cell is, we here present an overview of available data on L-cell development, L-cell peptide expression profiles, peptide production and secretory patterns of L-cells from different parts of the gut. We conclude that L-cells differ markedly depending on their anatomical location, and that the traditional definition of L-cells as a homogeneous population of cells that only produce GLP-1, GLP-2, glicentin and oxyntomodulin is no longer tenable. We suggest to sub-classify L-cells based on their differential peptide contents as well as their differential expression of nutrient sensors, which ultimately determine the secretory responses to different stimuli. A second purpose of this review is to describe and discuss the most frequently used experimental models for functional L-cell studies, highlighting their benefits and limitations. We conclude that no experimental model is perfect and that a comprehensive understanding must be built on results from a combination of models.
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Affiliation(s)
- Rune E. Kuhre
- Department of Obesity Pharmacology, Novo Nordisk, Måløv, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Rune E. Kuhre, ;
| | - Carolyn F. Deacon
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - Jens J. Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
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Kamakura R, Raza GS, Prasannan A, Walkowiak J, Herzig KH. Dipeptidyl peptidase-4 and GLP-1 interplay in STC-1 and GLUTag cell lines. Peptides 2020; 134:170419. [PMID: 32998057 DOI: 10.1016/j.peptides.2020.170419] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 09/11/2020] [Accepted: 09/21/2020] [Indexed: 12/12/2022]
Abstract
Glucagon like peptide-1 (GLP-1) is an incretin hormone, secreted from L-cells of distal ileum and colon in response to nutrient ingestion in human. GLP-1 plays a major role in gut motility, appetite regulation, and insulin secretion. Dipeptidyl peptidase-4 (DPP4), a serine peptidase, cleaves N-terminal dipeptides of GLP-1, rendering it inactive and responsible for its short half-life. DPP4 is widely expressed in numerous tissues in a membrane bound or soluble form. The enteroendocrine cell lines STC-1 and GLUTag are extensively used as models for in vitro studies, however, the basic parallel characterization between these cell lines is still missing. Previously, we demonstrated that these cell lines exhibit different responses to α-linolenic acid (αLA)-induced GLP-1 secretion. Therefore, we examined the basal and stimulated GLP-1 and DPP4 secretion between the two cell lines. GPR120 and GPR40 are known to bind long chain fatty acids. We found that STC-1 cells secreted significantly more basal and αLA-induced GLP-1 than GLUTag cells. In addition, STC-1 secreted DPP4 and expressed higher amounts of DPP4 and GPR120 than GLUTag cells, while GLUTag cells expressed higher GPR40 protein levels than STC-1 cells. Interestingly, the secreted soluble DPP4 did not change the active GLP-1 concentrations in the buffer group, and only 5.5 % of GLP-1 was degraded in the αLA stimulated group. These results suggested that STC-1 cells have a higher potential to secrete GLP-1 and DPP4 than GLUTag cells, and the membrane bound DPP4 may play a more significant role in the inactivation of GLP-1 secretion.
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Affiliation(s)
- Remi Kamakura
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland
| | - Ghulam Shere Raza
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland
| | - Aishwarya Prasannan
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland
| | - Jaroslaw Walkowiak
- Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland
| | - Karl-Heinz Herzig
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland; Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.
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The Protective Role of Hydrogen Sulfide Against Obesity-Associated Cellular Stress in Blood Glucose Regulation. Antioxidants (Basel) 2020; 9:antiox9111038. [PMID: 33114185 PMCID: PMC7690771 DOI: 10.3390/antiox9111038] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/16/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
Circulating palmitic acid (PA) is increased in obesity and causes metabolic stress, leading to diabetes. This includes the impairment of the glucoregulatory hormone glucagon-like peptide-1 (GLP-1) secreted from intestinal L-cells. Recently, the anti-inflammatory gasotransmitter hydrogen sulfide (H2S) has been implicated in the enhancement of GLP-1 secretion. We hypothesized that H2S can reduce the oxidative stress caused by palmitate and play a protective role in L-cell function. This study was conducted on both human and mouse L-cells and a mouse model of Western diet (WD)-induced obesity. PA-induced L-cell stress was assessed using DCF-DA. H2S was delivered using the donor GYY4137. C57BL/6 mice were fed either chow diet or PA-enriched WD for 20 weeks with ongoing measurements of glycemia and GLP-1 secretion. In both L-cell models, we demonstrated that PA caused an increase in reactive oxygen species (ROS). This ROS induction was partially blocked by the H2S administration. In mice, the WD elevated body weight in both sexes and elevated fasting blood glucose and lipid peroxidation in males. Additionally, a single GYY4137 injection improved oral glucose tolerance in WD-fed male mice and also enhanced glucose-stimulated GLP-1 release. To conclude, H2S reduces oxidative stress in GLP-1 cells and can improve glucose clearance in mice.
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Madsen TD, Hansen LH, Hintze J, Ye Z, Jebari S, Andersen DB, Joshi HJ, Ju T, Goetze JP, Martin C, Rosenkilde MM, Holst JJ, Kuhre RE, Goth CK, Vakhrushev SY, Schjoldager KT. An atlas of O-linked glycosylation on peptide hormones reveals diverse biological roles. Nat Commun 2020; 11:4033. [PMID: 32820167 PMCID: PMC7441158 DOI: 10.1038/s41467-020-17473-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 07/02/2020] [Indexed: 12/17/2022] Open
Abstract
Peptide hormones and neuropeptides encompass a large class of bioactive peptides that regulate physiological processes like anxiety, blood glucose, appetite, inflammation and blood pressure. Here, we execute a focused discovery strategy to provide an extensive map of O-glycans on peptide hormones. We find that almost one third of the 279 classified peptide hormones carry O-glycans. Many of the identified O-glycosites are conserved and are predicted to serve roles in proprotein processing, receptor interaction, biodistribution and biostability. We demonstrate that O-glycans positioned within the receptor binding motifs of members of the neuropeptide Y and glucagon families modulate receptor activation properties and substantially extend peptide half-lives. Our study highlights the importance of O-glycosylation in the biology of peptide hormones, and our map of O-glycosites in this large class of biomolecules serves as a discovery platform for an important class of molecules with potential opportunities for drug designs.
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Affiliation(s)
- Thomas D Madsen
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Lasse H Hansen
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark.,Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen O, Denmark
| | - John Hintze
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Zilu Ye
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Shifa Jebari
- Biofisika Institute (UPV/EHU, CSIC), Departamento de Bioquímica, Universidad del País Vasco, Bilbao, 48080, Spain
| | - Daniel B Andersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Hiren J Joshi
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Tongzhong Ju
- Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA
| | - Jens P Goetze
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen O, Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Cesar Martin
- Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Rune E Kuhre
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Christoffer K Goth
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Sergey Y Vakhrushev
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark
| | - Katrine T Schjoldager
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark.
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Sánchez-Moya T, Planes-Muñoz D, Frontela-Saseta C, Ros-Berruezo G, López-Nicolás R. Milk whey from different animal species stimulates the in vitro release of CCK and GLP-1 through a whole simulated intestinal digestion. Food Funct 2020; 11:7208-7216. [PMID: 32756716 DOI: 10.1039/d0fo00767f] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Milk whey is effective in enhancing satiety mainly due to its protein composition. Peptides and amino acids derived from digestion of whey protein can act as suppressants of appetite by stimulation of receptors of satiety gut hormones. But, the protein fraction of whey can vary depending on species of animal, season, lactation period, etc. The aim of this study is to evaluate the satiety effect of milk whey from different species of ruminants (cow, sheep, goat and a mixture of them) through a simulated in vitro digestion, which performed the whole gastrointestinal process, from oral digestion to colonic fermentation. The satiety effect of each sample was measured by the production of satiating hormones (CCK and GLP-1) secreted by enteroendocrine cell line (STC-1) after 2 hours of incubation with non-digested, digested and fermented whey. Digested samples have shown to be potent CCK and GLP-1 secretagogues followed by fermented and non-digested samples, showing that the last one showed a weak hormone stimulation. Digested goat whey was the most efficient stimulator of GLP-1 (86.33 ± 4.55 pg mL-1) and fermented mixture whey produced the major release of CCK (80.78±1.81 pg mL-1). This study demonstrates that milk whey is a suitable ingredient to stimulate satiety through the effect of peptides, amino acids produced from digestion, and metabolites released by fermentation.
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Affiliation(s)
- T Sánchez-Moya
- Department of Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence Campus Mare Nostrum, University of Murcia, Spain.
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Chaudhari SN, Harris DA, Aliakbarian H, Luo JN, Henke MT, Subramaniam R, Vernon AH, Tavakkoli A, Sheu EG, Devlin AS. Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects. Nat Chem Biol 2020; 17:20-29. [PMID: 32747812 PMCID: PMC7891870 DOI: 10.1038/s41589-020-0604-z] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 07/01/2020] [Indexed: 12/19/2022]
Abstract
Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone GLP-1 and changes in levels of circulating bile acids. The levels of individual bile acids in the GI tract following surgery, however, have remained largely unstudied. Using UPLC-MS-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a TGR5 agonist that increases Tgr5 expression and induces GLP-1 secretion. Further, CA7S administration increases glucose tolerance in insulin-resistant mice in a TGR5-dependent manner. CA7S remains gut-restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into circulation. By studying changes in individual metabolites following surgery, this study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.
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Affiliation(s)
- Snehal N Chaudhari
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - David A Harris
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hassan Aliakbarian
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - James N Luo
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Matthew T Henke
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Renuka Subramaniam
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ashley H Vernon
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ali Tavakkoli
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Eric G Sheu
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - A Sloan Devlin
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
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Huang WK, Xie C, Young RL, Zhao JB, Ebendorff-Heidepriem H, Jones KL, Rayner CK, Wu TZ. Development of innovative tools for investigation of nutrient-gut interaction. World J Gastroenterol 2020; 26:3562-3576. [PMID: 32742126 PMCID: PMC7366065 DOI: 10.3748/wjg.v26.i25.3562] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 05/29/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract is the key interface between the ingesta and the human body. There is wide recognition that the gastrointestinal response to nutrients or bioactive compounds, particularly the secretion of numerous hormones, is critical to the regulation of appetite, body weight and blood glucose. This concept has led to an increasing focus on "gut-based" strategies for the management of metabolic disorders, including type 2 diabetes and obesity. Understanding the underlying mechanisms and downstream effects of nutrient-gut interactions is fundamental to effective translation of this knowledge to clinical practice. To this end, an array of research tools and platforms have been developed to better understand the mechanisms of gut hormone secretion from enteroendocrine cells. This review discusses the evolution of in vitro and in vivo models and the integration of innovative techniques that will ultimately enable the development of novel therapies for metabolic diseases.
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Affiliation(s)
- Wei-Kun Huang
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Cong Xie
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
| | - Richard L Young
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Diabetes, Nutrition and Gut Health, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, SA 5005, Australia
| | - Jiang-Bo Zhao
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Heike Ebendorff-Heidepriem
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Karen L Jones
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
| | - Christopher K Rayner
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - Tong-Zhi Wu
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
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Li D, Lv B, Wang D, Xu D, Qin S, Zhang Y, Chen J, Zhang W, Zhang Z, Xu F. Network Pharmacology and Bioactive Equivalence Assessment Integrated Strategy Driven Q-markers Discovery for Da-Cheng-Qi Decoction to Attenuate Intestinal Obstruction. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 72:153236. [PMID: 32464544 DOI: 10.1016/j.phymed.2020.153236] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 04/14/2020] [Accepted: 04/24/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Intestinal obstruction (IO) is a kind of acute abdomen with high morbidity and mortality. Patients suffer from poor quality of life and tremendous financial pressure. Da-Cheng-Qi decoction (DCQD), a classical purgation prescription, has clinically been proven to be an effective treatment for IO. PURPOSE Network pharmacology integrated with bioactive equivalence assessment was used to discover the quality marker (Q-marker) of DCQD against IO. METHODS As there is hardly any targets recorded in database, thus the collection of IO targets was conducted by searching those of alternative diseases which have similar pathological symptoms with IO. In order to improve the reliability of the obtained targets, IO metabolomics data was introduced. Active compounds combination (ACC) was focused as potential Q-markers via component-target network analysis and function query from the identified components corresponding to the common targets. Bioequivalence between ACC and DCQD was assessed from the aspects of intestine motility (somatostatin secretion), inflammation (IL-6 secretion) and injury (wound healing assay) in vitro and was further validated in ileus rat model. PPI network analysis of core targets followed by gene pedigree classification and experimental validation confirmed the potential intervention pathway. RESULTS A combination of 11 ingredients, including emodin, physcion, aloe-emodin, rhein, chrysophanol, gallic acid, magnolol, honokiol, naringenin, tangeretin, and nobiletin was finally confirmed bioequivalence with DQCD to some extent and could serve as Q-markers for DCQD to attenuate IO. PI3K/AKT was verified as a possible affected pathway that DCQD exerted the effectiveness against IO. CONCLUSION For the disease with few recorded targets, searching those of alternative diseases which have similar pathological symptoms could be a feasible and effective approach. The proposed network pharmacology integrated bioactive equivalence evaluation paradigm is efficient to discover Q-marker of herbal formulae.
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Affiliation(s)
- Danting Li
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Bo Lv
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Di Wang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Doudou Xu
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Siyuan Qin
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Ying Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Jie Chen
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Wei Zhang
- State Key Laboratory for Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau, China
| | - Zunjian Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China.
| | - Fengguo Xu
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China.
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Walters ME, Willmore WG, Tsopmo A. Antioxidant, Physicochemical, and Cellular Secretion of Glucagon-Like Peptide-1 Properties of Oat Bran Protein Hydrolysates. Antioxidants (Basel) 2020; 9:antiox9060557. [PMID: 32604813 PMCID: PMC7346174 DOI: 10.3390/antiox9060557] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 01/25/2023] Open
Abstract
The aim of this work was to determine the physicochemical and biological activities of hydrolyzed proteins from sonicated oat brans. In addition to the control bran sample, two types of pre-treatment procedures-namely, ultrasonic bath and probe-type sonication-were performed to extract proteins, followed by hydrolysis with various proteases. Physicochemical analyses showed that Flavourzyme-hydrolysates had greater amounts of aromatic amino acids, Papain-hydrolysates low surface charges (-0.78 to -1.32 mV) compared to the others (-3.67 to -9.17 mV), and Alcalase-hydrolysates a higher surface hydrophobicity. The hydrolysates had good radical scavenging activities but, as the ultrasonic pre-treatment of the brans showed, in certain cases there was a reduction in activities of up to 22% for ROO• and HO• and 15% for O2•- radicals. In anti-diabetic tests, the maximum inhibition of α-amylase was 31.8%, while that of dipeptidyl peptidase-4 was 53.6%. In addition, the secretion of glucagon-like peptide-1 in NCI-H716 cells was enhanced by 11.5% in the presence of hydrolysates.
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Affiliation(s)
- Mallory E. Walters
- Food Science and Nutrition Program, Department of Chemistry, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada;
| | - William G. Willmore
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada;
- Institute of Biochemistry, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada
| | - Apollinaire Tsopmo
- Food Science and Nutrition Program, Department of Chemistry, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada;
- Institute of Biochemistry, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada
- Correspondence: ; Tel.: +1-613-520-2600
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Calderon G, McRae A, Rievaj J, Davis J, Zandvakili I, Linker-Nord S, Burton D, Roberts G, Reimann F, Gedulin B, Vella A, LaRusso NF, Camilleri M, Gribble FM, Acosta A. Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes. EBioMedicine 2020; 55:102759. [PMID: 32344198 PMCID: PMC7186521 DOI: 10.1016/j.ebiom.2020.102759] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/26/2020] [Accepted: 04/03/2020] [Indexed: 12/12/2022] Open
Abstract
Background The bile acid (BA) pathway plays a role in regulation of food intake and glucose metabolism, based mainly on findings in animal models. Our aim was to determine whether the BA pathway is altered and correctable in human obesity and diabetes. Methods We conducted 3 investigations: 1) BA receptor pathways were studied in NCI-H716 enteroendocrine cell (EEC) line, whole human colonic mucosal tissue and in human colonic EEC isolated by Fluorescence-activated Cell Sorting (ex vivo) from endoscopically-obtained biopsies colon mucosa; 2) We characterized the BA pathway in 307 participants by measuring during fasting and postprandial levels of FGF19, 7αC4 and serum BA; 3) In a placebo-controlled, double-blind, randomised, 28-day trial, we studied the effect of ileo-colonic delivery of conjugated BAs (IC-CBAS) on glucose metabolism, incretins, and lipids, in participants with obesity and diabetes. Findings Human colonic GLP-1-producing EECs express TGR5, and upon treatment with bile acids in vitro, human EEC differentially expressed GLP-1 at the protein and mRNA level. In Ussing Chamber, GLP-1 release was stimulated by Taurocholic acid in either the apical or basolateral compartment. FGF19 was decreased in obesity and diabetes compared to controls. When compared to placebo, IC-CBAS significantly decreased postprandial glucose, fructosamine, fasting insulin, fasting LDL, and postprandial FGF19 and increased postprandial GLP-1 and C-peptide. Increase in faecal BA was associated with weight loss and with decreased fructosamine. Interpretations In humans, BA signalling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. ClinicalTrials.gov number, NCT02871882, NCT02033876. Funding Research support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). AA, MC, and NFL report grants (AA- C-Sig P30DK84567, K23 DK114460; MC- NIH R01 DK67071; NFL- R01 DK057993) from the NIH. JR was supported by an Early Career Grant from Society for Endocrinology.
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Affiliation(s)
- Gerardo Calderon
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
| | - Alison McRae
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
| | - Juraj Rievaj
- University of Cambridge, UK; Current affiliation: Dosage Form Design & Development, AstraZeneca Granta Park, Cambridge CB21 6GH, UK
| | - Judith Davis
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
| | - Inuk Zandvakili
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
| | - Sara Linker-Nord
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
| | - Duane Burton
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
| | - Geoffrey Roberts
- Current affiliation: Dosage Form Design & Development, AstraZeneca Granta Park, Cambridge CB21 6GH, UK
| | | | | | - Adrian Vella
- Division of Endocrinology, Department of Medicine, Mayo Clinic, Rochester, MN, United States
| | - Nicholas F LaRusso
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
| | | | - Andres Acosta
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States.
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Reimann F, Diakogiannaki E, Hodge D, Gribble FM. Cellular mechanisms governing glucose-dependent insulinotropic polypeptide secretion. Peptides 2020; 125:170206. [PMID: 31756367 DOI: 10.1016/j.peptides.2019.170206] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/13/2019] [Accepted: 11/14/2019] [Indexed: 02/01/2023]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted from the upper small intestine, which plays an important physiological role in the control of glucose metabolism through its incretin action to enhance glucose-dependent insulin secretion. GIP has also been implicated in postprandial lipid homeostasis. GIP is secreted from enteroendocrine K-cells residing in the intestinal epithelium. K-cells sense a variety of components found in the gut lumen following food consumption, resulting in an increase in plasma GIP signal dependent on the nature and quantity of ingested nutrients. We review the evidence for an important role of sodium-coupled glucose uptake through SGLT1 for carbohydrate sensing, of free-fatty acid receptors FFAR1/FFAR4 and the monoacyl-glycerol sensing receptor GPR119 for lipid detection, of the calcium-sensing receptor CASR and GPR142 for protein sensing, and additional modulation by neurotransmitters such as somatostatin and galanin. These pathways have been identified through combinations of in vivo, in vitro and molecular approaches.
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Affiliation(s)
- Frank Reimann
- Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, United Kingdom.
| | - Eleftheria Diakogiannaki
- Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, United Kingdom
| | - Daryl Hodge
- Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, United Kingdom
| | - Fiona M Gribble
- Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, United Kingdom.
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Yang K, Yang Y, Qi C, Ju H. Effects of porcine STC-1 on cell metabolism and mitochondrial function. Gen Comp Endocrinol 2020; 286:113298. [PMID: 31606465 DOI: 10.1016/j.ygcen.2019.113298] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 10/09/2019] [Indexed: 12/25/2022]
Abstract
Stanniocalcin (STC-1), a kind of glycoprotein hormone, was first found in fish and mainly regulates calcium/phosphorus metabolism in the body. To explore the biological function of the porcine STC-1 gene, the effects of changes in stanniocalcin expression on cellular metabolism and mitochondrial function were studied. A vector overexpressing the STC-1 gene and an siRNA silencer of the STC-1 gene were transfected into porcine kidney epithelial PK15 cells. After the STC-1 gene expression level was induced to change, STC-1 protein- and mitochondrial function-related proteins such as PMP70, OPA, DRP, Mfn and STC-1-related acetylated protein were detected by Western blotting. Cell apoptosis, mitochondrial membrane potential, reactive oxygen species (ROS), and ATP were detected using flow cytometry methods. Transmission electron microscopy was used to observe the changes in mitochondrial structure and morphology. The results showed that overexpression of the STC-1 gene could significantly upregulate the levels of PMP70, OPA, DRP and Mfn. STC-1 gene expression, which could decrease the apoptosis rate and reactive oxygen species production to significantly increase the cell membrane potential and reduce the formation of intracellular ATP, which also affected the morphology and number of mitochondria. The results were reversed when the STC-1 gene expression was silenced. The results suggested that the porcine STC-1 gene is closely related to cell growth metabolism and mitochondrial function, which influence the mitochondrial function-related proteins. The present study is useful for further understanding STC-1 gene function and provides a theoretical basis for improving the production characteristics of domestic pigs.
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Affiliation(s)
- Kaidian Yang
- College of Veterinary Medicine, Yangzhou University/Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, Jiangsu, People's Republic of China; College of Animal Science and Technology, Jilin Agricultural University/Jilin Provincial Engineering Research Center of Animal Probiotics, Changchun 130118, Jilin, People's Republic of China
| | - Yuefei Yang
- College of Veterinary Medicine, Yangzhou University/Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, Jiangsu, People's Republic of China
| | - Chuanxiang Qi
- College of Veterinary Medicine, Yangzhou University/Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, Jiangsu, People's Republic of China; College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210000, People's Republic of China
| | - Huiming Ju
- College of Veterinary Medicine, Yangzhou University/Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, Jiangsu, People's Republic of China.
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