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Lafferty RA, Flatt PR, Irwin N. GLP-1/GIP analogues: potential impact in the landscape of obesity pharmacotherapy. Expert Opin Pharmacother 2023; 24:587-597. [PMID: 36927378 DOI: 10.1080/14656566.2023.2192865] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
INTRODUCTION : Obesity is recognised as a major healthcare challenge. Following years of slow progress in discovery of safe, effective therapies for weight management, recent approval of the glucagon-like peptide 1 receptor (GLP-1R) mimetics, liraglutide and semaglutide, for obesity has generated considerable excitement. It is anticipated these agents will pave the way for application of tirzepatide, a highly effective glucose-dependent insulinotropic polypeptide receptor (GIPR), GLP-1R co-agonist recently approved for management of type 2 diabetes mellitus. AREAS COVERED : Following promising weight loss in obese individuals in Phase III clinical trials, liraglutide and semaglutide were approved for weight management without diabetes. Tirzepatide has attained Fast Track designation for obesity management by the US Food and Drug Association. This narrative review summarises experimental, preclinical and clinical data for these agents and related GLP-1R/GIPR co-agonists, prioritising clinical research published within the last 10 years where possible. EXPERT OPINION : GLP-1R mimetics are often discontinued within 24-months, owing to gastrointestinal side-effects, meaning long-term application of these agents in obesity is questioned. Combined GIPR/GLP-1R agonism appears to induce fewer side-effects, indicating GLP-1R/GIPR co-agonists may be more suitable for enduring obesity management. After years of debate, this GIPR-biased GLP-1R/GIPR co-agonist highlights the therapeutic promise of including GIPR modulation for diabetes and obesity therapy.
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Affiliation(s)
- Ryan A Lafferty
- Diabetes Research Centre, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - Peter R Flatt
- Diabetes Research Centre, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - Nigel Irwin
- Diabetes Research Centre, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
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Gallwitz B. Clinical perspectives on the use of the GIP/GLP-1 receptor agonist tirzepatide for the treatment of type-2 diabetes and obesity. Front Endocrinol (Lausanne) 2022; 13:1004044. [PMID: 36313764 PMCID: PMC9606350 DOI: 10.3389/fendo.2022.1004044] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/27/2022] [Indexed: 11/24/2022] Open
Abstract
Incretin-based therapies with glucagon-like peptide-1 receptor agonists (GLP-1RA) are already established in the treatment of type 2 diabetes (T2D). The development of novel dual- or triple-receptor agonists that bind to the receptors not only for GLP-1 but also to the receptors for glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon is intended to address different metabolic pathways for carbohydrate, lipid, and protein metabolism simultaneously. Dual- and triple-receptor agonists acting via different receptors and postreceptor pathways seem attractive in view of potentially additive or synergistic effects in the treatment of T2D and obesity. Recently, the first approval for a dual-receptor agonist marks an important step in this development. The GIP/GLP-1-receptor agonist tirzepatide was approved for the treatment of T2D by the Food and Drug Administration (FDA) in the USA for once-weekly subcutaneous injections in May 2022 and has just received a positive opinion from the European Medicines Agency (EMA). Tirzepatide dose-dependently leads to clinically significant reductions in glycemic parameters and body weight and has been shown to have stronger effects in reducing these parameters than standard antidiabetic therapy. This article summarizes the current clinical study program and the respective outcomes and highlights further potential indications for tirzepatide in the treatment of obesity and potentially other comorbidities of T2D.
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Regazzo D, Barbot M, Scaroni C, Albiger N, Occhi G. The pathogenic role of the GIP/GIPR axis in human endocrine tumors: emerging clinical mechanisms beyond diabetes. Rev Endocr Metab Disord 2020; 21:165-183. [PMID: 31933128 DOI: 10.1007/s11154-019-09536-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone produced in the gastrointestinal tract in response to nutrients. GIP has a variety of effects on different systems, including the potentiation of insulin secretion from pancreatic β-cells after food intake (i.e. incretin effect), which is probably the most important. GIP effects are mediated by the GIP receptor (GIPR), a G protein-coupled receptor expressed in several tissues, including islet β-cells, adipocytes, bone cells, and brain. As well as its involvement in metabolic disorders (e.g. it contributes to the impaired postprandial insulin secretion in type 2 diabetes (T2DM), and to the pathogenesis of obesity and associated insulin resistance), an inappropriate GIP/GIPR axis activation of potential diagnostic and prognostic value has been reported in several endocrine tumors in recent years. The ectopic GIPR expression seen in patients with overt Cushing syndrome and primary bilateral macronodular adrenal hyperplasia or unilateral cortisol-producing adenoma has been associated with an inverse rhythm of cortisol secretion, with low fasting morning plasma levels that increase after eating. On the other hand, most acromegalic patients with an unusual GH response to oral glucose suppression have GIPR-positive somatotropinomas, and a milder phenotype, and are more responsive to medical treatment. Neuroendocrine tumors are characterized by a strong GIPR expression that may correlate positively or inversely with the proliferative index MIB-1, and that seems an attractive target for developing novel radioligands. The main purpose of this review is to summarize the role of the GIP/GIPR axis in endocrine neoplasia, in the experimental and the clinical settings.
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Affiliation(s)
- Daniela Regazzo
- Department of Medicine Endocrinology Unit, Padova University Hospital, Padova, Italy
| | - Mattia Barbot
- Department of Medicine Endocrinology Unit, Padova University Hospital, Padova, Italy
| | - Carla Scaroni
- Department of Medicine Endocrinology Unit, Padova University Hospital, Padova, Italy
| | - Nora Albiger
- Endocrinology Service, ULSS 6 Euganea, Padova, Italy
| | - Gianluca Occhi
- Department of Biology, University of Padova, Padova, Italy.
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Dahiya L, Kaur R, Kumar R, Kumar M, Palta K. GLP-1 Receptor Agonists in Type 2 Diabetes Mellitus. Curr Diabetes Rev 2020; 16:279-292. [PMID: 31057118 DOI: 10.2174/1573399815666190502114924] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 03/20/2019] [Accepted: 04/17/2019] [Indexed: 12/25/2022]
Abstract
The rising epidemic of type 2 diabetes mellitus & associated complications is a serious cause of concern for humanity. Glucagon-like peptide-1 receptor agonists commonly abbreviated as GLP-1 RAs, emerged as a promising therapeutic class based on incretin therapy that regulates glucose metabolism through multiple mechanisms. In the present study, various investigational & clinically used GLP-1 RAs have been reviewed with emphasis on their efficacy, structural modifications, adverse effects and toxicities. Various clinical trials justifying their efficacy have also been included, which highlighted the potential of GLP-1 RAs over conventional anti hyperglycaemic agents through a study of pooled effect on glycemic efficacy and weight-loss. The significant potency and appreciable safety of GLP-1 RAs manifested their potential as a logical approach for the management of type 2 diabetes.
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Affiliation(s)
- Lalita Dahiya
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
| | - Ramandeep Kaur
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
| | - Rajiv Kumar
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
| | - Manoj Kumar
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
| | - Kezia Palta
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
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Affiliation(s)
- Karl-Heinz Herzig
- Institute of Biomedicine and Biocenter of Oulu, Medical Research Center and University Hospital, University of Oulu, Finland.
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6
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Irwin N, Flatt PR. New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders. World J Diabetes 2015; 6:1285-1295. [PMID: 26557956 PMCID: PMC4635139 DOI: 10.4239/wjd.v6.i15.1285] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 09/25/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
The applicability of stable gut hormones for the treatment of obesity-related diabetes is now undisputable. This is based predominantly on prominent and sustained glucose-lowering actions, plus evidence that these peptides can augment insulin secretion and pancreatic islet function over time. This review highlights the therapeutic potential of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), oxyntomodulin (OXM) and cholecystokinin (CCK) for obesity-related diabetes. Stable GLP-1 mimetics have already been successfully adopted into the diabetic clinic, whereas GIP, CCK and OXM molecules offer promise as potential new classes of antidiabetic drugs. Moreover, recent studies have shown improved therapeutic effects following simultaneous modulation of multiple receptor signalling pathways by combination therapy or use of dual/triple agonist peptides. However, timing and composition of injections may be important to permit interludes of beta-cell rest. The review also addresses the possible perils of incretin based drugs for treatment of prediabetes. Finally, the unanticipated utility of stable gut peptides as effective treatments for complications of diabetes, bone disorders, cognitive impairment and cardiovascular dysfunction is considered.
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Irwin N, Flatt PR. Enteroendocrine hormone mimetics for the treatment of obesity and diabetes. Curr Opin Pharmacol 2013; 13:989-95. [DOI: 10.1016/j.coph.2013.09.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Revised: 08/21/2013] [Accepted: 09/04/2013] [Indexed: 12/13/2022]
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Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, Peters JA, Harmar AJ. The Concise Guide to PHARMACOLOGY 2013/14: G protein-coupled receptors. Br J Pharmacol 2013; 170:1459-581. [PMID: 24517644 PMCID: PMC3892287 DOI: 10.1111/bph.12445] [Citation(s) in RCA: 509] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. G protein-coupled receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.
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Affiliation(s)
- Stephen PH Alexander
- School of Life Sciences, University of Nottingham Medical SchoolNottingham, NG7 2UH, UK
| | - Helen E Benson
- The University/BHF Centre for Cardiovascular Science, University of EdinburghEdinburgh, EH16 4TJ, UK
| | - Elena Faccenda
- The University/BHF Centre for Cardiovascular Science, University of EdinburghEdinburgh, EH16 4TJ, UK
| | - Adam J Pawson
- The University/BHF Centre for Cardiovascular Science, University of EdinburghEdinburgh, EH16 4TJ, UK
| | - Joanna L Sharman
- The University/BHF Centre for Cardiovascular Science, University of EdinburghEdinburgh, EH16 4TJ, UK
| | | | - John A Peters
- Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of DundeeDundee, DD1 9SY, UK
| | - Anthony J Harmar
- The University/BHF Centre for Cardiovascular Science, University of EdinburghEdinburgh, EH16 4TJ, UK
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Park CR, Moon MJ, Park S, Kim DK, Cho EB, Millar RP, Hwang JI, Seong JY. A novel glucagon-related peptide (GCRP) and its receptor GCRPR account for coevolution of their family members in vertebrates. PLoS One 2013; 8:e65420. [PMID: 23776481 PMCID: PMC3679108 DOI: 10.1371/journal.pone.0065420] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 04/24/2013] [Indexed: 12/25/2022] Open
Abstract
The glucagon (GCG) peptide family consists of GCG, glucagon-like peptide 1 (GLP1), and GLP2, which are derived from a common GCG precursor, and the glucose-dependent insulinotropic polypeptide (GIP). These peptides interact with cognate receptors, GCGR, GLP1R, GLP2R, and GIPR, which belong to the secretin-like G protein-coupled receptor (GPCR) family. We used bioinformatics to identify genes encoding a novel GCG-related peptide (GCRP) and its cognate receptor, GCRPR. The GCRP and GCRPR genes were found in representative tetrapod taxa such as anole lizard, chicken, and Xenopus, and in teleosts including medaka, fugu, tetraodon, and stickleback. However, they were not present in mammals and zebrafish. Phylogenetic and genome synteny analyses showed that GCRP emerged through two rounds of whole genome duplication (2R) during early vertebrate evolution. GCRPR appears to have arisen by local tandem gene duplications from a common ancestor of GCRPR, GCGR, and GLP2R after 2R. Biochemical ligand-receptor interaction analyses revealed that GCRP had the highest affinity for GCRPR in comparison to other GCGR family members. Stimulation of chicken, Xenopus, and medaka GCRPRs activated Gαs-mediated signaling. In contrast to chicken and Xenopus GCRPRs, medaka GCRPR also induced Gαq/11-mediated signaling. Chimeric peptides and receptors showed that the K16M17K18 and G16Q17A18 motifs in GCRP and GLP1, respectively, may at least in part contribute to specific recognition of their cognate receptors through interaction with the receptor core domain. In conclusion, we present novel data demonstrating that GCRP and GCRPR evolved through gene/genome duplications followed by specific modifications that conferred selective recognition to this ligand-receptor pair.
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Affiliation(s)
- Cho Rong Park
- Laboratory of G-protein Coupled Receptors, Graduate School of Medicine Korea University, Seoul, Republic of Korea
| | - Mi Jin Moon
- Laboratory of G-protein Coupled Receptors, Graduate School of Medicine Korea University, Seoul, Republic of Korea
| | - Sumi Park
- Laboratory of G-protein Coupled Receptors, Graduate School of Medicine Korea University, Seoul, Republic of Korea
| | - Dong-Kyu Kim
- Laboratory of G-protein Coupled Receptors, Graduate School of Medicine Korea University, Seoul, Republic of Korea
| | - Eun Bee Cho
- Laboratory of G-protein Coupled Receptors, Graduate School of Medicine Korea University, Seoul, Republic of Korea
| | - Robert Peter Millar
- Mammal Research Institute, Department of Zoology & Entomology, University of Pretoria, Hatfield, South Africa
- Medical Research Council Receptor Biology Unit, University of Cape Town, Observatory 7925, South Africa
- Centre for Integrative Physiology, University of Edinburgh, Edinburgh, Scotland
| | - Jong-Ik Hwang
- Laboratory of G-protein Coupled Receptors, Graduate School of Medicine Korea University, Seoul, Republic of Korea
- * E-mail: (JIH); (JYS)
| | - Jae Young Seong
- Laboratory of G-protein Coupled Receptors, Graduate School of Medicine Korea University, Seoul, Republic of Korea
- * E-mail: (JIH); (JYS)
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10
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Hewage CM, Venneti KC. Structural aspects of gut peptides with therapeutic potential for type 2 diabetes. ChemMedChem 2013; 8:560-7. [PMID: 23292985 DOI: 10.1002/cmdc.201200445] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Indexed: 12/25/2022]
Abstract
Gut hormones represent a niche subset of pharmacologically active agents that are rapidly gaining importance in medicine. Due to their exceptional specificity for their receptors, these hormones along with their analogues have attracted considerable pharmaceutical interest for the treatment of human disorders including type 2 diabetes. With the recent advances in the structural biology, a significant amount of structural information for these hormones is now available. This Minireview presents an overview of the structural aspects of these hormones, which have roles in physiological processes such as insulin secretion, as well as a discussion on the relevant structural modifications used to improve these hormones for the treatment of type 2 diabetes.
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Affiliation(s)
- Chandralal M Hewage
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
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11
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Yu X, Wallqvist A, Reifman J. Inferring high-confidence human protein-protein interactions. BMC Bioinformatics 2012; 13:79. [PMID: 22558947 PMCID: PMC3416704 DOI: 10.1186/1471-2105-13-79] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Accepted: 05/04/2012] [Indexed: 01/09/2023] Open
Abstract
Background As numerous experimental factors drive the acquisition, identification, and interpretation of protein-protein interactions (PPIs), aggregated assemblies of human PPI data invariably contain experiment-dependent noise. Ascertaining the reliability of PPIs collected from these diverse studies and scoring them to infer high-confidence networks is a non-trivial task. Moreover, a large number of PPIs share the same number of reported occurrences, making it impossible to distinguish the reliability of these PPIs and rank-order them. For example, for the data analyzed here, we found that the majority (>83%) of currently available human PPIs have been reported only once. Results In this work, we proposed an unsupervised statistical approach to score a set of diverse, experimentally identified PPIs from nine primary databases to create subsets of high-confidence human PPI networks. We evaluated this ranking method by comparing it with other methods and assessing their ability to retrieve protein associations from a number of diverse and independent reference sets. These reference sets contain known biological data that are either directly or indirectly linked to interactions between proteins. We quantified the average effect of using ranked protein interaction data to retrieve this information and showed that, when compared to randomly ranked interaction data sets, the proposed method created a larger enrichment (~134%) than either ranking based on the hypergeometric test (~109%) or occurrence ranking (~46%). Conclusions From our evaluations, it was clear that ranked interactions were always of value because higher-ranked PPIs had a higher likelihood of retrieving high-confidence experimental data. Reducing the noise inherent in aggregated experimental PPIs via our ranking scheme further increased the accuracy and enrichment of PPIs derived from a number of biologically relevant data sets. These results suggest that using our high-confidence protein interactions at different levels of confidence will help clarify the topological and biological properties associated with human protein networks.
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Affiliation(s)
- Xueping Yu
- Biotechnology High-Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Ft. Detrick, MD 21702, USA
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Moon MJ, Kim HY, Park S, Kim DK, Cho EB, Park CR, You DJ, Hwang JI, Kim K, Choe H, Seong JY. Evolutionarily conserved residues at glucagon-like peptide-1 (GLP-1) receptor core confer ligand-induced receptor activation. J Biol Chem 2011; 287:3873-84. [PMID: 22105074 DOI: 10.1074/jbc.m111.276808] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important roles in insulin secretion through their receptors, GLP1R and GIPR. Although GLP-1 and GIP are attractive candidates for treatment of type 2 diabetes and obesity, little is known regarding the molecular interaction of these peptides with the heptahelical core domain of their receptors. These core domains are important not only for specific ligand binding but also for ligand-induced receptor activation. Here, using chimeric and point-mutated GLP1R/GIPR, we determined that evolutionarily conserved amino acid residues such as Ile(196) at transmembrane helix 2, Leu(232) and Met(233) at extracellular loop 1, and Asn(302) at extracellular loop 2 of GLP1R are responsible for interaction with ligand and receptor activation. Application of chimeric GLP-1/GIP peptides together with molecular modeling suggests that His(1) of GLP-1 interacts with Asn(302) of GLP1R and that Thr(7) of GLP-1 has close contact with a binding pocket formed by Ile(196), Leu(232), and Met(233) of GLP1R. This study may provide critical clues for the development of peptide and/or nonpeptide agonists acting at GLP1R.
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Affiliation(s)
- Mi Jin Moon
- Graduate School of Medicine, Korea University, Seoul 136-705, Korea
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Moon MJ, Kim HY, Kim SG, Park J, Choi DS, Hwang JI, Seong JY. Tyr1 and Ile7 of glucose-dependent insulinotropic polypeptide (GIP) confer differential ligand selectivity toward GIP and glucagon-like peptide-1 receptors. Mol Cells 2010; 30:149-54. [PMID: 20799012 DOI: 10.1007/s10059-010-0100-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Revised: 04/30/2010] [Accepted: 05/06/2010] [Indexed: 12/25/2022] Open
Abstract
Glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones released in response to food intake and potentiate insulin secretion from pancreatic beta cells through their distinct yet related G protein-coupled receptors, GLP1R and GIPR. While GLP-1 and GIP exhibit similarity in their N-terminal sequence and overall alpha-helical structure, GLP-1 does not bind to GIPR and vice versa. To determine which amino acid residues of these peptide ligands are responsible for specific interaction with their respective receptors, we generated mutant GIP in which several GLP-1-specific amino acid residues were substituted for the original amino acids. The potency of the mutant ligands was examined using HEK293 cells transfected with GLP1R or GIPR expression plasmids together with a cAMP-responsive element-driven luciferase (CRE-luc) reporter plasmid. A mutated GIP peptide in which Tyr(1), Ile(7), Asp(15), and His(18) were replaced by His, Thr, Glu, and Ala, respectively, was able to activate both GLP1R and GIPR with moderate potency. Replacing the original Tyr(1) and/or Ile(7) in the N-terminal moiety of this mutant peptide allowed full activation of GIPR but not of GLP1R. However, reintroducing Asp(15) and/or His(18) in the central alpha-helical region did not significantly alter the ligand potency. These results suggest that Tyr/His(1) and Ile/Thr(7) of GIP/GLP-1 peptides confer differential ligand selectivity toward GIPR and GLP1R.
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Affiliation(s)
- Mi Jin Moon
- Graduate School of Medicine, Korea University, Seoul 136-705, Korea
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14
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Chen Q, Pinon DI, Miller LJ, Dong M. Molecular basis of glucagon-like peptide 1 docking to its intact receptor studied with carboxyl-terminal photolabile probes. J Biol Chem 2009; 284:34135-44. [PMID: 19815559 DOI: 10.1074/jbc.m109.038109] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The glucagon-like peptide 1 (GLP1) receptor is a member of Family B G protein-coupled receptors and represents an important drug target for type 2 diabetes. Despite recent solution of the structure of the amino-terminal domain of this receptor and that of several close family members, understanding of the molecular basis of natural ligand GLP1 binding to its intact receptor remains limited. The goal of this study was to explore spatial approximations between specific receptor residues within the carboxyl terminus of GLP1 and its receptor as normally docked. Therefore, we developed and characterized two high affinity, full-agonist photolabile GLP1 probes having sites for covalent attachment in positions 24 and 35. Both probes labeled the receptor specifically and saturably. Subsequent peptide mapping using chemical and proteinase cleavages of purified wild-type and mutant GLP1 receptor identified that the Arg(131)-Lys(136) segment at the juxtamembrane region of the receptor amino terminus contained the site of labeling for the position 24 probe, and the specific receptor residue labeled by this probe was identified as Glu(133) by radiochemical sequencing. Similarly, nearby residue Glu(125) within the same region of the receptor amino-terminal domain was identified as the site of labeling by the position 35 probe. These data represent the first direct demonstration of spatial approximation between GLP1 and its intact receptor as docked, providing two important constraints for the modeling of this interaction. This should expand our understanding of the molecular basis of natural agonist ligand binding to the GLP1 receptor and may be relevant to other family members.
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Affiliation(s)
- Quan Chen
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona 85259, USA
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Abstract
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are physiological gut peptides with insulin-releasing and extrapancreatic glucoregulatory actions. Incretin analogues/mimetics activate GLP-1 or GIP receptors whilst avoiding physiological inactivation by dipeptidyl peptidase 4 (DPP-4), and they represent one of the newest classes of antidiabetic drug. The first clinically approved GLP-1 mimetic for the treatment of type-2 diabetes is exenatide (Byetta/exendin) which is administered subcutaneously twice daily. Clinical trials of liraglutide, a GLP-1 analogue suitable for once-daily administration, are ongoing. A number of other incretin molecules are at earlier stages of development. This review discusses the various attributes of GLP-1 and GIP for diabetes treatment and summarises current clinical data. Additionally, it explores the therapeutic possibilities offered by preclinical agents, such as non-peptide GLP-1 mimetics, GLP-1/glucagon hybrid peptides, and specific GIP receptor antagonists.
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Affiliation(s)
- Brian D Green
- School of Biological Sciences, Queens University Belfast, David Keir Building, Stranmillis Road, Belfast BT6 0NJ, Northern Ireland, UK.
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16
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Parthier C, Kleinschmidt M, Neumann P, Rudolph R, Manhart S, Schlenzig D, Fanghänel J, Rahfeld JU, Demuth HU, Stubbs MT. Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor. Proc Natl Acad Sci U S A 2007; 104:13942-7. [PMID: 17715056 PMCID: PMC1955799 DOI: 10.1073/pnas.0706404104] [Citation(s) in RCA: 199] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2007] [Indexed: 11/18/2022] Open
Abstract
Incretins, endogenous polypeptide hormones released in response to food intake, potentiate insulin secretion from pancreatic beta cells after oral glucose ingestion (the incretin effect). This response is signaled by the two peptide hormones glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) and glucagon-like peptide 1 through binding and activation of their cognate class 2 G protein-coupled receptors (GPCRs). Because the incretin effect is lost or significantly reduced in patients with type 2 diabetes mellitus, glucagon-like peptide 1 and GIP have attracted considerable attention for their potential in antidiabetic therapy. A paucity of structural information precludes a detailed understanding of the processes of hormone binding and receptor activation, hampering efforts to develop novel pharmaceuticals. Here we report the crystal structure of the complex of human GIP receptor extracellular domain (ECD) with its agonist, the incretin GIP(1-42). The hormone binds in an alpha-helical conformation in a surface groove of the ECD largely through hydrophobic interactions. The N-terminal ligand residues would remain free to interact with other parts of the receptor. Thermodynamic data suggest that binding is concomitant with structural organization of the hormone, resulting in a complex mode of receptor-ligand recognition. The presentation of a well structured, alpha-helical ligand by the ECD is expected to be conserved among other hormone receptors of this class.
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Affiliation(s)
| | | | | | - Rainer Rudolph
- *Institut für Biochemie und Biotechnologie and
- *Mitteldeutsches Zentrum für Struktur und Dynamik der Proteine, Martin–Luther–Universität Halle–Wittenberg, D-06120 Halle (Saale), Germany; and
| | - Susanne Manhart
- Probiodrug AG, Biocenter Halle, D-06120 Halle (Saale), Germany
| | | | - Jörg Fanghänel
- *Mitteldeutsches Zentrum für Struktur und Dynamik der Proteine, Martin–Luther–Universität Halle–Wittenberg, D-06120 Halle (Saale), Germany; and
| | | | | | - Milton T. Stubbs
- *Institut für Biochemie und Biotechnologie and
- *Mitteldeutsches Zentrum für Struktur und Dynamik der Proteine, Martin–Luther–Universität Halle–Wittenberg, D-06120 Halle (Saale), Germany; and
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17
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Malde AK, Srivastava SS, Coutinho EC. Understanding interactions of gastric inhibitory polypeptide (GIP) with its G-protein coupled receptor through NMR and molecular modeling. J Pept Sci 2007; 13:287-300. [PMID: 17437246 DOI: 10.1002/psc.839] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Gastric inhibitory polypeptide (GIP, or glucose-dependent insulinotropic polypeptide) is a 42-amino acid incretin hormone moderating glucose-induced insulin secretion. Antidiabetic therapy based on GIP holds great promise because of the fact that its insulinotropic action is highly dependent on the level of glucose, overcoming the sideeffects of hypoglycemia associated with the current therapy of Type 2 diabetes. The truncated peptide, GIP(1-30)NH2, has the same activity as the full length native peptide. We have studied the structure of GIP(1-30)NH2 and built a model of its G-protein coupled receptor (GPCR). The structure of GIP(1-30)NH2 in DMSO-d6 and H2O has been studied using 2D NMR (total correlation spectroscopy (TOCSY), nuclear overhauser effect spectroscopy (NOESY), double quantum filtered-COSY (DQF-COSY), 13C-heteronuclear single quantum correlation (HSQC) experiments, and its conformation built by MD simulations with the NMR data as constraints. The peptide in DMSO-d6 exhibits an alpha-helix between residues Ile12 and Lys30 with a discontinuity at residues Gln19 and Gln20. In H2O, the alpha-helix starts at Ile7, breaks off at Gln19, and then continues right through to Lys30. GIP(1-30)NH2 has all the structural features of peptides belonging to family B1 GPCRs, which are characterized by a coil at the N-terminal and a long C-terminal alpha-helix with or without a break. A model of the seven transmembrane (TM) helices of the GIP receptor (GIPR) has been built on the principles of comparative protein modeling, using the crystal structure of bovine rhodopsin as a template. The N-terminal domain of GIPR has been constructed from the NMR structure of the N-terminal of corticoptropin releasing factor receptor (CRFR), a family B1 GCPR. The intra and extra cellular loops and the C-terminal have been modeled from fragments retrieved from the PDB. On the basis of the experimental data available for some members of family B1 GPCRs, four pairs of constraints between GIP(1-30)NH2 and its receptor were used in the FTDOCK program, to build the complete model of the GIP(1-30)NH2:GIPR complex. The model can rationalize the various experimental observations including the potency of the truncated GIP peptide. This work is the first complete model at the atomic level of GIP(1-30)NH2 and of the complex with its GPCR.
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MESH Headings
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Gastric Inhibitory Polypeptide/chemistry
- Gastric Inhibitory Polypeptide/metabolism
- Gastric Inhibitory Polypeptide/therapeutic use
- Gastrointestinal Agents/chemistry
- Gastrointestinal Agents/metabolism
- Gastrointestinal Agents/therapeutic use
- Glucose/metabolism
- Humans
- Insulin/metabolism
- Models, Molecular
- Nuclear Magnetic Resonance, Biomolecular
- Protein Structure, Quaternary
- Protein Structure, Secondary
- Receptors, G-Protein-Coupled/chemistry
- Receptors, G-Protein-Coupled/metabolism
- Receptors, Gastrointestinal Hormone/chemistry
- Receptors, Gastrointestinal Hormone/metabolism
- Structure-Activity Relationship
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Affiliation(s)
- Alpeshkumar K Malde
- Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400 098, India
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18
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Nauck MA, Meier JJ. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. ACTA ACUST UNITED AC 2005; 128:135-48. [PMID: 15780433 DOI: 10.1016/j.regpep.2004.07.014] [Citation(s) in RCA: 123] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2004] [Accepted: 07/08/2004] [Indexed: 01/09/2023]
Abstract
Glucagon-like peptide 1 (GLP-1) was discovered as an insulinotropic gut hormone, suggesting a physiological role as an incretin hormone, i.e., being responsible, in part, for the higher insulin secretory response after oral as compared to intravenous glucose administration. This difference, the incretin effect, is partially lost in patients with Type 2 diabetes. The actions of GLP-1 include (a) a stimulation of insulin secretion in a glucose-dependent manner, (b) a suppression of glucagon, (c) a reduction in appetite and food intake, (d) a deceleration of gastric emptying, (e) a stimulation of beta-cell neogenesis, growth and differentiation in animal and tissue culture experiments, and (f) an in vitro inhibition of beta-cell apoptosis induced by different toxins. Intravenous GLP-1 can normalize and subcutaneous GLP-1 can significantly lower plasma glucose in the majority of patients with Type 2 diabetes. GLP-1 itself, however, is inactivated rapidly in vivo and thus does not appear to be useful as a therapeutic agent in the long-term treatment of Type 2 diabetes. Other agents acting on GLP-1 receptors have been found (like exendin-4) or developed as GLP-1 derivatives (like liraglutide or GLP-1/CJC-1131). Clinical trials with exenatide (two injections per day) and liraglutide (one injection per day) have shown reductions in glucose concentrations and HbA1c by more than 1%, associated with moderate weight loss (2-3 kg), but also some nausea and, rarely, vomiting. It is hoped that this new class of drugs interacting with the GLP-1 or other incretin receptors, the so-called "incretin mimetics", will broaden our armamentarium of antidiabetic medications in the nearest future.
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Affiliation(s)
- Michael A Nauck
- Diabeteszentrum Bad Lauterberg Kirchberg 21 D-37431 Bad Lauterberg im Harz, Germany.
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19
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Alaña I, Hewage CM, Malthouse JPG, Parker JC, Gault VA, O'Harte FPM. NMR structure of the glucose-dependent insulinotropic polypeptide fragment, GIP(1–30)amide. Biochem Biophys Res Commun 2004; 325:281-6. [PMID: 15522230 DOI: 10.1016/j.bbrc.2004.10.033] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2004] [Indexed: 11/27/2022]
Abstract
Glucose-dependent insulinotropic polypeptide is an incretin hormone that stimulates insulin secretion and reduces postprandial glycaemic excursions. The glucose-dependent action of GIP on pancreatic beta-cells has attracted attention towards its exploitation as a potential drug for type 2 diabetes. Use of NMR or X-ray crystallography is vital to determine the three-dimensional structure of the peptide. Therefore, to understand the basic structural requirements for the biological activity of GIP, the solution structure of the major biologically active fragment, GIP(1-30)amide, was investigated by proton NMR spectroscopy and molecular modelling. The structure is characterised by a full length alpha-helical conformation between residues F(6) and A(28). This structural information could play an important role in the design of therapeutic agents based upon GIP receptor agonists.
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Affiliation(s)
- Iñigo Alaña
- Department of Biochemistry, Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
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20
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Hinke SA, Manhart S, Speck M, Pederson RA, Demuth HU, McIntosh CHS. In depth analysis of the N-terminal bioactive domain of gastric inhibitory polypeptide. Life Sci 2004; 75:1857-70. [PMID: 15302229 DOI: 10.1016/j.lfs.2004.03.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2003] [Accepted: 03/29/2004] [Indexed: 11/27/2022]
Abstract
Gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) is an important gastrointestinal regulator of insulin release and glucose homeostasis following a meal. Strategies have been undertaken to delineate the bioactive domains of GIP with the intention of developing small molecular weight GIP mimetics. The molecular cloning of receptors for GIP and the related hormone GLP-1 (glucagon-like peptide-1) has allowed examination of the characteristics of incretin analogs in transfected cell models. The current report examines the N-terminal bioactive domain of GIP residing in residues 1-14 by alanine scanning mutagenesis and N-terminal substitution/modification. Further studies examined peptide chimeras of GIP and GLP-1 designed to localize bioactive determinants of the two hormones. The alanine scan of the GIP(1-14) sequence established that the peptide was extremely sensitive to structural perturbations. Only replacement of amino acids 2 and 13 with those found in glucagon failed to dramatically reduce receptor binding and activation. Of four GIP(1-14) peptides modified by the introduction of DP IV-resistant groups, a peptide with a reduced bond between Ala2 and Glu3 demonstrated improved receptor potency compared to native GIP(1-14). The peptide chimera studies supported recent results on the importance of a mid-region helix for bioactivity of GIP, and confirmed existence of two separable regions with independent intrinsic receptor binding and activation properties. Furthermore, peptide chimeras showed that binding of GLP-1 also involves both N- and C-terminal domains, but that it apparently contains only a single bioactive domain in its N-terminus. Together, these results should facilitate development of incretin based therapies using rational drug design for potential treatment of diabetes.
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Affiliation(s)
- Simon A Hinke
- Department of Physiology, Faculty of Medicine, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada
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21
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Vilsbøll T, Knop FK, Krarup T, Johansen A, Madsbad S, Larsen S, Hansen T, Pedersen O, Holst JJ. The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype. J Clin Endocrinol Metab 2003; 88:4897-903. [PMID: 14557471 DOI: 10.1210/jc.2003-030738] [Citation(s) in RCA: 164] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
The effect of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma insulin response (20-120 min) to glucose by the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma insulin and C-peptide responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2 diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index < 25 kg/m(2)); 3) patients with latent autoimmune diabetes in adults; 4) diabetic patients with mutations in the HNF-1alpha gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7-36)amide/kg body weight.min or 4 pmol GIP pmol/kg body weight.min. The early-phase (0-20 min) plasma insulin response tended to be enhanced by both GIP and GLP-1, compared with glucose alone, in all five groups. In contrast, the late-phase (20-120 min) plasma insulin response to GIP was attenuated, compared with the plasma insulin response to GLP-1, in all five groups. Significantly higher glucose infusion rates were required during the late phase of the GLP-1 stimulation, compared with the GIP stimulation. In conclusion, lack of GIP amplification of the late-phase plasma insulin response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes.
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Affiliation(s)
- T Vilsbøll
- Department of Internal Medicine F, Gentofte Hospital, DK-2900 Hellerup, Denmark.
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22
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Meier JJ, Nauck MA, Schmidt WE, Gallwitz B. Gastric inhibitory polypeptide: the neglected incretin revisited. REGULATORY PEPTIDES 2002; 107:1-13. [PMID: 12137960 DOI: 10.1016/s0167-0115(02)00039-3] [Citation(s) in RCA: 161] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
After the ingestion of fat- and glucose-rich meals, gut hormones are secreted into the circulation in order to stimulate insulin secretion. This so-called "incretin effect" is primarily conferred by Glucagon-like peptide 1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP). In contrast to GLP-1, GIP has lost most of its insulinotropic effect in type 2 diabetic patients. In addition to its main physiological role in the regulation of endocrine pancreatic secretion, GIP exerts various peripheral effects on adipose tissue and lipid metabolism, thereby leading to increased lipid deposition in the postprandial state. In some animal models, an influence on gastrointestinal functions has been described. However, such effects do not seem to play an important role in humans. During the last years, the major line of research has focussed on GLP-1, due to its promising potential for the treatment of type 2 diabetes mellitus. However, the physiological importance of GIP in the regulation of insulin secretion has been shown to even exceed that of GLP-1. Furthermore, work from various groups has provided evidence that GIP contributes to the pathogenesis of type 2 diabetes to a considerable degree. Recent data with modified GIP analogues further suggested a possibility of therapeutic use in the treatment of type 2 diabetes. Thus, it seems worthwhile to refocus on this important and-sometimes-neglected incretin hormone. The present work aims to review the physiological functions of GIP, to characterize its role in the pathogenesis of type 2 diabetes, and to discuss possible clinical applications and future perspectives in the light of new findings.
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Affiliation(s)
- Juris J Meier
- Medizinische Klinik I, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum, Gudrunstrasse 56, 44791, Bochum, Germany
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23
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Bazarsuren A, Grauschopf U, Wozny M, Reusch D, Hoffmann E, Schaefer W, Panzner S, Rudolph R. In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor. Biophys Chem 2002; 96:305-18. [PMID: 12034449 DOI: 10.1016/s0301-4622(02)00023-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The N-terminal, extracellular domain of the receptor for glucagon-like peptide 1 (GLP-1 receptor) was expressed at a high level in E. coli and isolated as inclusion bodies. Renaturation with concomitant disulfide bond formation was achieved from guanidinium-solubilized material. A soluble and active fraction of the protein was isolated by ion exchange chromatography and gel filtration. Complex formation with GLP-1 was shown by cross-linking experiments, surface plasmon resonance measurements, and isothermal titration calorimetry. The existence of disulfide bridges in the N-terminal receptor fragment was proven after digestion of the protein with pepsin. Further analysis revealed a disulfide-binding pattern with links between cysteines 46 and 71, 62 and 104, and between 85 and 126.
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Affiliation(s)
- Ariuna Bazarsuren
- Institut für Biotechnologie der Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
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24
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Kühn-Wache K, Manhart S, Hoffmann T, Hinke SA, Gelling R, Pederson RA, McIntosh CH, Demuth HU. Analogs of glucose-dependent insulinotropic polypeptide with increased dipeptidyl peptidase IV resistance. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2001; 477:187-95. [PMID: 10849746 DOI: 10.1007/0-306-46826-3_21] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Affiliation(s)
- K Kühn-Wache
- Probiodrug GmbH, Biocenter, Halle, Saale, Germany
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25
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Abstract
The gastrointestinal hormone, gastric inhibitory polypeptide (GIP), is synthesized and released from the duodenum and proximal jejunum postprandially. Its release depends upon several factors including meal content and pre-existing health status (ie. obesity, diabetes, age, etc.). It was initially discovered and named for its gastric acid inhibitory properties. However, its more physiologically relevant role appears to be as an insulinotropic agent with a stimulatory effect on insulin release and synthesis. Accordingly, it was later renamed glucose-dependent insulinotropic polypeptide because its action on insulin release depends upon an increase in circulating levels of glucose. GIP is considered to be one of the principle incretin factors of the enteroinsular axis. The GIP receptor is a G-protein-coupled receptor belonging to the family of secretin/VIP receptors. GIP receptor mRNA is widely distributed in peripheral organs, including the pancreas, gut, adipose tissue, heart, adrenal cortex, and brain, suggesting it may have other functions in addition to the ones mentioned above. An overactive enteroinsular axis has been suggested to play a role in the pathogenesis of diabetes and obesity. In addition to stimulating insulin release, GIP has been shown to amplify the effect of insulin on target tissues. In adipose tissue, GIP has been reported to (1) stimulate fatty acid synthesis, (2) enhance insulin-stimulated incorporation of fatty acids into triglycerides, (3) increase insulin receptor affinity, and (4) increase sensitivity of insulin-stimulated glucose transport. In addition, although controversial, lipolytic properties of GIP have been proposed. The mechanism of action of GIP-induced effects on adipocytes is unknown, and it is unclear whether these effects of GIP on adipocytes are direct or indirect. However, there is now evidence that GIP receptors are expressed on adipocytes and that these receptors respond to GIP stimulation. Given the location of its release and the timing of its release, GIP is an ideal anabolic agent and expanding our understanding of its physiology will be needed to determine its exact role in the etiology of diabetes mellitus and obesity.
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Affiliation(s)
- R G Yip
- Department of Medicine, Boston University School of Medicine, Boston Medical Center, MA 02118, USA
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26
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Gallwitz B, Ropeter T, Morys-Wortmann C, Mentlein R, Siegel EG, Schmidt WE. GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro. REGULATORY PEPTIDES 2000; 86:103-11. [PMID: 10672909 DOI: 10.1016/s0167-0115(99)00095-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and improves glycemic control in type 2 diabetes. In serum the peptide is degraded by dipeptidyl peptidase IV (DPP IV). The resulting short biological half-time limits the therapeutic use of GLP-1. DPP IV requires an intact alpha-amino-group of the N-terminal histidine of GLP-1 in order to perform its enzymatic activity. Therefore, the following GLP- analogues with alterations in the N-terminal position 1 were synthesized: N-methylated- (N-me-GLP-1), alpha-methylated (alpha-me-GLP-1), desamidated- (desamino-GLP-1) and imidazole-lactic-acid substituted GLP-1 (imi-GLP-1). All GLP-1 analogues except alpha-me-GLP-1 were hardly degraded by DPP IV in vitro. The GLP-1 analogues showed receptor affinity and in vitro biological activity comparable to native GLP-1 in RINm5F cells. GLP-1 receptor affinity was highest for imi-GLP-1, followed by alpha-me-GLP-1 and N-me-GLP-1. Only desamino-GLP-1 showed a 15-fold loss of receptor affinity compared to native GLP-1. All analogues stimulated intracellular cAMP production in RINm5F cells in concentrations comparable to GLP-1. N-terminal modifications might therefore be useful in the development of long-acting GLP-1 analogues for type 2 diabetes therapy.
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Affiliation(s)
- B Gallwitz
- Department of Medicine I, St. Josef-Hospital, Ruhr-University of Bochum, Medical School, Gudrunstr, Germany.
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27
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Bungo T, Shimojo M, Masuda Y, Saito N, Sugahara K, Hasegawa S, Furuse M. Effects of substitution of N-terminal amino acid of glucagon-like peptide-1 (7-36) amide on food intake of the neonatal chick. Life Sci 2000; 65:PL295-9. [PMID: 10619374 DOI: 10.1016/s0024-3205(99)00535-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Glucagon-like peptide-1 (GLP-1), a member of glucagon superfamily, is synthesized from a large precursor, preproglucagon, and has been postulated to be a novel incretin. Recently, it was reported that central administration of GLP-1 (7-36) amide decreased food intake in rats and chickens. Generally, the amino acid sequences of the glucagon superfamily members except for gastric inhibitory peptide and growth hormone-releasing factor are identical at N-terminal histidine. It is well known that the GLP-1 receptor is highly specific for GLP-1 and does not bind other peptides of the glucagon superfamily. The aim of this study was to elucidate whether central injection of substituted GLP-1 in which N-terminal histidine of mammalian GLP-1 (7-36) amide was replaced with tyrosine, inhibits food intake in the chick. Intracerebroventricular administration of substituted GLP-1 inhibits food intake in the chick, although the effect of substituted GLP-1 was 11 to 13 fold less than that of mammalian GLP-1 (7-36) amide. These results indicate that N-terminal histidine of GLP-1 (7-36) amide is important for efficacy, but not essential for its bioactivity.
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Affiliation(s)
- T Bungo
- Division of Animal and Marine Bioresources Science, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka, Japan
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28
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Affiliation(s)
- T J Kieffer
- Department of Medicine, University of Alberta, Edmonton, Canada.
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29
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Siegel EG, Scharf G, Gallwitz B, Mentlein R, Morys-Wortmann C, Fölsch UR, Schmidt WE. Comparison of the effect of native glucagon-like peptide 1 and dipeptidyl peptidase IV-resistant analogues on insulin release from rat pancreatic islets. Eur J Clin Invest 1999; 29:610-4. [PMID: 10411667 DOI: 10.1046/j.1365-2362.1999.00440.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and may improve glycaemic control in type 2 diabetes. Therapeutic use is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. MATERIALS AND METHODS Five GLP-1 analogues with alterations at cleavage positions were synthesized according to the Fmoc strategy and tested for metabolic stability by incubation with rat kidney membranes containing dipeptidyl peptidase IV activity. Their insulinotropic effect was compared in isolated rat pancreatic islets after 24 h maintenance in tissue culture. Ten islets per vial were incubated for 30 min; insulin was measured radioimmunologically. Each analogue was compared with GLP-1 in the same experiment. RESULTS All analogues were biologically active in isolated islets in the potency order da2d8 = da2 > d2d9 > da2ds8 > desamino. At 16.7 mmol L-1 glucose, GLP-1 and GLP-1 analogues altered as position 2, or 2 and 8 significantly (P < 0.05) increased insulin release at 10(-9) mol L-1. N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation in rat kidney membranes in vitro. CONCLUSIONS The analogues tested are biologically active and resistant to degradation by dipeptidyl peptidase IV. Their greater metabolic stability may help to realize the potential of GLP-1 analogues in diabetes therapy.
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Affiliation(s)
- E G Siegel
- Christian-Albrechts-University of Kiel, Kiel, Germany
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30
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Meurer JA, Colca JR, Burton PS, Elhammer AP. Properties of native and in vitro glycosylated forms of the glucagon-like peptide-1 receptor antagonist exendin(9-39). Metabolism 1999; 48:716-24. [PMID: 10381145 DOI: 10.1016/s0026-0495(99)90170-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The intestinal hormone glucagon-like peptide-1-(7-36)-amide (GLP-1) has recently been implicated as a possible therapeutic agent for the management of type 2 non-insulin-dependent diabetes mellitus (NIDDM). However, a major difficulty with the delivery of peptide-based agents is their short plasma half-life, mainly due to rapid serum clearance and proteolytic degradation. Using a peptide analog of GLP-1, the GLP-1 receptor antagonist exendin(9-39), we investigated whether the conjugation of a carbohydrate structure to exendin(9-39) would generate a peptide with intact biological activity and improved survival in circulation. The C-terminal portion of exendin(9-39) was reengineered to generate an efficient site for enzymatic O-glycosylation. The modified exendin(9-39) peptide (exe-M) was glycosylated by recombinant UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 1 (GalNAc-T1) alone or in conjunction with a recombinant GalNAc alpha2,6-sialyltransferase (Sialyl-T), resulting in exe-M peptides containing either the monosaccharide GalNAc or the disaccharide NeuAc alpha2,6GalNAc. The nonglycosylated and glycosylated forms of exe-M competed with nearly equal potency (> 90% of control) with the binding of [125I]GLP-1 to human GLP-1 receptors expressed on stably transfected COS-7 cells. In addition, each peptide was equally effective for inhibiting GLP-1-induced cyclic adenosine monophosphate (cAMP) production in vitro. Studies with rats demonstrated that the modified and glycosylated forms of exendin(9-39) could antagonize exogenously administered GLP-1 in vivo. Interestingly, glycosylated exendin(9-39) homologs were more than twice as effective as the nonglycosylated peptide for inhibiting GLP-1-stimulated insulin production in vivo, suggesting a longer functional half-life in the circulation for glycosylated peptides. Results from in vivo studies with 3H-labeled peptides suggest that the glycosylated peptides may be less susceptible to modification in the circulation.
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Affiliation(s)
- J A Meurer
- Unit of Protein Research, Pharmacia & Upjohn, Kalamazoo, MI, USA
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Siegel EG, Gallwitz B, Scharf G, Mentlein R, Morys-Wortmann C, Fölsch UR, Schrezenmeir J, Drescher K, Schmidt WE. Biological activity of GLP-1-analogues with N-terminal modifications. REGULATORY PEPTIDES 1999; 79:93-102. [PMID: 10100921 DOI: 10.1016/s0167-0115(98)00155-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and improves glycemic control in type 2 diabetes. In serum the peptide is degraded by dipeptidyl peptidase IV (DPP IV). The resulting short biological half-time limits the therapeutic use of GLP-1. Therefore, various GLP-1 analogues with alterations in cleavage positions were synthesized. GLP-1-receptor binding was investigated in RINm5F cells. Biological activity of the GLP-1 analogues was investigated in vitro by measuring cAMP production in RINm5F cells. GLP-1 analogues with modifications in position 2 were not cleaved by DPP IV and showed receptor affinity and in vitro biological activity comparable to native GLP-1. Analogues with alterations in positions 2 and 8, 2 and 9 or 8 and 9 showed a significant decrease in receptor affinity and biological activity. In vivo biological activity was tested in pigs. GLP-1 analogues were administered subcutaneously followed by an intravenous bolus injection of glucose. Plasma glucose and insulin were monitored over 4 h. Compared to native GLP-1, analogues with an altered position 2 showed similar or increased potency and biological half-time. Other GLP-1 analogues were less active. Despite the lack of degradation of these GLP-1 analogues by DPP IV in vitro, their biological action is as short as that of GLP-1, except for desamino-GLP-1, indicating that other degradation enzymes are important in vivo. Alterations of GLP-1 in positions 8 or 9 result in a loss of biological activity without extending biological half-time.
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Affiliation(s)
- E G Siegel
- Laboratory for Molecular Gastroenterology and Hepatology, First Department of Medicine, Christian-Albrechts-University, Kiel, Germany
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Holz GG, Habener JF. Black widow spider alpha-latrotoxin: a presynaptic neurotoxin that shares structural homology with the glucagon-like peptide-1 family of insulin secretagogic hormones. Comp Biochem Physiol B Biochem Mol Biol 1998; 121:177-84. [PMID: 9972293 PMCID: PMC2924186 DOI: 10.1016/s0305-0491(98)10088-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
alpha-Latrotoxin is a presynaptic neurotoxin isolated from the venom of the black widow spider Latrodectus tredecimguttatus. It exerts toxic effects in the vertebrate central nervous system by depolarizing neurons, by increasing [Ca2+]i and by stimulating uncontrolled exocytosis of neurotransmitters from nerve terminals. The actions of alpha-latrotoxin are mediated, in part, by a GTP-binding protein-coupled receptor referred to as CIRL or latrophilin. Exendin-4 is also a venom toxin, and it is derived from the salivary gland of the Gila monster Heloderma suspectum. It acts as an agonist at the receptor for glucagon-like peptide-1(7-36)-amide (GLP-1), thereby stimulating secretion of insulin from pancreatic beta-cells of the islets of Langerhans. Here is reported a surprising structural homology between alpha-latrotoxin and exendin-4 that is also apparent amongst all members of the GLP-1-like family of secretagogic hormones (GLP-1, glucagon, vasoactive intestinal polypeptide, secretin, pituitary adenylyl cyclase activating polypeptide). On the basis of this homology, we report the synthesis and initial characterization of a chimeric peptide (Black Widow GLP-1) that stimulates Ca2+ signaling and insulin secretion in human beta-cells and MIN6 insulinoma cells. It is also reported here that the GTP-binding protein-coupled receptors for alpha-latrotoxin and exendin-4 share highly significant structural similarity in their extracellularly-oriented amino-termini. We propose that molecular mimicry has generated conserved structural motifs in secretagogic toxins and their receptors, thereby explaining the evolution of defense or predatory strategies that are shared in common amongst distantly related species including spiders, lizards, and snakes. Evidently, the toxic effects of alpha-latrotoxin and exendin-4 are explained by their ability to interact with GTP-binding protein-coupled receptors that normally mediate the actions of endogenous hormones or neuropeptides.
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Affiliation(s)
- G G Holz
- Diabetes Unit, Howard Hughes Medical Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
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Montrose-Rafizadeh C, Yang H, Rodgers BD, Beday A, Pritchette LA, Eng J. High potency antagonists of the pancreatic glucagon-like peptide-1 receptor. J Biol Chem 1997; 272:21201-6. [PMID: 9261127 DOI: 10.1074/jbc.272.34.21201] [Citation(s) in RCA: 131] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
GLP-1-(7-36)-amide and exendin-4-(1-39) are glucagon-like peptide-1 (GLP-1) receptor agonists, whereas exendin-(9-39) is the only known antagonist. To analyze the transition from agonist to antagonist and to identify the amino acid residues involved in ligand activation of the GLP-1 receptor, we used exendin analogs with successive N-terminal truncations. Chinese hamster ovary cells stably transfected with the rat GLP-1 receptor were assayed for changes in intracellular cAMP caused by the test peptides in the absence or presence of half-maximal stimulatory doses of GLP-1. N-terminal truncation of a single amino acid reduced the agonist activity of the exendin peptide, whereas N-terminal truncation of 3-7 amino acids produced antagonists that were 4-10-fold more potent than exendin-(9-39). N-terminal truncation of GLP-1 by 2 amino acids resulted in weak agonist activity, but an 8-amino acid N-terminal truncation inactivated the peptide. Binding studies performed using 125I-labeled GLP-1 confirmed that all bioactive peptides specifically displaced tracer with high potency. In a set of exendin/GLP-1 chimeric peptides, substitution of GLP-1 sequences into exendin-(3-39) produced loss of antagonist activity with conversion to a weak agonist. The results show that receptor binding and activation occur in separate domains of exendin, but they are more closely coupled in GLP-1.
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Affiliation(s)
- C Montrose-Rafizadeh
- Laboratory of Clinical Physiology, NIA, National Institutes of Health, Baltimore, Maryland 21224, USA
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O'Harte FP, Gray AM, Abdel-Wahab YH, Flatt PR. Effects of non-glycated and glycated glucagon-like peptide-1(7-36) amide on glucose metabolism in isolated mouse abdominal muscle. Peptides 1997; 18:1327-33. [PMID: 9392833 DOI: 10.1016/s0196-9781(97)00201-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
This study investigated the actions of non-glycated and glycated glucagon-like peptide-1(7-36)amide (tGLP-1) on glucose uptake and metabolism in isolated mouse abdominal muscle. Monoglycated tGLP-1 (Mr 3463.8) was prepared under hyperglycemic reducing conditions and purified by HPLC. Non-glycated tGLP-1 (10(-10)-10(-8) mol/l) stimulated both 2-deoxy-D-[1-3H]glucose uptake (1.3-1.5 fold) and 14C-glucose oxidation (1.4-1.7 fold) in muscle compared to controls without tGLP-1. Glycation reduced these stimulatory effects by 27-33% and 25% (at 10(-9) mol/l), respectively. tGLP-1 (10(-10)-10(-8) mol/l) promoted muscle glycogenesis and lactate production, whereas glycated peptide was ineffective below 10(-9) mol/l. This study demonstrates that tGLP-1 has potent glycogenic effects in mouse abdominal muscle in vitro and that glycation impairs its action.
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Affiliation(s)
- F P O'Harte
- School of Biomedical Sciences, University of Ulster, Coleraine, N. Ireland.
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