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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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Dao GM, Kowalski GM, Bruce CR, O'Neal DN, Smart CE, Zaharieva DP, Hennessy DT, Zhao S, Morrison DJ. The Glycemic Impact of Protein Ingestion in People With Type 1 Diabetes. Diabetes Care 2025; 48:509-518. [PMID: 39951019 DOI: 10.2337/dci24-0096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/07/2025] [Indexed: 03/23/2025]
Abstract
In individuals with type 1 diabetes, carbohydrate is commonly recognized as the primary macronutrient influencing postprandial glucose levels. Accumulating evidence indicates that protein ingestion also contributes to the increment in postprandial glucose levels, despite endocrine and metabolic responses different from those with carbohydrate ingestion. However, findings regarding protein ingestion's glycemic effect in people with type 1 diabetes are equivocal, with the magnitude of glycemic response seemingly dependent on the rate of absorption and composition of protein ingested. Therefore, the aim of this article is to outline the physiological mechanisms by which ingested protein influences blood glucose regulation in individuals with type 1 diabetes and provide clinical implications on use of dietary protein in the context of glycemic management. Specifically, protein ingestion raises plasma amino acid levels, which directly or indirectly (via gut hormones) stimulates glucagon secretion. Together with the increase in gluconeogenic precursors and an absent endogenous insulin response in individuals with type 1 diabetes, this provides a synergistic physiological environment for increased endogenous glucose production and subsequently increasing circulating glucose levels for several hours. While there is a dearth of well-controlled studies in this area, we provide clinical implications and directions for future research regarding the potential for using ingestion of fast-absorbing protein (such as whey protein) as a tool to prevent and mitigate overnight- and exercise-induced hypoglycemia in people with type 1 diabetes.
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Affiliation(s)
- Giang M Dao
- Institute for Physical Activity and Nutrition, School of Medicine, Deakin University, Geelong, Victoria, Australia
| | - Greg M Kowalski
- Institute for Physical Activity and Nutrition, School of Medicine, Deakin University, Geelong, Victoria, Australia
| | - Clinton R Bruce
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - David N O'Neal
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Carmel E Smart
- Department of Pediatrics Diabetes and Endocrinology, John Hunter Children's Hospital, Newcastle, New South Wales, Australia
| | - Dessi P Zaharieva
- Division of Pediatric Endocrinology, Department of Pediatrics, Stanford University, Stanford, CA
| | - Declan T Hennessy
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Sam Zhao
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Dale J Morrison
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
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Yang X, Lin R, Feng C, Kang Q, Yu P, Deng Y, Jin Y. Research Progress on Peptide Drugs for Type 2 Diabetes and the Possibility of Oral Administration. Pharmaceutics 2024; 16:1353. [PMID: 39598478 PMCID: PMC11597531 DOI: 10.3390/pharmaceutics16111353] [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: 08/19/2024] [Revised: 10/10/2024] [Accepted: 10/21/2024] [Indexed: 11/29/2024] Open
Abstract
Diabetes is a global disease that can lead to a range of complications. Currently, the treatment of type 2 diabetes focuses on oral hypoglycemic drugs and insulin analogues. Studies have shown that drugs such as oral metformin are useful in the treatment of diabetes but can limit the liver's ability to release sugar. The development of glucose-lowering peptides has provided new options for the treatment of type 2 diabetes. Peptide drugs have low oral utilization due to their easy degradation, short half-life, and difficulty passing through the intestinal mucosa. Therefore, improving the oral utilization of peptide drugs remains an urgent problem. This paper reviews the research progress of peptide drugs in the treatment of diabetes mellitus and proposes that different types of nano-formulation carriers, such as liposomes, self-emulsifying drug delivery systems, and polymer particles, should be combined with peptide drugs for oral administration to improve their absorption in the gastrointestinal tract.
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Affiliation(s)
- Xinxin Yang
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China; (X.Y.); (R.L.)
| | - Ruiting Lin
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China; (X.Y.); (R.L.)
| | - Changzhuo Feng
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China; (C.F.); (Q.K.); (P.Y.)
| | - Qiyuan Kang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China; (C.F.); (Q.K.); (P.Y.)
| | - Peng Yu
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China; (C.F.); (Q.K.); (P.Y.)
| | - Yongzhi Deng
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China; (X.Y.); (R.L.)
| | - Ye Jin
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China; (X.Y.); (R.L.)
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Holst JJ. GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management. Nat Metab 2024; 6:1866-1885. [PMID: 39160334 DOI: 10.1038/s42255-024-01113-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 07/17/2024] [Indexed: 08/21/2024]
Abstract
The introduction of the highly potent incretin receptor agonists semaglutide and tirzepatide has marked a new era in the treatment of type 2 diabetes and obesity. With normalisation of glycated haemoglobin levels and weight losses around 15-25%, therapeutic goals that were previously unrealistic are now within reach, and clinical trials have documented that these effects are associated with reduced risk of cardiovascular events and premature mortality. Here, I review this remarkable development from the earliest observations of glucose lowering and modest weight losses with native glucagon-like peptide (GLP)-1 and short acting compounds, to the recent development of highly active formulations and new molecules. I will classify these agents as GLP-1-based therapies in the understanding that these compounds or combinations may have actions on other receptors as well. The physiology of GLP-1 is discussed as well as its mechanisms of actions in obesity, in particular, the role of sensory afferents and GLP-1 receptors in the brain. I provide details regarding the development of GLP-1 receptor agonists for anti-obesity therapy and discuss the possible mechanism behind their beneficial effects on adverse cardiovascular events. Finally, I highlight new pharmacological developments, including oral agents, and discuss important questions regarding maintenance therapy.
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Affiliation(s)
- Jens Juul Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences. Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
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Chowdhury AS, Palui R, Pramanik S, Mondal S. Glycemic variability in chronic calcific pancreatitis with diabetes mellitus and its possible determinants. Diabetes Metab Syndr 2024; 18:103100. [PMID: 39142092 DOI: 10.1016/j.dsx.2024.103100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 08/04/2024] [Accepted: 08/06/2024] [Indexed: 08/16/2024]
Abstract
AIMS To study glycemic patterns and variability in patients with pancreatic diabetes or type 3c Diabetes mellitus (DM) due to chronic pancreatitis and its subtypes and assess the role of pancreatic enzyme replacement therapy (ERT) in modulating glycemic variability. METHODS Patients having type 3c DM due to chronic pancreatitis, and on insulin underwent Flash continuous-glucose-monitoring (CGM) for 14 days. Parameters were compared between patients with fibrocalculous pancreatic diabetes (FCPD) and non-FCPD-chronic calcific pancreatitis (non-FCPD) and between the recipients and non-recipients of pancreatic enzyme-replacement-therapy (ERT). RESULTS Out of 54 patients with pancreatic diabetes, 35 patients had chronic calcific pancreatitis. They underwent CGM, median HbA1c 9.20 % (77 mmol/mol) and mean Time-In-Range (TIR) being 41.21 % (23.48). Only 5 (15.2 %) patients achieved target TIR>70 % while 16 (48.5 %) patients had high glycemic-variability [Coefficient-of-variation (CV) > 36 %]. Patients with FCPD (n = 14) had higher hypoglycemia-indices like Time-Below-Range (18.92 % vs 8.20 %; p = 0.03) and Low-Blood-Glucose-Index (18.14 % vs 6.04 %; p = 0.02) compared to non-FCPD (n = 21). HbA1c% and hyperglycemic excursions were similar in both groups. Recipients of ERT (n = 20) had lower glycemic-variability [Standard Deviation (SD) 52.15 % vs 68.14 % and CV 32.59 % vs 41.79 %, p < 0.05 for both) than non-recipients. ERT-recipients had no serious hypoglycemia within the 14 days. On subgroup analysis, lower glycemic-variability and hypoglycemia with ERT were seen only in FCPD but not in non-FCPD subgroup (50.13 vs 77.91, 30.09 vs 48.36 for SD and CV respectively, p < 0.05). CONCLUSION Patients with type 3c DM due to chronic pancreatitis have high frequency of hyperglycemic and hypoglycemic excursions, with those with FCPD having a particularly higher risk of hypoglycemia and glycemic-variability. Those receiving pancreatic ERT had lesser glycemic variability and hypoglycemia. The small sample size and lack of objective markers of documentation of exocrine pancreatic insufficiency like fecal elastase highlight the need for further larger studies in this field.
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Affiliation(s)
| | - Rajan Palui
- Department of Endocrinology, The Mission Hospital, Durgapur, West Bengal, India.
| | | | - Sunetra Mondal
- Department of Endocrinology and Metabolism, HealthWorld hospitals, Durgapur, India.
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Lewandowski SL, El K, Campbell JE. Evaluating glucose-dependent insulinotropic polypeptide and glucagon as key regulators of insulin secretion in the pancreatic islet. Am J Physiol Endocrinol Metab 2024; 327:E103-E110. [PMID: 38775725 PMCID: PMC11390117 DOI: 10.1152/ajpendo.00360.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/27/2024] [Accepted: 05/09/2024] [Indexed: 06/04/2024]
Abstract
The incretin axis is an essential component of postprandial insulin secretion and glucose homeostasis. There are two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert multiple actions throughout the body. A key cellular target for the incretins are pancreatic β-cells, where they potentiate nutrient-stimulated insulin secretion. This feature of incretins has made this system an attractive target for therapeutic interventions aimed at controlling glycemia. Here, we discuss the role of GIP in both β-cells and α-cells within the islet, to stimulate insulin and glucagon secretion, respectively. Moreover, we discuss how glucagon secretion from α-cells has important insulinotropic actions in β-cells through an axis termed α- to β-cell communication. These recent advances have elevated the potential of GIP and glucagon as a therapeutic targets, coinciding with emerging compounds that pharmacologically leverage the actions of these two peptides in the context of diabetes and obesity.
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Affiliation(s)
- Sophie L Lewandowski
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
| | - Kimberley El
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
- Division of Endocrinology, Department of Medicine, Duke University, Durham, North Carolina, United States
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, United States
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Helsted MM, Schaltz NL, Gasbjerg LS, Christensen MB, Vilsbøll T, Knop FK. Safety of native glucose-dependent insulinotropic polypeptide in humans. Peptides 2024; 177:171214. [PMID: 38615716 DOI: 10.1016/j.peptides.2024.171214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/04/2024] [Accepted: 04/09/2024] [Indexed: 04/16/2024]
Abstract
In this systematic review, we assessed the safety and possible safety events of native glucose-dependent insulinotropic polypeptide (GIP)(1-42) in human studies with administration of synthetic human GIP. We searched the PubMed database for all trials investigating synthetic human GIP(1-42) administration. A total of 67 studies were included. Study duration ranged from 30 min to 6 days. In addition to healthy individuals, the studies included individuals with impaired glucose tolerance, type 2 diabetes, type 1 diabetes, chronic pancreatitis and secondary diabetes, latent autoimmune diabetes in adults, diabetes caused by a mutation in the hepatocyte nuclear factor 1-alpha gene, end-stage renal disease, chronic renal insufficiency, critical illness, hypoparathyroidism, or cystic fibrosis-related diabetes. Of the included studies, 78% did not mention safety events, 10% of the studies reported that no safety events were observed in relation to GIP administration, and 15% of the studies reported safety events in relation to GIP administration with most frequently reported event being a moderate and transient increased heart rate. Gastrointestinal safety events, and changes in blood pressure were also reported. Plasma concentration of active GIP(1-42) increased linearly with dose independent of participant phenotype. There was no significant correlation between achieved maximal concentration of GIP(1-42) and reported safety events. Clearance rates of GIP(1-42) were similar between participant groups. In conclusion, the available data indicate that GIP(1-42) in short-term (up to 6 days) infusion studies is generally well-tolerated. The long-term safety of continuous GIP(1-42) administration is unknown.
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Affiliation(s)
- Mads M Helsted
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Nina L Schaltz
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Herlev, Denmark.
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Gasbjerg LS, Rasmussen RS, Dragan A, Lindquist P, Melchiorsen JU, Stepniewski TM, Schiellerup S, Tordrup EK, Gadgaard S, Kizilkaya HS, Willems S, Zhong Y, Wang Y, Wright SC, Lauschke VM, Hartmann B, Holst JJ, Selent J, Rosenkilde MM. Altered desensitization and internalization patterns of rodent versus human glucose-dependent insulinotropic polypeptide (GIP) receptors. An important drug discovery challenge. Br J Pharmacol 2024. [PMID: 38952084 DOI: 10.1111/bph.16478] [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: 07/12/2023] [Revised: 04/10/2024] [Accepted: 05/06/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND AND PURPOSE The gut hormone glucose-dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR), resulting in postprandial potentiation of glucose-stimulated insulin secretion. The translation of results from rodent studies to human studies has been challenged by the unexpected effects of GIPR-targeting compounds. We, therefore, investigated the variation between species, focusing on GIPR desensitization and the role of the receptor C-terminus. EXPERIMENTAL APPROACH The GIPR from humans, mice, rats, pigs, dogs and cats was studied in vitro for cognate ligand affinity, G protein activation (cAMP accumulation), recruitment of beta-arrestin and internalization. Variants of the mouse, rat and human GIPRs with swapped C-terminal tails were studied in parallel. KEY RESULTS The human GIPR is more prone to internalization than rodent GIPRs. Despite similar agonist affinities and potencies for Gαs activation, especially, the mouse GIPR shows reduced receptor desensitization, internalization and beta-arrestin recruitment. Using an enzyme-stabilized, long-acting GIP analogue, the species differences were even more pronounced. 'Tail-swapped' human, rat and mouse GIPRs were all fully functional in their Gαs coupling, and the mouse GIPR regained internalization and beta-arrestin 2 recruitment properties with the human tail. The human GIPR lost the ability to recruit beta-arrestin 2 when its own C-terminus was replaced by the rat or mouse tail. CONCLUSIONS AND IMPLICATIONS Desensitization of the human GIPR is dependent on the C-terminal tail. The species-dependent functionality of the C-terminal tail and the different species-dependent internalization patterns, especially between human and mouse GIPRs, are important factors influencing the preclinical evaluation of GIPR-targeting therapeutic compounds.
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Affiliation(s)
- Lærke Smidt Gasbjerg
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rasmus Syberg Rasmussen
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Adrian Dragan
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter Lindquist
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Josefine Ulrikke Melchiorsen
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tomasz Maciej Stepniewski
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Research Institute and Pompeu Fabra University, Barcelona, Spain
- InterAx Biotech AG, Villigen, Switzerland
- Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Warsaw, Poland
| | - Sine Schiellerup
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Esther Karen Tordrup
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sarina Gadgaard
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Bainan Biotech, Copenhagen, Denmark
| | - Hüsün Sheyma Kizilkaya
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sabine Willems
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Yi Zhong
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yi Wang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, China
- National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China
| | - Shane C Wright
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Volker M Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Center for Basic Metabolic Research, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jana Selent
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Research Institute and Pompeu Fabra University, Barcelona, Spain
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Rosenkilde MM, Lindquist P, Kizilkaya HS, Gasbjerg LS. GIP-derived GIP receptor antagonists - a review of their role in GIP receptor pharmacology. Peptides 2024; 177:171212. [PMID: 38608836 DOI: 10.1016/j.peptides.2024.171212] [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: 02/03/2024] [Revised: 04/01/2024] [Accepted: 04/08/2024] [Indexed: 04/14/2024]
Abstract
Surprisingly, agonists, as well as antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR), are currently being used or investigated as treatment options for type 2 diabetes and obesity - and both, when combined with glucagon-like peptide 1 receptor (GLP-1R) agonism, enhance GLP-1-induced glycemia and weight loss further. This paradox raises several questions regarding not only the mechanisms of actions of GIP but also the processes engaged during the activation of both the GIP and GLP-1 receptors. Here, we provide an overview of studies of the properties and actions of peptide-derived GIPR antagonists, focusing on GIP(3-30)NH2, a naturally occurring N- and C-terminal truncation of GIP(1-42). GIP(3-30)NH2 was the first GIPR antagonist administered to humans. GIP(3-30)NH2 and a few additional antagonists, like Pro3-GIP, have been used in both in vitro and in vivo studies to elucidate the molecular and cellular consequences of GIPR inhibition, desensitization, and internalization and, at a larger scale, the role of the GIP system in health and disease. We provide an overview of these studies combined with recent knowledge regarding the effects of naturally occurring variants of the GIPR system and species differences within the GIP system to enhance our understanding of the GIPR as a drug target.
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Affiliation(s)
- Mette Marie Rosenkilde
- Molecular and Translational Pharmacology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Peter Lindquist
- Molecular and Translational Pharmacology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hüsün Sheyma Kizilkaya
- Molecular and Translational Pharmacology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lærke Smidt Gasbjerg
- Molecular and Translational Pharmacology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
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10
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Liu H, Xiao H, Lin S, Zhou H, Cheng Y, Xie B, Xu D. Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis. Front Pharmacol 2024; 15:1372399. [PMID: 38725663 PMCID: PMC11079205 DOI: 10.3389/fphar.2024.1372399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 03/25/2024] [Indexed: 05/12/2024] Open
Abstract
Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.
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Affiliation(s)
- Hongyu Liu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Huimin Xiao
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Sufen Lin
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Huan Zhou
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Yizhao Cheng
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Baocheng Xie
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Department of Pharmacy, The 10th Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Dongguan, China
| | - Daohua Xu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
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11
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Dong Y, Zhang J, Xu H, Shen H, Lu Q, Feng J, Cai Z. Design of a novel long-acting dual GLP-1/GIP receptor agonist. Bioorg Med Chem 2024; 100:117630. [PMID: 38330849 DOI: 10.1016/j.bmc.2024.117630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/21/2024] [Accepted: 01/31/2024] [Indexed: 02/10/2024]
Abstract
Tirzepatide, the first approved dual GLP-1/GIP receptor agonist (RA), has achieved better clinical outcomes than other GLP-1RAs. However, it is an imbalanced dual GIP/GLP-1 RA, and it remains unclear whether the degree of imbalance is optimal. Here, we present a novel long-acting dual GLP-1/GIP RA that exhibits better activity than tirzepatide toward GLP-1R. A candidate conjugate, D314, identified via peptide design, synthesis, conjugation, and experimentation, was evaluated using chronic studies in db/db and diet induced obese (DIO) mice. D314 achieved favorable blood glucose and body weight-lowering effects, equal to those of tirzepatide. Its half-life in dogs (T1/2: 78.3 ± 14.01 h) reveals its suitability for once-weekly administration in humans. This preclinical study suggests the potential role of D314 as an effective agent for treating T2DM and obesity.
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Affiliation(s)
- Yuanzhen Dong
- China State Institute of Pharmaceutical Industry, 201203 Shanghai, China; Shanghai Duomirui Biotechnology Ltd, 201203 Shanghai, China
| | - Jinhua Zhang
- China State Institute of Pharmaceutical Industry, 201203 Shanghai, China
| | - Hongjiang Xu
- Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd, Nanjing, China
| | - Hengqiao Shen
- Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd, Nanjing, China
| | - Qin Lu
- Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd, Nanjing, China
| | - Jun Feng
- China State Institute of Pharmaceutical Industry, 201203 Shanghai, China; Shanghai Duomirui Biotechnology Ltd, 201203 Shanghai, China.
| | - Zhengyan Cai
- China State Institute of Pharmaceutical Industry, 201203 Shanghai, China.
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12
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Jędrysik M, Wyszomirski K, Różańska-Walędziak A, Grosicka-Maciąg E, Walędziak M, Chełstowska B. The Role of GLP-1, GIP, MCP-1 and IGFBP-7 Biomarkers in the Development of Metabolic Disorders: A Review and Predictive Analysis in the Context of Diabetes and Obesity. Biomedicines 2024; 12:159. [PMID: 38255264 PMCID: PMC10813748 DOI: 10.3390/biomedicines12010159] [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: 12/01/2023] [Revised: 12/29/2023] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
Metabolic illnesses, including obesity and type 2 diabetes, have become worldwide epidemics that have an effect on public health. Clinical investigations and further exploration of these mechanisms could lead to innovative, effective, and personalized treatment strategies for individuals. It is important to screen biomarkers in previous studies to discover what is missing. Glucagon-like peptide-1's role in insulin secretion and glucose control highlights its diagnostic and therapeutic potential. Glucose-dependent insulinotropic peptide's influence on postprandial satiety and weight management signifies its importance in understanding metabolic processes. Monocyte chemoattractant protein-1's involvement in inflammation and insulin resistance underlines its value as a diagnostic marker. Insulin-like growth factor-binding protein-7's association with insulin sensitivity and kidney function presents it as a potential target for these diseases' management. In validating these biomarkers, it will be easier to reflect pathophysiological processes, and clinicians will be able to better assess disease severity, monitor disease progression, and tailor treatment strategies. The purpose of the study was to elucidate the significance of identifying novel biomarkers for type 2 diabetes mellitus and obesity, which can revolutionize early detection, risk assessment, and personalized treatment strategies. Standard literature searches of PubMed (MEDLINE), EMBASE, and Cochrane Library were conducted in the year 2023 to identify both original RCTs and recent systematic reviews that have explored the importance of identifying novel biomarkers for T2D and obesity. This search produced 1964 results, and then was reduced to randomized controlled trial and systematic reviews, producing 145 results and 44 results, respectively. Researchers have discovered potential associations between type 2 diabetes mellitus and obesity and the biomarkers glucagon-like peptide-1, glucose-dependent insulinotropic peptide, monocyte chemoattractant protein-1, and insulin-like growth factor-binding protein-7. Understanding the role of those biomarkers in disease pathogenesis offers hope for improving diagnostics, personalized treatment, and prevention strategies.
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Affiliation(s)
- Malwina Jędrysik
- Department of Biochemistry and Laboratory Diagnostics, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, 01-938 Warsaw, Poland; (M.J.); (E.G.-M.); (B.C.)
| | - Krzysztof Wyszomirski
- Department of Human Physiology and Pathophysiology, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, 01-938 Warsaw, Poland;
| | - Anna Różańska-Walędziak
- Department of Human Physiology and Pathophysiology, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, 01-938 Warsaw, Poland;
| | - Emilia Grosicka-Maciąg
- Department of Biochemistry and Laboratory Diagnostics, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, 01-938 Warsaw, Poland; (M.J.); (E.G.-M.); (B.C.)
| | - Maciej Walędziak
- Department of General, Oncological, Metabolic and Thoracic Surgery, Military Institute of Medicine—National Research Institute, Szaserów 128 St., 04-141 Warsaw, Poland;
| | - Beata Chełstowska
- Department of Biochemistry and Laboratory Diagnostics, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, 01-938 Warsaw, Poland; (M.J.); (E.G.-M.); (B.C.)
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13
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Bany Bakar R, Reimann F, Gribble FM. The intestine as an endocrine organ and the role of gut hormones in metabolic regulation. Nat Rev Gastroenterol Hepatol 2023; 20:784-796. [PMID: 37626258 DOI: 10.1038/s41575-023-00830-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2023] [Indexed: 08/27/2023]
Abstract
Gut hormones orchestrate pivotal physiological processes in multiple metabolically active tissues, including the pancreas, liver, adipose tissue, gut and central nervous system, making them attractive therapeutic targets in the treatment of obesity and type 2 diabetes mellitus. Most gut hormones are derived from enteroendocrine cells, but bioactive peptides that are derived from other intestinal epithelial cell types have also been implicated in metabolic regulation and can be considered gut hormones. A deeper understanding of the complex inter-organ crosstalk mediated by the intestinal endocrine system is a prerequisite for designing more effective drugs that are based on or target gut hormones and their receptors, and extending their therapeutic potential beyond obesity and diabetes mellitus. In this Review, we present an overview of gut hormones that are involved in the regulation of metabolism and discuss their action in the gastrointestinal system and beyond.
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Affiliation(s)
- Rula Bany Bakar
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Frank Reimann
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Fiona M Gribble
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
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14
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Gasbjerg LS, Rosenkilde MM, Meier JJ, Holst JJ, Knop FK. The importance of glucose-dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide. Diabetes Obes Metab 2023; 25:3079-3092. [PMID: 37551549 DOI: 10.1111/dom.15216] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/22/2023] [Accepted: 07/02/2023] [Indexed: 08/09/2023]
Abstract
Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.
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Affiliation(s)
- Laerke S Gasbjerg
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Juris J Meier
- Department of Internal Medicine, Gastroenterology and Diabetology, Augusta Clinic, Bochum, Germany
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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15
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Goodarzi MO, Petrov MS. Diabetes of the Exocrine Pancreas: Implications for Pharmacological Management. Drugs 2023:10.1007/s40265-023-01913-5. [PMID: 37410209 PMCID: PMC10361873 DOI: 10.1007/s40265-023-01913-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/12/2023] [Indexed: 07/07/2023]
Abstract
Post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes are often underappreciated. As a result, a substantial proportion of people with these sub-types of diabetes receive antidiabetic medications that may be suboptimal, if not harmful, in the context of their underlying disease of the exocrine pancreas. The present article delineates both classical (biguanides, insulin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and meglitinides) and newer (glucagon-like peptide-1 receptor agonists, amylin analogs, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, D2 receptor agonists, bile acid sequestrants, and dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor co-agonists) therapies and provides recommendations for managing people with diabetes of the exocrine pancreas based on the most up-to-date clinical evidence. Also, several emerging directions (lipid-enriched pathways, Y4 receptor agonism, glucagon-like peptide-1 and glucagon receptor co-agonism) are presented with a view to informing the process of new drug discovery and development.
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Affiliation(s)
- Mark O Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Maxim S Petrov
- School of Medicine, University of Auckland, Auckland, New Zealand.
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16
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Le Solliec MA, Arabo A, Takhlidjt S, Maucotel J, Devère M, Berrahmoune H, Bénani A, Nedelec E, Lefranc B, Leprince J, Picot M, Chartrel N, Prévost G. Interactions between the regulatory peptide 26RFa (QRFP) and insulin in the regulation of glucose homeostasis in two complementary models: The high fat 26RFa-deficient mice and the streptozotocin insulin-deficient mice. Neuropeptides 2023; 98:102326. [PMID: 36791581 DOI: 10.1016/j.npep.2023.102326] [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: 11/21/2022] [Revised: 01/18/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023]
Abstract
The regulatory peptide 26RFa (QRFP) is involved in the control of glucose homeostasis at the periphery by acting as an incretin, and in the brain by mediating the central antihyperglycemic effect of insulin, indicating the occurrence of a close relationship between 26RFa and insulin in the regulation of glucose metabolism. Here, we investigated the physiological interactions between 26RFa and insulin in two complementary models i.e. a model of obese/hyperglycemic mice deficient for 26RFa and a model of diabetic mice deficient for insulin. For this, transgenic 26RFa-deficient mice were made obese and chronically hyperglycemic by a 3-month high fat diet (HFD) and second group of mice was made diabetic by destruction of the β cells of the pancreatic islets using a single injection of streptozotocin. Our data reveal that 26RFa deficiency does not impact significantly the "glycemic" phenotype of the HFD mice. The pancreatic islets, liver, white adipose tissue masses are not altered by the lack of 26RFa production but the brown adipose tissue (BAT) weight is significantly increased in these animals. In diabetic insulin-deficient mice, the injection of 26RFa does not exhibit any beneficial effect on the impaired glucose homeostasis characterizing this model. Finally, we show that streptozotocin diabetic mice display lowered plasma 26RFa levels as compared to untreated mice, whereas the expression of the peptide in the duodenum is not affected. Taken together, the present results indicate that dysregulation of glucose homeostasis in obese/hyperglycemic mice is not aggravated by the absence of 26RFa that may be compensated by the increase of BAT mass. In diabetic insulin-deficient mice, the antihypergycemic effect of 26RFa is totally blunted probably as a result of the impaired insulin production characterizing this model, avoiding therefore the action of the peptide.
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Affiliation(s)
| | - Arnaud Arabo
- Univ Rouen Normandie, INSERM US 31, CNRS UAR 2026, HeRacLeS, F-76000 Rouen, France
| | - Saloua Takhlidjt
- Univ Rouen Normandie, INSERM UMR 1239, NorDiC, F-76000 Rouen, France
| | - Julie Maucotel
- Univ Rouen Normandie, INSERM US 31, CNRS UAR 2026, HeRacLeS, F-76000 Rouen, France
| | - Mélodie Devère
- Univ Rouen Normandie, INSERM UMR 1239, NorDiC, F-76000 Rouen, France
| | - Hind Berrahmoune
- Univ Rouen Normandie, INSERM UMR 1239, NorDiC, F-76000 Rouen, France
| | - Alexandre Bénani
- Center for Taste and Feeding Behaviour, CNRS (UMR6265), INRA (UMR1324), AgroSup Dijon, Université de Bourgogne-Franche Comté, 21000 Dijon, France
| | - Emmanuelle Nedelec
- Center for Taste and Feeding Behaviour, CNRS (UMR6265), INRA (UMR1324), AgroSup Dijon, Université de Bourgogne-Franche Comté, 21000 Dijon, France
| | - Benjamin Lefranc
- Univ Rouen Normandie, INSERM UMR 1239, NorDiC, F-76000 Rouen, France; Univ Rouen Normandie, Cell Imaging Platform of Normandy (PRIMACEN), F-76000 Rouen, France
| | - Jérôme Leprince
- Univ Rouen Normandie, INSERM UMR 1239, NorDiC, F-76000 Rouen, France; Univ Rouen Normandie, Cell Imaging Platform of Normandy (PRIMACEN), F-76000 Rouen, France
| | - Marie Picot
- Univ Rouen Normandie, INSERM UMR 1239, NorDiC, F-76000 Rouen, France
| | - Nicolas Chartrel
- Univ Rouen Normandie, INSERM UMR 1239, NorDiC, F-76000 Rouen, France.
| | - Gaëtan Prévost
- Normandie Univ, UNIROUEN, Inserm U1239, CHU Rouen, Department of Endocrinology, Diabetes and metabolic diseases, F-76000 Rouen, France
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17
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Maagensen H, Helsted MM, Gasbjerg LS, Vilsbøll T, Knop FK. The Gut-Bone Axis in Diabetes. Curr Osteoporos Rep 2023; 21:21-31. [PMID: 36441432 DOI: 10.1007/s11914-022-00767-2] [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] [Accepted: 11/03/2022] [Indexed: 11/29/2022]
Abstract
PURPOSE OF REVIEW To describe recent advances in the understanding of how gut-derived hormones regulate bone homeostasis in humans with emphasis on pathophysiological and therapeutic perspectives in diabetes. RECENT FINDINGS The gut-derived incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is important for postprandial suppression of bone resorption. The other incretin hormone, glucagon-like peptide 1 (GLP-1), as well as the intestinotrophic glucagon-like peptide 2 (GLP-2) has been shown to suppress bone resorption in pharmacological concentrations, but the role of the endogenous hormones in bone homeostasis is uncertain. For ambiguous reasons, both patients with type 1 and type 2 diabetes have increased fracture risk. In diabetes, the suppressive effect of endogenous GIP on bone resorption seems preserved, while the effect of GLP-2 remains unexplored both pharmacologically and physiologically. GLP-1 receptor agonists, used for the treatment of type 2 diabetes and obesity, may reduce bone loss, but results are inconsistent. GIP is an important physiological suppressor of postprandial bone resorption, while GLP-1 and GLP-2 may also exert bone-preserving effects when used pharmacologically. A better understanding of the actions of these gut hormones on bone homeostasis in patients with diabetes may lead to new strategies for the prevention and treatment of skeletal frailty related to diabetes.
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Affiliation(s)
- Henrik Maagensen
- Clinical Research, Copenhagen University Hospital-Steno Diabetes Center Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
| | - Mads M Helsted
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Clinical Research, Copenhagen University Hospital-Steno Diabetes Center Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Clinical Research, Copenhagen University Hospital-Steno Diabetes Center Copenhagen, Herlev, Denmark.
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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18
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Krogh LSL, Henriksen K, Stensen S, Skov-Jeppesen K, Bergmann NC, Størling J, Rosenkilde MM, Hartmann B, Holst JJ, Gasbjerg LS, Knop FK. The naturally occurring GIP(1-30)NH2 is a GIP receptor agonist in humans. Eur J Endocrinol 2023; 188:6979719. [PMID: 36651162 DOI: 10.1093/ejendo/lvac015] [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: 10/19/2022] [Revised: 11/30/2022] [Accepted: 12/14/2022] [Indexed: 01/11/2023]
Abstract
OBJECTIVE The gut hormone glucose-dependent insulinotropic polypeptide (GIP) is an important regulator of glucose and bone metabolism. In rodents, the naturally occurring GIP variant, GIP(1-30)NH2, has shown similar effects as full-length GIP (GIP(1-42)), but its effects in humans are unsettled. Here, we investigated the actions of GIP(1-30)NH2 compared to GIP(1-42) on glucose and bone metabolism in healthy men and in isolated human pancreatic islets. METHODS Nine healthy men completed three separate three-step glucose clamps (0-60 minutes at fasting plasma glucose (FPG) level, 60-120 minutes at 1.5× FPG, and 120-180 minutes at 2× FPG) with infusion of GIP(1-42) (4 pmol/kg/min), GIP(1-30)NH2 (4 pmol/kg/min), and saline (9 mg/mL) in randomised order. Blood was sampled for measurement of relevant hormones and bone turnover markers. Human islets were incubated with low (2 mmol/L) or high (20 mmol/L) d-glucose with or without GIP(1-42) or GIP(1-30)NH2 in three different concentrations for 30 minutes, and secreted insulin and glucagon were measured. RESULTS Plasma glucose (PG) levels at FPG, 1.5× FPG, and 2× FPG were obtained by infusion of 1.45 g/kg, 0.97 g/kg, and 0.6 g/kg of glucose during GIP(1-42), GIP(1-30)NH2, and saline, respectively (P = .18), and were similar on the three experimental days. Compared to placebo, GIP(1-30)NH2 resulted in similar glucagonotropic, insulinotropic, and carboxy-terminal type 1 collagen crosslinks-suppressing effects as GIP(1-42). In vitro experiments on human islets showed similar insulinotropic and glucagonotropic effects of the two GIP variants. CONCLUSIONS GIP(1-30)NH2 has similar effects on glucose and bone metabolism in healthy individuals and in human islets in vitro as GIP(1-42).
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Affiliation(s)
- Liva S L Krogh
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Kristine Henriksen
- Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Signe Stensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Kirsa Skov-Jeppesen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Natasha C Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Joachim Størling
- Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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19
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Study of relationship between glucagon level, glycemic status, and β-cell function in newly diagnosed T2DM patients, treated with insulin. Int J Diabetes Dev Ctries 2022. [DOI: 10.1007/s13410-022-01154-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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20
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Nyirjesy SC, Peleckis AJ, Eiel JN, Gallagher K, Doliba A, Tami A, Flatt AJ, De Leon DD, Hadjiliadis D, Sheikh S, Stefanovski D, Gallop R, D’Alessio DA, Rubenstein RC, Kelly A, Rickels MR. Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis. Diabetes 2022; 71:2153-2165. [PMID: 35796669 PMCID: PMC9501647 DOI: 10.2337/db22-0399] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/01/2022] [Indexed: 01/07/2023]
Abstract
Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.
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Affiliation(s)
- Sarah C. Nyirjesy
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Amy J. Peleckis
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Jack N. Eiel
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Kathryn Gallagher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Andriana Doliba
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Abigail Tami
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Anneliese J. Flatt
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Diva D. De Leon
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Denis Hadjiliadis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Saba Sheikh
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Darko Stefanovski
- New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA
| | - Robert Gallop
- Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA
- Department of Mathematics, West Chester University of Pennsylvania, West Chester, PA
| | - David A. D’Alessio
- Division of Endocrinology and Metabolism, Department of Medicine, Duke University School of Medicine, Durham, NC
| | - Ronald C. Rubenstein
- Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Michael R. Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
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21
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ADGRL3 genomic variation implicated in neurogenesis and ADHD links functional effects to the incretin polypeptide GIP. Sci Rep 2022; 12:15922. [PMID: 36151371 PMCID: PMC9508192 DOI: 10.1038/s41598-022-20343-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 09/12/2022] [Indexed: 11/09/2022] Open
Abstract
Attention deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder. Single nucleotide polymorphisms (SNPs) in the Adhesion G Protein-Coupled Receptor L3 (ADGRL3) gene are associated with increased susceptibility to developing ADHD worldwide. However, the effect of ADGRL3 non-synonymous SNPs (nsSNPs) on the ADGRL3 protein function is vastly unknown. Using several bioinformatics tools to evaluate the impact of mutations, we found that nsSNPs rs35106420, rs61747658, and rs734644, previously reported to be associated and in linkage with ADHD in disparate populations from the world over, are predicted as pathogenic variants. Docking analysis of rs35106420, harbored in the ADGLR3-hormone receptor domain (HRM, a common extracellular domain of the secretin-like GPCRs family), showed that HRM interacts with the Glucose-dependent insulinotropic polypeptide (GIP), part of the incretin hormones family. GIP has been linked to the pathogenesis of diabetes mellitus, and our analyses suggest a potential link to ADHD. Overall, the comprehensive application of bioinformatics tools showed that functional mutations in the ADGLR3 gene disrupt the standard and wild ADGRL3 structure, most likely affecting its metabolic regulation. Further in vitro experiments are granted to evaluate these in silico predictions of the ADGRL3-GIP interaction and dissect the complexity underlying the development of ADHD.
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22
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Stensen S, Krogh LL, Sparre-Ulrich AH, Dela F, Hartmann B, Vilsbøll T, Holst JJ, Rosenkilde MM, Christensen MB, Gasbjerg LS, Knop FK. Acute concomitant glucose-dependent insulinotropic polypeptide receptor antagonism during glucagon-like peptide 1 receptor agonism does not affect appetite, resting energy expenditure or food intake in patients with type 2 diabetes and overweight/obesity. Diabetes Obes Metab 2022; 24:1882-1887. [PMID: 35491518 DOI: 10.1111/dom.14736] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 04/15/2022] [Accepted: 04/28/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Signe Stensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Liva L Krogh
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Alexander H Sparre-Ulrich
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Antag Therapeutics Aps, Copenhagen, Denmark
| | - Flemming Dela
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Geriatrics, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Centre for Translational Research, Copenhagen University Hospital, Copenhagen, Denmark
| | - Laerke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Herlev, Denmark
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23
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Comprehensive evaluation of patterns of hypoglycemia unawareness (HUA) and glycemic variability (GV) in patients with fibrocalculous pancreatic diabetes (FCPD): A cross-sectional study from South India. PLoS One 2022; 17:e0270788. [PMID: 35819935 PMCID: PMC9275701 DOI: 10.1371/journal.pone.0270788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/20/2022] [Indexed: 11/19/2022] Open
Abstract
Objectives Hypoglycemia unawareness (HUA) in patients with FCPD is common with an unclear etiology. We evaluated the prevalence, characteristics of HUA, glycemic variability (GV), its possible association with pancreatic glucagon secretion & cardiac autonomic function in patients with FCPD. Methods A two-week ambulatory glucose profile (AGP) and cardiac autonomic function test was done in patients with FCPD (n = 60), and categorized into UNAWARE (n = 44) and AWARE (n = 16) groups based on the Hypoglycemia Unawareness Index (HUI) score. Glycaemic variability was assessed from the AGP data using Easy GV 9.0.2 software. A subset of patients from both the groups (n = 11) underwent a mixed-meal challenge test and were compared with healthy individuals (controls; n = 11). Results HUA was evidenced in 73% (44/60) of patients with FCPD. Significant hypoglycemia, nocturnal hypoglycemia, duration of hypoglycemia and poor cardiac autonomic functions (p = 0.01) were prominent in the UNAWARE group. The overall GV was greater in the UNAWARE group. In the UNAWARE group, significantly reduced fasting and post prandial glucagon levels negatively correlated with HUI (r = -0.74, p < 0.05) and GV-hypoglycemia indices (p < 0.05) In contrast, significantly higher post prandial glucagon levels in the AWARE group positively correlated with post prandial hyperglycemia (r = 0.61, p < 0.05). Conclusion Heterogeneity in patterns of glucagon secretion were significantly associated with HUA and GV. Reduced glucagon levels contribute to greater risks of HUA, nocturnal hypoglycemia and greater GV, while hyperglucagonemia predisposes to postprandial hyperglycemia and hypoglycemia awareness in patients with FCPD.
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24
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Obirikorang Y, Acheampong E, Anto EO, Afrifa-Yamoah E, Adua E, Taylor J, Fondjo LA, Lokpo SY, Adu EA, Adutwum B, Antwi EO, Acheampong EN, Gyamfi MA, Aidoo F, Owiredu EW, Obirikorang C. Nexus between constructs of social cognitive theory model and diabetes self-management among Ghanaian diabetic patients: A mediation modelling approach. PLOS GLOBAL PUBLIC HEALTH 2022; 2:e0000736. [PMID: 36962448 PMCID: PMC10022127 DOI: 10.1371/journal.pgph.0000736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 06/13/2022] [Indexed: 11/19/2022]
Abstract
The promotion of Diabetes Self-Management (DSM) practices, education, and support is vital to improving the care and wellbeing of diabetic patients. Identifying factors that affect DSM behaviours may be useful to promote healthy living among these patients. The study assessed the determinants of DSM practices among Type 2 diabetes mellitus (T2DM) patients using a model-based social cognitive theory (SCT). This cross-sectional study comprised 420 (T2DM) patients who visited the Diabetic Clinic of the Komfo Anokye Teaching Hospital (KATH), Kumasi-Ghana. Data was collected using self-structured questionnaires to obtain socio-demographic characteristics, T2DM-related knowledge, DSM practices, SCT constructs; beliefs in treatment effectiveness, level of self-efficacy, perceived family support, and healthcare provider-patient communication. Path analysis was used to determine direct and indirect effects of T2DM-related knowledge, perceived family support, and healthcare provider service on DSM practices with level of self-efficacy mediating the relationships, and beliefs in treatment effectiveness as moderators. The mean age of the participants was 53.1(SD = 11.4) years and the average disease duration of T2DM was 10 years. Most of the participants (65.5%) had high (>6.1mmol/L) fasting blood glucose (FBG) with an average of 6.93(SD = 2.41). The path analysis model revealed that age (p = 0.176), gender (p = 0.901), and duration of T2DM (p = 0.119) did not confound the relationships between the SCT constructs and DSM specified in the model. A significant direct positive effect of family and friends' support (Critical ratio (CR) = 5.279, p < 0.001) on DSM was observed. Self-efficacy was a significant mediator in this relationship (CR = 4.833, p < 0.001). There were significant conditional indirect effects (CIE) for knowledge of T2DM and family and friends' support at medium and high levels of belief in treatment effectiveness (p < 0.05) via level of self-efficacy on DSM practices. However, no evidence of moderated-mediation was observed for the exogenous variables on DSM. Diabetes-related knowledge of T2DM, family and friends' support, level of self-efficacy, and belief in treatment effectiveness are crucial in DSM practices among Ghanaian T2DM patients. It is incumbent to consider these factors when designing interventions to improve DSM adherence.
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Affiliation(s)
- Yaa Obirikorang
- Department of Nursing, Faculty of Health Sciences, Garden City University College (GCUC), Kenyasi, Kumasi, Ghana
| | - Emmanuel Acheampong
- Department of Molecular Medicine, School of Medical Science, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
- Centre for Precision Health, ECU Strategic Research Centre, Edith Cowan University, Perth, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
| | - Enoch Odame Anto
- Centre for Precision Health, ECU Strategic Research Centre, Edith Cowan University, Perth, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
- Department of Medical Diagnostics, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | | | - Eric Adua
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
| | - John Taylor
- Centre for Precision Health, ECU Strategic Research Centre, Edith Cowan University, Perth, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
| | - Linda Ahenkorah Fondjo
- Department of Molecular Medicine, School of Medical Science, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| | - Sylvester Yao Lokpo
- Department of Medical Laboratory Sciences, School of Allied Health Sciences, University of Health and Allied Sciences, Ho, Ghana
| | - Evans Asamoah Adu
- Department of Molecular Medicine, School of Medical Science, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| | - Bernard Adutwum
- Department of Nursing, Faculty of Health Sciences, Garden City University College (GCUC), Kenyasi, Kumasi, Ghana
| | - Enoch Ofori Antwi
- Department of Nursing, Faculty of Health Sciences, Garden City University College (GCUC), Kenyasi, Kumasi, Ghana
| | - Emmanuella Nsenbah Acheampong
- Department of Molecular Medicine, School of Medical Science, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| | - Michael Adu Gyamfi
- Department of Medical Laboratory Sciences, School of Allied Health Sciences, University of Health and Allied Sciences, Ho, Ghana
| | - Freeman Aidoo
- Department of Molecular Medicine, School of Medical Science, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| | - Eddie-Williams Owiredu
- Department of Molecular Medicine, School of Medical Science, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| | - Christian Obirikorang
- Department of Molecular Medicine, School of Medical Science, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
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25
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Rizvi AA, Rizzo M. The Emerging Role of Dual GLP-1 and GIP Receptor Agonists in Glycemic Management and Cardiovascular Risk Reduction. Diabetes Metab Syndr Obes 2022; 15:1023-1030. [PMID: 35411165 PMCID: PMC8994606 DOI: 10.2147/dmso.s351982] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/18/2022] [Indexed: 12/11/2022] Open
Abstract
The incretin pathway is a self-regulating feedback system connecting the gut with the brain, pancreas, and liver. Its predominant action is on the postprandial glucose levels, with extraglycemic effects on fat metabolism and endovascular function. Of the two main incretin hormones released with food ingestion, the actions of glucagon-like peptide-1 (GLP-1) have been exploited for therapeutic benefit. However, little attention has been paid to glucose-dependent insulinotropic polypeptide (GIP) until the recent experimental introduction of dual agonists, or "twincretins". Interestingly, simultaneous activation of both receptors is not only replicative of normal physiology, it seems to be an innovative way to enhance their mutual salubrious actions. In patients with type 2 diabetes, dual agonists can have powerful benefits for glucose control and weight reduction. Additionally, there is mounting evidence of their favorable cardiovascular impact, making them potentially appealing pharmacologic agents of choice in the future. Although we seem to be poised on the horizons of exciting new breakthroughs, much knowledge has yet to be gained before these novel agents are ready for prime time.
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Affiliation(s)
- Ali A Rizvi
- Department of Medicine, University of Central Florida College of Medicine, Orlando, Florida, USA
- Correspondence: Ali A Rizvi, Department of Medicine, University of Central Florida College of Medicine, 3400 Quadrangle Blvd, Orlando, Florida, 32817, USA, Tel +1 803-609-1935, Fax +1 407-882-4799, Email
| | - Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, Palermo, Italy
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Ma T, Lu W, Wang Y, Qian P, Tian H, Gao X, Yao W. An oral GLP-1 and GIP dual receptor agonist improves metabolic disorders in high fat-fed mice. Eur J Pharmacol 2021; 914:174635. [PMID: 34800466 DOI: 10.1016/j.ejphar.2021.174635] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/01/2021] [Accepted: 11/11/2021] [Indexed: 12/15/2022]
Abstract
Dual activation of the glucagon-like peptide 1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor has potential as a novel strategy for treatment of diabesity. Here, we created a hybrid peptide which we named 19W, and show that it is more stable in presence of murine plasma than exendin-4 is. In vitro studies were performed to reveal that 19W could stimulate insulin secretion from INS-1 cells in a dose-dependent manner, just like the native peptide GIP and exendin-4 do. 19W effectively evoked dose-dependent cAMP production in cells targeting both GLP-1R and GIPR. In healthy C57BL/6J mice, the single administration of 19W significantly improved glucose tolerance. When administered in combination with sodium deoxycholate (SDC), its oral hypoglycemic activity was enhanced. Pharmacokinetics studies in Wistar rats revealed that 19W was absorbed following oral uptake, while SDC increased its bioavailability. A long-term (28 days) exposure study of twice-daily oral administration to high fat-fed (HFF) mice showed that 19W significantly reduced animal food intake, body weight, fasting blood glucose, total serum cholesterol (T-CHO), non-esterified free fatty acids (NEFA), and low-density lipoprotein cholesterol (LDL-C) levels. It also significantly improved glucose tolerance and the pancreatic β/α cell ratio, and decreased the area of liver fibrosis. These results clearly demonstrate the beneficial action of this novel oral GLP-1/GIP dual receptor agonist to reduce adiposity and hyperglycemia in diabetic mice and to ameliorate liver fibrosis associated with obesity. This dual-acting peptide can be considered a good candidate for novel oral therapy to treat obesity and diabetes.
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Affiliation(s)
- Teng Ma
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China, Pharmaceutical University, Nanjing, 210009, China
| | - Weisheng Lu
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China, Pharmaceutical University, Nanjing, 210009, China
| | - Yongkang Wang
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China, Pharmaceutical University, Nanjing, 210009, China
| | - Peng Qian
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China, Pharmaceutical University, Nanjing, 210009, China
| | - Hong Tian
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China, Pharmaceutical University, Nanjing, 210009, China
| | - Xiangdong Gao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China, Pharmaceutical University, Nanjing, 210009, China.
| | - Wenbing Yao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China, Pharmaceutical University, Nanjing, 210009, China.
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Holst JJ, Gasbjerg LS, Rosenkilde MM. The Role of Incretins on Insulin Function and Glucose Homeostasis. Endocrinology 2021; 162:6199910. [PMID: 33782700 PMCID: PMC8168943 DOI: 10.1210/endocr/bqab065] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Indexed: 12/14/2022]
Abstract
The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.
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Affiliation(s)
- Jens Juul Holst
- Department of Biomedical Sciences and the NovoNordisk Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, The Panum Institute, Copenhagen N, DK-2200 Denmark
- Correspondence: Jens Juul Holst, MD, University of Copenhagen, Department of Biomedical Sciences, The Panum Institute, 3 Blegdamsvej, Copenhagen, DK-2200 Denmark.
| | - Lærke Smidt Gasbjerg
- Department of Biomedical Sciences and the NovoNordisk Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, The Panum Institute, Copenhagen N, DK-2200 Denmark
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences and the NovoNordisk Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, The Panum Institute, Copenhagen N, DK-2200 Denmark
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28
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Hansen HH, Grønlund RV, Baader-Pagler T, Haebel P, Tammen H, Larsen LK, Jelsing J, Vrang N, Klein T. Characterization of combined linagliptin and Y2R agonist treatment in diet-induced obese mice. Sci Rep 2021; 11:8060. [PMID: 33850212 PMCID: PMC8044192 DOI: 10.1038/s41598-021-87539-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/31/2021] [Indexed: 02/01/2023] Open
Abstract
Dipeptidyl peptidase IV (DPP-IV) inhibitors improve glycemic control by prolonging the action of glucagon-like peptide-1 (GLP-1). In contrast to GLP-1 analogues, DPP-IV inhibitors are weight-neutral. DPP-IV cleavage of PYY and NPY gives rise to PYY3-36 and NPY3-36 which exert potent anorectic action by stimulating Y2 receptor (Y2R) function. This invites the possibility that DPP-IV inhibitors could be weight-neutral by preventing conversion of PYY/NPY to Y2R-selective peptide agonists. We therefore investigated whether co-administration of an Y2R-selective agonist could unmask potential weight lowering effects of the DDP-IV inhibitor linagliptin. Male diet-induced obese (DIO) mice received once daily subcutaneous treatment with linagliptin (3 mg/kg), a Y2R-selective PYY3-36 analogue (3 or 30 nmol/kg) or combination therapy for 14 days. While linagliptin promoted marginal weight loss without influencing food intake, the PYY3-36 analogue induced significant weight loss and transient suppression of food intake. Both compounds significantly improved oral glucose tolerance. Because combination treatment did not further improve weight loss and glucose tolerance in DIO mice, this suggests that potential negative modulatory effects of DPP-IV inhibitors on endogenous Y2R peptide agonist activity is likely insufficient to influence weight homeostasis. Weight-neutrality of DPP-IV inhibitors may therefore not be explained by counter-regulatory effects on PYY/NPY responses.
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Affiliation(s)
| | | | - Tamara Baader-Pagler
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co., Biberach, Germany
| | - Peter Haebel
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co., Biberach, Germany
| | | | | | - Jacob Jelsing
- Gubra, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | - Niels Vrang
- Gubra, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | - Thomas Klein
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co., Biberach, Germany
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Guimarães M, Pereira SS, Monteiro MP. From Entero-Endocrine Cell Biology to Surgical Interventional Therapies for Type 2 Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1307:273-297. [PMID: 32016913 DOI: 10.1007/5584_2020_480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The physiological roles of the enteroendocrine system in relation to energy and glucose homeostasis regulation have been extensively studied in the past few decades. Considerable advances were made that enabled to disclose the potential use of gastro-intestinal (GI) hormones to target obesity and type 2 diabetes (T2D). The recognition of the clinical relevance of these discoveries has led the pharmaceutical industry to design several hormone analogues to either to mitigate physiological defects or target pharmacologically T2D.Amongst several advances, a major breakthrough in the field was the unexpected observation that enteroendocrine system modulation to T2D target could be achieved by surgically induced anatomical rearrangement of the GI tract. These findings resulted from the widespread use of bariatric surgery procedures for obesity treatment, which despite initially devised to induce weight loss by limiting the systemic availably of nutrients, are now well recognized to influence GI hormone dynamics in a manner that is highly dependent on the type of anatomical rearrangement produced.This chapter will focus on enteroendocrine system related mechanisms leading to improved glycemic control in T2D after bariatric surgery interventions.
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Affiliation(s)
- Marta Guimarães
- Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal.,Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.,Department of General Surgery, Centro Hospitalar de Entre o Douro e Vouga, Santa Maria da Feira, Portugal
| | - Sofia S Pereira
- Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal.,Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Mariana P Monteiro
- Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal. .,Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
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Christensen AS, Hædersdal S, Storgaard H, Rose K, Hansen NL, Holst JJ, Hansen T, Knop FK, Vilsbøll T. GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1α Mutation Carriers. Diabetes 2020; 69:1989-2002. [PMID: 32518064 PMCID: PMC7458039 DOI: 10.2337/db20-0074] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 05/31/2020] [Indexed: 01/18/2023]
Abstract
Sulfonylureas (SUs) provide an efficacious first-line treatment in patients with hepatocyte nuclear factor 1α (HNF1A) diabetes, but SUs have limitations due to risk of hypoglycemia. Treatment based on the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) is characterized by their glucose-dependent insulinotropic actions without risk of hypoglycemia. The effect of SUs together with GIP or GLP-1, respectively, on insulin and glucagon secretion in patients with HNF1A diabetes is currently unknown. To investigate this, 10 HNF1A mutation carriers and 10 control subjects without diabetes were recruited for a double-blinded, placebo-controlled, crossover study including 6 experimental days in a randomized order involving 2-h euglycemic-hyperglycemic clamps with coadministration of: 1) SU (glimepiride 1 mg) or placebo, combined with 2) infusions of GIP (1.5 pmol/kg/min), GLP-1 (0.5 pmol/kg/min), or saline (NaCl). In HNF1A mutation carriers, we observed: 1) hypoinsulinemia, 2) insulinotropic effects of both GIP and GLP-1, 3) additive to supra-additive effects on insulin secretion when combining SU+GIP and SU+GLP-1, respectively, and 4) increased fasting and arginine-induced glucagon levels compared with control subjects without diabetes. Our study suggests that a combination of SU and incretin-based treatment may be efficacious in patients with HNF1A diabetes via potentiation of glucose-stimulated insulin secretion.
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Affiliation(s)
- Alexander S Christensen
- Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Sofie Hædersdal
- Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Heidi Storgaard
- Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Kathrine Rose
- Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Nina L Hansen
- Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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31
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Christensen MB, Lund AB, Jørgensen NR, Holst JJ, Vilsbøll T, Knop FK. Glucose-Dependent Insulinotropic Polypeptide (GIP) Reduces Bone Resorption in Patients With Type 2 Diabetes. J Endocr Soc 2020; 4:bvaa097. [PMID: 32904711 PMCID: PMC7458112 DOI: 10.1210/jendso/bvaa097] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 07/13/2020] [Indexed: 12/26/2022] Open
Abstract
CONTEXT In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP's insulinotropic effect is impaired and effects on bone may be reduced. OBJECTIVE To investigate GIP's effect on bone biomarkers in patients with T2D. DESIGN Randomized, double-blinded, crossover study investigating 6 interventions. PATIENTS Twelve male patients with T2D. INTERVENTIONS A primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with "insulin-induced hypoglycemia" (PG lowered to 3 mmol/L), "fasting hyperglycemia" (mean PG ~8 mmol/L), or "aggravated hyperglycemia" (mean PG ~12 mmol/L). MAIN OUTCOME MEASURES Bone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH. RESULTS On days with insulin-induced hypoglycemia, CTX was suppressed by up to 40 ± 15% during GIP administration compared with 12 ± 11% during placebo infusion (P < 0.0001). On days with fasting hyperglycemia, CTX was suppressed by up to 36 ± 15% during GIP administration, compared with 0 ± 9% during placebo infusion (P < 0.0001). On days with aggravated hyperglycemia, CTX was suppressed by up to 47 ± 23% during GIP administration compared with 10 ± 9% during placebo infusion (P = 0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes. CONCLUSIONS Short-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients. PRÉCIS Short-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.
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Affiliation(s)
- Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Asger B Lund
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Niklas R Jørgensen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Chemistry, Rigshospitalet, University of Copenhagen, Glostrup, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark
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Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Pottakkat B. Islet cell dysfunction in patients with chronic pancreatitis. World J Diabetes 2020; 11:280-292. [PMID: 32843931 PMCID: PMC7415230 DOI: 10.4239/wjd.v11.i7.280] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/02/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis (CP) is characterized by progressive inflammation and fibrosis of the pancreas that eventually leads to pancreatic exocrine and endocrine insufficiency. Diabetes in the background of CP is very difficult to manage due to high glycemic variability and concomitant malabsorption. Progressive beta cell loss leading to insulin deficiency is the cardinal mechanism underlying diabetes development in CP. Alpha cell dysfunction leading to deranged glucagon secretion has been described in different studies using a variety of stimuli in CP. However, the emerging evidence is varied probably because of dependence on the study procedure, the study population as well as on the stage of the disease. The mechanism behind islet cell dysfunction in CP is multifactorial. The intra-islet alpha and beta cell regulation of each other is often lost. Moreover, secretion of the incretin hormones such as glucagon like peptide-1 and glucose-dependent insulinotropic polypeptide is dysregulated. This significantly contributes to islet cell disturbances. Persistent and progressive inflammation with changes in the function of other cells such as islet delta cells and pancreatic polypeptide cells are also implicated in CP. In addition, the different surgical procedures performed in patients with CP and antihyperglycemic drugs used to treat diabetes associated with CP also affect islet cell function. Hence, different factors such as chronic inflammation, dysregulated incretin axis, surgical interventions and anti-diabetic drugs all affect islet cell function in patients with CP. Newer therapies targeting alpha cell function and beta cell regeneration would be useful in the management of pancreatic diabetes in the near future.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Medical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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Gimeno RE, Briere DA, Seeley RJ. Leveraging the Gut to Treat Metabolic Disease. Cell Metab 2020; 31:679-698. [PMID: 32187525 PMCID: PMC7184629 DOI: 10.1016/j.cmet.2020.02.014] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 11/23/2019] [Accepted: 02/20/2020] [Indexed: 02/07/2023]
Abstract
25 years ago, the future of treating obesity and diabetes focused on end organs known to be involved in energy balance and glucose regulation, including the brain, muscle, adipose tissue, and pancreas. Today, the most effective therapies are focused around the gut. This includes surgical options, such as vertical sleeve gastrectomy and Roux-en-Y gastric bypass, that can produce sustained weight loss and diabetes remission but also extends to pharmacological treatments that simulate or amplify various signals that come from the gut. The purpose of this Review is to discuss the wealth of approaches currently under development that seek to further leverage the gut as a source of novel therapeutic opportunities with the hope that we can achieve the effects of surgical interventions with less invasive and more scalable solutions.
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Affiliation(s)
- Ruth E Gimeno
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46225, USA
| | - Daniel A Briere
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46225, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
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Christensen MB, Gasbjerg LS, Heimbürger SM, Stensen S, Vilsbøll T, Knop FK. GIP's involvement in the pathophysiology of type 2 diabetes. Peptides 2020; 125:170178. [PMID: 31682875 DOI: 10.1016/j.peptides.2019.170178] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 02/06/2023]
Abstract
During the past four decades derangements in glucose-dependent insulinotropic polypeptide (GIP) biology has been viewed upon as contributing factors to various parts of the pathophysiology type 2 diabetes. This overview outlines and discusses the impaired insulin responses to GIP as well as the effect of GIP on glucagon secretion and the potential involvement of GIP in the obesity and bone disease associated with type 2 diabetes. As outlined in this review, it is unlikely that the impaired insulinotropic effect of GIP occurs as a primary event in the development of type 2 diabetes, but rather develops once the diabetic state is present and beta cells are unable to maintain normoglycemia. In various models, GIP has effects on glucagon secretion, bone and lipid homeostasis, but whether these effects contribute substantially to the pathophysiology of type 2 diabetes is at present controversial. The review also discusses the substantial uncertainty surrounding the translation of preclinical data relating to the GIP system and outline future research directions.
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Affiliation(s)
- Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sebastian M Heimbürger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Signe Stensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte Hospital, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte Hospital, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Gasbjerg LS, Bergmann NC, Stensen S, Christensen MB, Rosenkilde MM, Holst JJ, Nauck M, Knop FK. Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists. Peptides 2020; 125:170183. [PMID: 31693916 DOI: 10.1016/j.peptides.2019.170183] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/22/2019] [Accepted: 10/24/2019] [Indexed: 02/07/2023]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) potentiate glucose-induced insulin secretion and are therefore thought to be responsible for the incretin effect. The magnitude of the incretin effect, defined as the fraction of postprandial insulin secretion stimulated by intestinal factors, has been reported to be up to ∼60% in healthy individuals. In several pathological conditions but especially in patients with type 2 diabetes, the incretin effect is severely reduced or even absent. In line with this, the insulinotropic effects of GIP and GLP-1 are impaired in patients with type 2 diabetes, even when administered in supraphysiological doses. In healthy individuals, GIP has been proposed to be the most important incretin hormone of the two, but the individual contribution of the two is difficult to determine. However, using incretin hormone receptor antagonists: the novel GIP receptor antagonist GIP(3-30)NH2 and the widely used GLP-1 receptor antagonist exendin(9-39)NH2, we can now distinguish between the effects of the two hormones. In this review, we present and discuss studies in which the individual contribution of GIP and GLP-1 to the incretin effect in healthy individuals have been estimated and discuss the limitations of using incretin hormone receptor antagonists.
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Affiliation(s)
- Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Natasha C Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Signe Stensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Michael Nauck
- Diabetes Division, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark
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Bailey CJ. GIP analogues and the treatment of obesity-diabetes. Peptides 2020; 125:170202. [PMID: 31756366 DOI: 10.1016/j.peptides.2019.170202] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/09/2019] [Accepted: 11/11/2019] [Indexed: 12/18/2022]
Abstract
The potential application of glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide, GIP) in the management of obesity and type 2 diabetes has been controversial. Initial interest in the therapeutic use of GIP was dampened by evidence that its insulinotropic activity was reduced in type 2 diabetes and by reports that it increased glucagon secretion and adipose deposition in non-diabetic individuals. Also, attention was diverted away from GIP by the successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, and a therapeutic strategy for GIP became uncertain when evidence emerged that both inhibition and enhancement of GIP action could prevent or reverse obese non-insulin dependent forms of diabetes in rodents. Species differences in GIP receptor responsiveness complicated the extrapolation of evidence from rodents to humans, but initial clinical studies are investigating the effect of a GIP antagonist in non-diabetic individuals. A therapeutic role for GIP agonists was reconsidered when clinical studies noted that the insulinotropic effect of GIP was increased if near-normal glycaemia was re-established, and GIP was found to have little effect on glucagon secretion or adipose deposition in obese type 2 diabetes patients. This encouraged the development of designer peptides that act as GIP receptor agonists, including chimeric peptides that mimic the incretin partnership of GIP with GLP-1, where the two agents exert complementary and often additive effects to improve glycaemic control and facilitate weight loss. Polyagonist peptides that exert agonism at GIP, GLP-1 and glucagon receptors are also under investigation as potential treatments for obese type 2 diabetes.
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Affiliation(s)
- Clifford J Bailey
- School of Life and Health Sciences, Aston University, B4 7ET, Birmingham, UK.
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GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease-A Systematic Review. Int J Mol Sci 2020; 21:ijms21041509. [PMID: 32098413 PMCID: PMC7073149 DOI: 10.3390/ijms21041509] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 02/20/2020] [Accepted: 02/21/2020] [Indexed: 02/06/2023] Open
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut hormones that are secreted from enteroendocrine L cells and K cells in response to digested nutrients, respectively. They are also referred to incretin for their ability to stimulate insulin secretion from pancreatic beta cells in a glucose-dependent manner. Furthermore, GLP-1 exerts anorexic effects via its actions in the central nervous system. Since native incretin is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4), DPP-resistant GLP-1 receptor agonists (GLP-1RAs), and DPP-4 inhibitors are currently used for the treatment of type 2 diabetes as incretin-based therapy. These new-class agents have superiority to classical oral hypoglycemic agents such as sulfonylureas because of their low risks for hypoglycemia and body weight gain. In addition, a number of preclinical studies have shown the cardioprotective properties of incretin-based therapy, whose findings are further supported by several randomized clinical trials. Indeed, GLP-1RA has been significantly shown to reduce the risk of cardiovascular and renal events in patients with type 2 diabetes. However, the role of GIP in cardiovascular disease remains to be elucidated. Recently, pharmacological doses of GIP receptor agonists (GIPRAs) have been found to exert anti-obesity effects in animal models. These observations suggest that combination therapy of GLP-1R and GIPR may induce superior metabolic and anti-diabetic effects compared with each agonist individually. Clinical trials with GLP-1R/GIPR dual agonists are ongoing in diabetic patients. Therefore, in this review, we summarize the cardiovascular effects of GIP and GIPRAs in cell culture systems, animal models, and humans.
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Abstract
PURPOSE OF REVIEW Among the gastrointestinal hormones, the incretins: glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 have attracted interest because of their importance for the development and therapy of type 2 diabetes and obesity. New agonists and formulations of particularly the GLP-1 receptor have been developed recently showing great therapeutic efficacy for both diseases. RECENT FINDINGS The status of the currently available GLP-1 receptor agonists (GLP-1RAs) is described, and their strengths and weaknesses analyzed. Their ability to also reduce cardiovascular and renal risk is described and analysed. The most recent development of orally available agonists and of very potent monomolecular co-agonists for both the GLP-1 and GIP receptor is also discussed. SUMMARY The GLP-1RAs are currently the most efficacious agents for weight loss, and show potential for further efficacy in combination with other food-intake-regulating peptides. Because of their glycemic efficacy and cardiorenal protection, the GLP-1 RAs will be prominent elements in future diabetes therapy.
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Affiliation(s)
- Jens Juul Holst
- NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, The Panum Institute, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N, Denmark
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39
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Jørgensen MB, Idorn T, Rydahl C, Hansen HP, Bressendorff I, Brandi L, Wewer Albrechtsen NJ, van Hall G, Hartmann B, Holst JJ, Knop FK, Hornum M, Feldt-Rasmussen B. Effect of the Incretin Hormones on the Endocrine Pancreas in End-Stage Renal Disease. J Clin Endocrinol Metab 2020; 105:5586894. [PMID: 31608934 DOI: 10.1210/clinem/dgz048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 09/25/2019] [Indexed: 11/19/2022]
Abstract
CONTEXT The insulin-stimulating and glucagon-regulating effects of the 2 incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), contribute to maintain normal glucose homeostasis. Impaired glucose tolerance occurs with high prevalence among patients with end-stage renal disease (ESRD). OBJECTIVE To evaluate the effect of the incretin hormones on endocrine pancreatic function in patients with ESRD. DESIGN AND SETTING Twelve ESRD patients on chronic hemodialysis and 12 matched healthy controls, all with normal oral glucose tolerance test, were included. On 3 separate days, a 2-hour euglycemic clamp followed by a 2-hour hyperglycemic clamp (3 mM above fasting level) was performed with concomitant infusion of GLP-1 (1 pmol/kg/min), GIP (2 pmol/kg/min), or saline administered in a randomized, double-blinded fashion. A 30% lower infusion rate was used in the ESRD group to obtain comparable incretin hormone plasma levels. RESULTS During clamps, comparable plasma glucose and intact incretin hormone concentrations were achieved. The effect of GLP-1 to increase insulin concentrations relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (50 [8-72]%, P = 0.03). Similarly, the effect of GIP relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (34 [13-50]%, P = 0.005). Glucagon was suppressed in both groups, with controls reaching lower concentrations than ESRD patients. CONCLUSIONS The effect of incretin hormones to increase insulin release is reduced in ESRD, which, together with elevated glucagon levels, could contribute to the high prevalence of impaired glucose tolerance among ESRD patients.
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Affiliation(s)
- Morten B Jørgensen
- Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Idorn
- Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Casper Rydahl
- Department of Nephrology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Henrik P Hansen
- Department of Nephrology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Iain Bressendorff
- Department of Cardiology, Endocrinology and Nephrology, Nordsjællands Hospital, University of Copenhagen, Hillerød, Denmark
| | - Lisbet Brandi
- Department of Cardiology, Endocrinology and Nephrology, Nordsjællands Hospital, University of Copenhagen, Hillerød, Denmark
| | | | - Gerrit van Hall
- Clinical Metabolomics Core Facility, Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Mads Hornum
- Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Bo Feldt-Rasmussen
- Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Makrilakis K. The Role of DPP-4 Inhibitors in the Treatment Algorithm of Type 2 Diabetes Mellitus: When to Select, What to Expect. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16152720. [PMID: 31366085 PMCID: PMC6696077 DOI: 10.3390/ijerph16152720] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/26/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus is a growing global public health problem, the prevalence of which is projected to increase in the succeeding decades. It is potentially associated with many complications, affecting multiple organs and causing a huge burden to the society. Due to its multi-factorial pathophysiology, its treatment is varied and based upon a multitude of pharmacologic agents aiming to tackle the many aspects of the disease pathophysiology (increasing insulin availability [either through direct insulin administration or through agents that promote insulin secretion], improving sensitivity to insulin, delaying the delivery and absorption of carbohydrates from the gastrointestinal tract, or increasing urinary glucose excretion). DPP-4 (dipeptidyl peptidase-4) inhibitors (or “gliptins”) represent a class of oral anti-hyperglycemic agents that inhibit the enzyme DPP-4, thus augmenting the biological activity of the “incretin” hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) and restoring many of the pathophysiological problems of diabetes. They have already been used over more than a decade in the treatment of the disease. The current manuscript will review the mechanism of action, therapeutic utility, and the role of DPP-4 inhibitors for the treatment of type 2 diabetes mellitus.
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Affiliation(s)
- Konstantinos Makrilakis
- National and Kapodistrian University of Athens Medical School, Laiko General Hospital, 17 Ag. Thoma St., 11527 Athens, Greece.
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Harger A, Stemmer K, Tschöp MH, Müller TD. [Incretin-based co- and tri-agonists : Innovative polypharmacology for the treatment of obesity and diabetes]. Internist (Berl) 2019; 60:895-902. [PMID: 31346639 DOI: 10.1007/s00108-019-0649-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND The worldwide rise in overweight and obesity is paralleled by an increasing prevalence of type-2 diabetes. Apart from bariatric surgery, treatment options to decrease body weight are often underwhelming. Innovative pharmacological options are required to cope with the global "diabesity" pandemic. OBJECTIVES Particular novel pharmacological approaches are discussed, with a special focus on polyagonist-based pharmacotherapies. MATERIALS AND METHODS Articles on co- and tri-agonists for the treatment of obesity and diabetes are presented and discussed. RESULTS Unimolecular peptides have been developed for the treatment of obesity and type-2 diabetes. These peptides activate the receptors of multiple hormones and bundle their positive effects in one single molecule. In preclinical studies, polyagonists targeting the receptors for glucagon-like peptide-1 (GLP-1), glucagon, or glucose-dependent insulinotropic peptide (GIP) were promising to reduce body weight and blood glucose. GLP-1-mediated delivery of the nuclear hormones estrogen or dexamethasone also yielded beneficial effects in preclinical studies of obesity. CONCLUSIONS Polyagonists represent an innovative strategy for the development of novel pharmacotherapies to treat obesity and diabetes.
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Affiliation(s)
- A Harger
- Institut für Diabetes und Adipositas, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Deutschland.,Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Deutschland
| | - K Stemmer
- Institut für Diabetes und Adipositas, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Deutschland.,Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Deutschland
| | - M H Tschöp
- Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Deutschland.,Lehrstuhl für Stoffwechselerkrankungen, Fakultät für Medizin, Technische Universität München, München, Deutschland.,Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Deutschland
| | - T D Müller
- Institut für Diabetes und Adipositas, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Deutschland. .,Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Deutschland.
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Holst JJ. The incretin system in healthy humans: The role of GIP and GLP-1. Metabolism 2019; 96:46-55. [PMID: 31029770 DOI: 10.1016/j.metabol.2019.04.014] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/11/2019] [Accepted: 04/23/2019] [Indexed: 01/07/2023]
Abstract
The incretin effect, the amplification of insulin secretion occurring when glucose is taken in orally as compared to infused intravenously, is one of the factors that help the body to tolerate carbohydrate/glucose ingestion. These include 1) amount and type of carbohydrates; 2) gastric emptying rate; 3) digestion and absorption of the carbohydrates; 4) secretion and effect of the incretin hormones; 5) disposition of absorbed nutrients/glucose. The incretin effect can also be viewed as the fraction of the ingested glucose load handled via gastrointestinal mechanisms (including the incretin effect); it is calculated by comparison of the amount of glucose required to copy, by intravenous infusion, the oral load. Typically, for 75 g of oral glucose, about 25 g are required. This means that the GastroIntestinal Glucose Disposal (GIGD) is 66%. Both the GIGD and the incretin effect depend on the amount of glucose ingested: for higher doses the GIGD may amount to 80%, which shows that this effect is a major contributor to glucose tolerance. The main mechanism behind it is stimulation of insulin secretion by a proportional secretion of the insulinotropic hormones GIP and GLP-1. Recently it has become possible to estimate their contributions in healthy humans using specific and potent receptor antagonists. Both hormones act to improve glucose tolerance (i.e. the antagonists impair tolerance) and their effects are additive. GIP seems to be quantitatively the most important, particularly regarding insulin secretion, whereas the action of GLP-1 is mainly displayed via inhibition of glucagon secretion.
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Affiliation(s)
- Jens Juul Holst
- The NNF center for Basic Metabolic Research and Department of Biomedical Sciences, the Panum Institute, University of Copenhagen, DK-2200, Denmark.
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Petersen J, Strømgaard K, Frølund B, Clemmensen C. Designing Poly-agonists for Treatment of Metabolic Diseases: Challenges and Opportunities. Drugs 2019; 79:1187-1197. [DOI: 10.1007/s40265-019-01153-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Gasbjerg LS, Helsted MM, Hartmann B, Jensen MH, Gabe MBN, Sparre-Ulrich AH, Veedfald S, Stensen S, Lanng AR, Bergmann NC, Christensen MB, Vilsbøll T, Holst JJ, Rosenkilde MM, Knop FK. Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals. Diabetes 2019; 68:906-917. [PMID: 30626611 DOI: 10.2337/db18-1123] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 01/05/2019] [Indexed: 11/13/2022]
Abstract
The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted postprandially and contribute importantly to postprandial glucose tolerance. In this study, we assessed the individual and combined contributions of endogenous GIP and GLP-1 to the postprandial changes in glucose and glucoregulatory hormones using the novel GIP receptor antagonist GIP(3-30)NH2 and the well-established GLP-1 receptor antagonist exendin(9-39)NH2 During 4-h oral glucose tolerance tests (75 g) combined with an ad libitum meal test, 18 healthy men received on four separate days in randomized, double-blinded order intravenous infusions of A) GIP(3-30)NH2 (800 pmol/kg/min) plus exendin(9-39)NH2 (0-20 min: 1,000 pmol/kg/min; 20-240 min: 450 pmol/kg/min), B) GIP(3-30)NH2, C) exendin(9-39)NH2, and D) saline, respectively. Glucose excursions were significantly higher during A than during B, C, and D, while glucose excursions during B were higher than during C and D. Insulin secretion (assessed by C-peptide/glucose ratio) was reduced by 37 ± 16% (A), 30 ± 17% (B), and 8.6 ± 16% (C) compared with D (mean ± SD). A and C resulted in higher glucagon levels and faster gastric emptying. In conclusion, endogenous GIP affects postprandial plasma glucose excursions and insulin secretion more than endogenous GLP-1, but the hormones contribute additively to postprandial glucose regulation in healthy individuals.
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Affiliation(s)
- Lærke S Gasbjerg
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mads M Helsted
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette H Jensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Antag Therapeutics ApS, Copenhagen, Denmark
| | - Maria B N Gabe
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alexander H Sparre-Ulrich
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Antag Therapeutics ApS, Copenhagen, Denmark
| | - Simon Veedfald
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Signe Stensen
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Amalie R Lanng
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Natasha C Bergmann
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Zealand Pharma A/S, Glostrup, Denmark
| | - Mikkel B Christensen
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Holst JJ. From the Incretin Concept and the Discovery of GLP-1 to Today's Diabetes Therapy. Front Endocrinol (Lausanne) 2019; 10:260. [PMID: 31080438 PMCID: PMC6497767 DOI: 10.3389/fendo.2019.00260] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 04/08/2019] [Indexed: 12/24/2022] Open
Abstract
Researchers have been looking for insulin-stimulating factors for more than 100 years, and in the 1960ties it was definitively proven that the gastrointestinal tract releases important insulinotropic factors upon oral glucose intake, so-called incretin hormones. The first significant factor identified was the duodenal glucose-dependent insulinotropic polypeptide, GIP, which however, turned out not to stimulate insulin secretion in patients with type 2 diabetes. But resection experiments clearly indicated the presence of an additional incretin, and in 1986, an unexpected processing fragment of the recently identified glucagon precursor, proglucagon, namely truncated glucagon-like peptide 1 (GLP-1 7-36 amide), was isolated from the gut and found to both stimulate insulin secretion and inhibit glucagon secretion. The peptide also inhibited appetite and food intake. Unlike GIP, this peptide had preserved effects in patients with type 2 diabetes and it was soon documented to have powerful antidiabetic effects in clinical studies. Its utility was limited, however, because of an extremely short half-life in humans, but this problem had two solutions, both of which gave rise to important antidiabetic drugs: (1) orally active inhibitors of the enzyme dipeptidylpeptidase 4 (DPP-4 inhibitors), which was responsible for the rapid degradation; the inhibitors protect endogenous GLP-1 from degradation and thereby unfold its antidiabetic activity, and (2) long-acting injectable analogs of GLP-1 protected against DPP-4 degradation. Particularly, the latter, the GLP-1 receptor agonists, either alone or in various combinations, are so powerful that treatment allows more than 2/3 of type 2 diabetes patients to reach glycemic targets. In addition, these agents cause a weight loss which, with the most successful compounds, may exceed 10% of body weight. Most recently they have also been shown to be renoprotective and reduce cardiovascular risk and mortality.
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Affiliation(s)
- Jens Juul Holst
- Department of Biomedical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
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Bergmann NC, Lund A, Gasbjerg LS, Meessen ECE, Andersen MM, Bergmann S, Hartmann B, Holst JJ, Jessen L, Christensen MB, Vilsbøll T, Knop FK. Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study. Diabetologia 2019; 62:665-675. [PMID: 30683945 DOI: 10.1007/s00125-018-4810-0] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 12/07/2018] [Indexed: 11/28/2022]
Abstract
AIMS/HYPOTHESIS Glucagon-like peptide 1 (GLP-1) reduces appetite and energy intake in humans, whereas the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), seems to have no effect on eating behaviour. Interestingly, studies in rodents have shown that concomitant activation of GIP and GLP-1 receptors may potentiate the satiety-promoting effect of GLP-1, and a novel dual GLP-1/GIP receptor agonist was recently shown to trigger greater weight losses compared with a GLP-1 receptor agonist in individuals with type 2 diabetes. The aim of this study was to delineate the effects of combined GIP and GLP-1 receptor activation on energy intake, appetite and resting energy expenditure in humans. METHODS We examined 17 overweight/obese men in a crossover design with 5 study days. On day 1, a 50 g OGTT was performed; on the following 4 study days, the men received an isoglycaemic i.v. glucose infusion (IIGI) plus saline (154 mmol/l NaCl; placebo), GIP (4 pmol kg-1 min-1), GLP-1 (1 pmol kg-1 min-1) or GIP+GLP-1 (4 and 1 pmol kg-1 min-1, respectively). All IIGIs were performed in a randomised order blinded for the participant and the investigators. The primary endpoint was energy intake as measured by an ad libitum meal after 240 min. Secondary endpoints included appetite ratings and resting energy expenditure, as well as insulin, C-peptide and glucagon responses. RESULTS Energy intake was significantly reduced during IIGI+GLP-1 compared with IIGI+saline infusion (2715 ± 409 vs 4483 ± 568 kJ [mean ± SEM, n = 17], p = 0.014), whereas there were no significant differences in energy intake during IIGI+GIP (4062 ± 520 kJ) or IIGI+GIP+GLP-1 (3875 ± 451 kJ) infusion compared with IIGI+saline (p = 0.590 and p = 0.364, respectively). Energy intake was higher during IIGI+GIP+GLP-1 compared with IIGI+GLP-1 infusion (p = 0.039). CONCLUSIONS/INTERPRETATION While GLP-1 infusion lowered energy intake in overweight/obese men, simultaneous GIP infusion did not potentiate this GLP-1-mediated effect. TRIAL REGISTRATION ClinicalTrials.gov NCT02598791 FUNDING: This study was supported by grants from the Innovation Fund Denmark and the Vissing Foundation.
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Affiliation(s)
- Natasha C Bergmann
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark
- Department of In Vivo Pharmacology, Zealand Pharma A/S, Glostrup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Asger Lund
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark
- Department of Medicine, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Emma C E Meessen
- Department of Endocrinology and Metabolism, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Maria M Andersen
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark
| | - Sigrid Bergmann
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lene Jessen
- Department of In Vivo Pharmacology, Zealand Pharma A/S, Glostrup, Denmark
| | - Mikkel B Christensen
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark.
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Hasib A, Ng MT, Tanday N, Craig SL, Gault VA, Flatt PR, Irwin N. Exendin-4(Lys 27 PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice. Diabetes Metab Res Rev 2019; 35:e3106. [PMID: 30499633 DOI: 10.1002/dmrr.3106] [Citation(s) in RCA: 12] [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: 09/28/2018] [Revised: 11/19/2018] [Accepted: 11/27/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND Therapeutic benefits of peptide-based drugs is limited by rapid renal elimination. METHODS Therefore, to prolong the biological action profile of the recently characterized triple-acting hybrid peptide, exendin-4/gastrin/xenin-8-Gln, a fatty acid (C-16) has been covalently attached, creating exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln. Exendin-4/gastrin and liraglutide/gastrin/xenin-8-Gln were also synthesized as direct comparator peptides. RESULTS All hybrid peptides evoked significant concentration-dependent increases of insulin secretion from isolated murine islets and BRIN-BD11 cells. Following administration of peptides with glucose to mice, all hybrids significantly reduced the overall glycaemic excursion and increased insulin concentrations. In contrast to other treatments, exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln displayed impressive antihyperglycaemic actions even 12 hours after administration, highlighting protracted duration of effects. Exendin-4/gastrin/xenin-8-Gln, exendin-4/gastrin, and exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln were then progressed to a 31-day twice-daily treatment regimen in obese-diabetic ob/ob mice. All treatments decreased nonfasting glucose and HbA1c concentrations, as well as enhancing circulating and pancreatic insulin levels. Exendin-4/gastrin and exendin-4/gastrin/xenin-8-Gln also decreased food intake. Glucose tolerance was improved by all treatments, but only exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln augmented glucose-induced insulin secretion. Interestingly, treatment regimens that included a xenin component induced clear advantages on the metabolic response to glucose-dependent insulinotropic polypeptide (GIP) and the glucose-lowering actions of insulin. CONCLUSION This study emphasizes the therapeutic promise of long-acting, multi-targeting hybrid gut peptides for type 2 diabetes.
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Affiliation(s)
- Annie Hasib
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Ming T Ng
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Neil Tanday
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Sarah L Craig
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Victor A Gault
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Peter R Flatt
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Nigel Irwin
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
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Schiellerup SP, Skov-Jeppesen K, Windeløv JA, Svane MS, Holst JJ, Hartmann B, Rosenkilde MM. Gut Hormones and Their Effect on Bone Metabolism. Potential Drug Therapies in Future Osteoporosis Treatment. Front Endocrinol (Lausanne) 2019; 10:75. [PMID: 30863364 PMCID: PMC6399108 DOI: 10.3389/fendo.2019.00075] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 01/28/2019] [Indexed: 12/19/2022] Open
Abstract
Bone homeostasis displays a circadian rhythm with increased resorption during the night time as compared to day time, a difference that seems-at least partly-to be caused by food intake during the day. Thus, ingestion of a meal results in a decrease in bone resorption, but people suffering from short bowel syndrome lack this response. Gut hormones, released in response to a meal, contribute to this link between the gut and bone metabolism. The responsible hormones appear to include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), known as incretin hormones due to their role in regulating glucose homeostasis by enhancing insulin release in response to food intake. They interact with their cognate receptors (GIPR and GLP-1R), which are both members of the class B G protein-coupled receptors (GPCRs), and already recognized as targets for treatment of metabolic diseases, such as type 2 diabetes mellitus (T2DM) and obesity. Glucagon-like peptide-2 (GLP-2), secreted concomitantly with GLP-1, acting via another class B receptor (GLP-2R), is also part of this gut-bone axis. Several studies, including human studies, have indicated that these three hormones inhibit bone resorption and, moreover, that GIP increases bone formation. Another hormone, peptide YY (PYY), is also secreted from the enteroendocrine L-cells (together with GLP-1 and GLP-2), and acts mainly via interaction with the class A GPCR NPY-R2. PYY is best known for its effect on appetite regulation, but recent studies have also shown an effect of PYY on bone metabolism. The aim of this review is to summarize the current knowledge of the actions of GIP, GLP-1, GLP-2, and PYY on bone metabolism, and to discuss future therapies targeting these receptors for the treatment of osteoporosis.
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Affiliation(s)
- Sine Paasch Schiellerup
- Laboratory of Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kirsa Skov-Jeppesen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Johanne Agerlin Windeløv
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Maria Saur Svane
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Mette Marie Rosenkilde
- Laboratory of Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Murray M, Dordevic AL, Ryan L, Bonham MP. A Single-Dose of a Polyphenol-Rich Fucus Vesiculosus Extract is Insufficient to Blunt the Elevated Postprandial Blood Glucose Responses Exhibited by Healthy Adults in the Evening: A Randomised Crossover Trial. Antioxidants (Basel) 2019; 8:antiox8020049. [PMID: 30813480 PMCID: PMC6406275 DOI: 10.3390/antiox8020049] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 02/12/2019] [Accepted: 02/16/2019] [Indexed: 12/14/2022] Open
Abstract
When healthy adults consume carbohydrates at night, postprandial blood glucose responses are elevated and prolonged compared to daytime.Extended postprandial hyperglycaemia is a risk factor for type 2 diabetes. Polyphenols are bioactive secondary metabolites of plants and algae with potential to moderate postprandial glycaemia. This study investigated whether a polyphenol-rich alga (Fucus vesiculosus) extract moderated postprandial glycaemia in the evening in healthy adults. In a double blind, placebo-controlled, randomised three-way crossover trial, 18 participants consumed a polyphenol-rich extract, a cellulose placebo and rice flour placebo (7:15 p.m.) prior to 50 g available carbohydrate from bread (7:45 p.m.), followed by three hours of blood sampling to assess glucose and insulin. A subset of participants (n = 8) completed the same protocol once in the morning with only the cellulose placebo (7:15 a.m.). No effect of the polyphenol-rich extract was observed on postprandial glycaemia in the evening, compared with placebos, in the group as a whole. However, in females only, peak blood glucose concentration was reduced following the polyphenol-rich extract. In the subset analysis, as expected, participants exhibited elevated postprandial blood glucose in the evening compared with the morning following the cellulose placebo. This was the first study to investigate whether a polyphenol intervention moderated evening postprandial hyperglycaemia. The lowering effect observed in females suggests that this warrants further investigation.
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Affiliation(s)
- Margaret Murray
- Department of Nutrition, Dietetics and Food, Monash University, Notting Hill VIC 3168, Australia.
- School of Chemistry, Monash University, Clayton, VIC 3800, Australia.
| | - Aimee L Dordevic
- Department of Nutrition, Dietetics and Food, Monash University, Notting Hill VIC 3168, Australia.
| | - Lisa Ryan
- School of Science and Computing, Galway-Mayo Institute of Technology, Galway H91 T8NW, Ireland.
| | - Maxine P Bonham
- Department of Nutrition, Dietetics and Food, Monash University, Notting Hill VIC 3168, Australia.
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50
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Coppolino G, Leporini C, Rivoli L, Ursini F, di Paola ED, Cernaro V, Arturi F, Bolignano D, Russo E, De Sarro G, Andreucci M. Exploring the effects of DPP-4 inhibitors on the kidney from the bench to clinical trials. Pharmacol Res 2018; 129:274-294. [PMID: 29223646 DOI: 10.1016/j.phrs.2017.12.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 10/15/2017] [Accepted: 12/01/2017] [Indexed: 02/06/2023]
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