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Wean J, Kowalsky AH, Laker R, Will S, Drucker DJ, Rhodes CJ, Seeley RJ. Specific loss of GIPR signaling in GABAergic neurons enhances GLP-1R agonist-induced body weight loss. Mol Metab 2025; 95:102074. [PMID: 39612941 PMCID: PMC11946504 DOI: 10.1016/j.molmet.2024.102074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 11/13/2024] [Accepted: 11/19/2024] [Indexed: 12/01/2024] Open
Abstract
OBJECTIVES Dual incretin agonists are among the most effective pharmaceutical treatments for obesity and type 2 diabetes to date. Such therapeutics can target two receptors, such as the glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor in the case of tirzepatide, to improve glycemia and reduce body weight. Regarding body weight effects, GIPR signaling is thought to involve at least two relevant mechanisms: the enhancement of food intake reduction and the attenuation of aversive effects caused by GLP-1R agonists. Although it is known that dual GLP-1R-GIPR agonism produces greater weight loss than GLP-1R agonism alone, the precise mechanism is unknown. METHODS To address this question, we used mice lacking GIPR in the whole body, GABAergic neurons, or glutamatergic neurons. These mice were given various combinations of GLP-1R and GIPR agonist drugs with subsequent food intake and conditioned taste aversion measurements. RESULTS A GIPR knockout in either the whole body or selectively in inhibitory GABAergic neurons protects against diet-induced obesity, whereas a knockout in excitatory glutamatergic neurons had a negligible effect. Furthermore, we found that GIPR in GABAergic neurons is essential for the enhanced weight loss efficacy of dual incretin agonism, yet, surprisingly, its removal enhances the effect of GLP-1R agonism alone. Finally, GIPR knockout in GABAergic neurons prevents the anti-aversive effects of GIPR agonism. CONCLUSIONS Our findings are consistent with GIPR research at large in that both enhancement and removal of GIPR signaling are metabolically beneficial. Notably, however, our findings suggest that future obesity therapies designed to modulate GIPR signaling, whether by agonism or antagonism, would be best targeted towards GABAergic neurons.
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Affiliation(s)
- Jordan Wean
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | | | - Rhianna Laker
- Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Sarah Will
- Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Daniel J Drucker
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, Toronto, Canada
| | - Christopher J Rhodes
- Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
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2
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Zhou C, Gong B, Liu X, Hu G, Sun L. Glucose-dependent insulinotropic peptide and beyond: co-agonist innovations in the treatment of metabolic diseases. Eur J Pharmacol 2025; 999:177681. [PMID: 40306536 DOI: 10.1016/j.ejphar.2025.177681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 04/12/2025] [Accepted: 04/24/2025] [Indexed: 05/02/2025]
Abstract
Glucose-dependent insulinotropic peptide (GIP), a key incretin hormone, has emerged as a pivotal therapeutic target in metabolic disorders. Historically, its therapeutic potential in type 2 diabetes mellitus (T2DM) has been underestimated owing to GIP resistance and its limited acute effects on glycemic control and body weight regulation. However, emerging evidence has demonstrated that GIP resistance is reversible through sustained glycemic improvement, thereby restoring its physiological effectiveness. With the development of gut hormone co-agonists, the potential of GIP in the treatment of metabolic diseases has been reevaluated. The study of GIP and its co-agonists such as glucagon-like peptide-1 (GLP-1), revealed that its mechanism of action in regulating blood glucose, fat metabolism, and bone metabolism is complex and diverse. A better understanding of GIP evolution can help in designing more effective GIP-based treatment strategies. In this review, we summarize the physiological functions of GIP, systematically explores its diverse structural modifications, delves into the realm of unimolecular multi-agonists, and provides a nuanced portrayal of the developmental prospects of GIP analogs.
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Affiliation(s)
- Chenxu Zhou
- College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Binbin Gong
- College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Xiyu Liu
- College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Guoqiang Hu
- Taizhou Hospital, Zhejiang University, Taizhou, 317000, China
| | - Lidan Sun
- College of Medicine, Jiaxing University, Jiaxing, 314001, China; Taizhou Hospital, Zhejiang University, Taizhou, 317000, China.
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3
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Zandvakili I, Perez-Tilve D. The unexpected role of GIP in transforming obesity treatment. Trends Endocrinol Metab 2025; 36:330-338. [PMID: 39198118 DOI: 10.1016/j.tem.2024.07.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 09/01/2024]
Abstract
Despite sharing incretin activity with glucagon-like peptide 1 (GLP-1), the development of gastric inhibitory polypeptide (GIP)-based drugs has been hindered by the minor effects of native GIP on appetite and body weight and genetic studies associating loss-of-function with reduced obesity. Yet, pharmacologically optimized GIP-based molecules have demonstrated profound weight lowering benefits of GIPR agonism when combined with GLP-1-based therapies, which has re-energized deeper exploration of the molecular mechanisms and downstream signaling of GIPR. Interestingly, both GIPR agonism and antagonism offer metabolic benefits, leading to differing viewpoints on how to target GIPR therapeutically. Here we summarize the emerging evidence about the tissue-specific mechanisms that positions GIP-based therapies as important targets for the next generation of anti-obesity and metabolic therapies.
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Affiliation(s)
- Inuk Zandvakili
- Division of Digestive Diseases, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Diego Perez-Tilve
- Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
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4
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Song DK, Jung N, Sung YA, Hong YS, Lee H. Differences in GIP Receptor Expression by Feeding Status in the Mouse Brain. Int J Mol Sci 2025; 26:1142. [PMID: 39940910 PMCID: PMC11818402 DOI: 10.3390/ijms26031142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/19/2025] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
Gastric inhibitory polypeptide (GIP) contributes to energy metabolism regulation. We investigated differences in GIP receptor expression in the brain by feeding status among lean and obese mice and the effect of acute central GIP administration on the expression of appetite-regulating hypothalamic neuropeptides. We divided the mice into four groups: fed/lean, fasted/lean, fed/obese, and fasted/obese. The arcuate nucleus (ARC), paraventricular nucleus of the hypothalamus, and nucleus of the solitary tract in the brainstem were harvested. GIP (6 nmol) or saline was injected for the acute intracerebroventricular administration test, followed by the collection of hypothalamic tissue after 2 h. Fed/obese mice had higher ARC GIP receptor mRNA levels than fasted/obese and lean mice. This difference was not observed among lean mice by feeding status. Obese mice had higher blood GIP levels than lean mice. Fed/obese mice had higher blood GIP levels than fasted/obese mice. This difference was not observed among lean mice by feeding status. GIP administration significantly increased proopiomelano-cortin (Pomc) mRNA levels (GIP: 7.59 ± 0.14; saline: 3.44 ± 1.38 arbitrary units; p = 0.030). Increased GIP receptor expression in the ARC in obese mice indicates its central nervous system involvement in energy balance regulation. GIP potentially regulates POMC-mediated appetite regulation in the hypothalamus. It is possible that POMC neurons are targets of GIP action in the brain.
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Affiliation(s)
| | | | | | | | - Hyejin Lee
- Department of Internal Medicine, Ewha Womans University School of Medicine, 25, Magokdong-ro 2-gil, Gangseo-gu, Seoul 07804, Republic of Korea; (D.K.S.); (N.J.); (Y.-A.S.); (Y.S.H.)
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5
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Oteng AB, Liu L, Cui Y, Gavrilova O, Lu H, Chen M, Weinstein LS, Campbell JE, Lewis JE, Gribble FM, Reimann F, Wess J. Activation of Gs signaling in mouse enteroendocrine K cells greatly improves obesity- and diabetes-related metabolic deficits. J Clin Invest 2024; 134:e182325. [PMID: 39436694 DOI: 10.1172/jci182325] [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: 04/22/2024] [Accepted: 10/15/2024] [Indexed: 10/25/2024] Open
Abstract
Following a meal, glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the 2 major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L and K cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K cells. GPCRs couple to 1 or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the α-subunit of Gs, selectively in K cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K cell Gs signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K cell-specific Gnas-KO mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases.
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Affiliation(s)
- Antwi-Boasiako Oteng
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
- Center for Research on Genomics and Global Health (CRGGH), National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA
| | - Liu Liu
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
| | - Yinghong Cui
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
| | | | - Huiyan Lu
- Mouse Transgenic Core Facility, NIDDK, NIH, Bethesda, Maryland, USA
| | - Min Chen
- Signal Transduction Section, Metabolic Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA
| | - Lee S Weinstein
- Signal Transduction Section, Metabolic Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - Jo E Lewis
- MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Fiona M Gribble
- MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Frank Reimann
- MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Jürgen Wess
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
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6
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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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7
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Zomer HD, Cooke PS. Advances in Drug Treatments for Companion Animal Obesity. BIOLOGY 2024; 13:335. [PMID: 38785817 PMCID: PMC11117622 DOI: 10.3390/biology13050335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/06/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024]
Abstract
Companion animal obesity has emerged as a significant veterinary health concern globally, with escalating rates posing challenges for preventive and therapeutic interventions. Obesity not only leads to immediate health problems but also contributes to various comorbidities affecting animal well-being and longevity, with consequent emotional and financial burdens on owners. While past treatment strategies have shown limited success, recent breakthroughs in human medicine present new opportunities for addressing this complex issue in companion animals. Here, we discuss the potential of GLP-1 receptor agonists, specifically semaglutide and tirzepatide, already approved for human use, for addressing companion animal obesity. These drugs, originally developed to treat type 2 diabetes in humans and subsequently repurposed to treat obesity, have demonstrated remarkable weight loss effects in rodents, non-human primates and people. Additionally, newer drug combinations have shown even more promising results in clinical trials. Despite current cost and supply challenges, advancements in oral and/or extended-release formulations and increased production may make these drugs more accessible for veterinary use. Thus, these drugs may have utility in companion animal weight management, and future feasibility studies exploring their efficacy and safety in treating companion animal obesity are warranted.
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Affiliation(s)
| | - Paul S. Cooke
- Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, USA;
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8
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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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Bailey CJ, Flatt PR. Duodenal enteroendocrine cells and GIP as treatment targets for obesity and type 2 diabetes. Peptides 2024; 174:171168. [PMID: 38320643 DOI: 10.1016/j.peptides.2024.171168] [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: 12/16/2023] [Revised: 02/02/2024] [Accepted: 02/02/2024] [Indexed: 02/08/2024]
Abstract
The duodenum is an important source of endocrine and paracrine signals controlling digestion and nutrient disposition, notably including the main incretin hormone glucose-dependent insulinotropic polypeptide (GIP). Bariatric procedures that prevent nutrients from contact with the duodenal mucosa are particularly effective interventions to reduce body weight and improve glycaemic control in obesity and type 2 diabetes. These procedures take advantage of increased nutrient delivery to more distal regions of the intestine which enhances secretion of the other incretin hormone glucagon-like peptide-1 (GLP-1). Preclinical experiments have shown that either an increase or a decrease in the secretion or action of GIP can decrease body weight and blood glucose in obesity and non-insulin dependent hyperglycaemia, but clinical studies involving administration of GIP have been inconclusive. However, a synthetic dual agonist peptide (tirzepatide) that exerts agonism at receptors for GIP and GLP-1 has produced marked weight-lowering and glucose-lowering effects in people with obesity and type 2 diabetes. This appears to result from chronic biased agonism in which the novel conformation of the peptide triggers enhanced signalling by the GLP-1 receptor through reduced internalisation while reducing signalling by the GIP receptor directly or via functional antagonism through increased internalisation and degradation.
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Affiliation(s)
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA Northern Ireland, UK
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10
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Véniant MM, Lu SC, Atangan L, Komorowski R, Stanislaus S, Cheng Y, Wu B, Falsey JR, Hager T, Thomas VA, Ambhaikar M, Sharpsten L, Zhu Y, Kurra V, Jeswani R, Oberoi RK, Parnes JR, Honarpour N, Neutel J, Strande JL. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat Metab 2024; 6:290-303. [PMID: 38316982 PMCID: PMC10896721 DOI: 10.1038/s42255-023-00966-w] [Citation(s) in RCA: 62] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 12/12/2023] [Indexed: 02/07/2024]
Abstract
Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity ( NCT04478708 ), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133.
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Affiliation(s)
- Murielle M Véniant
- Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks, CA, USA.
| | - Shu-Chen Lu
- Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks, CA, USA
| | - Larissa Atangan
- Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks, CA, USA
| | - Renee Komorowski
- Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks, CA, USA
| | - Shanaka Stanislaus
- Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks, CA, USA
| | - Yuan Cheng
- Amgen Research, Department of Therapeutic Discovery, Thousand Oaks, CA, USA
| | - Bin Wu
- Amgen Research, Department of Therapeutic Discovery, Thousand Oaks, CA, USA
| | - James R Falsey
- Amgen Research, Department of Therapeutic Discovery, Thousand Oaks, CA, USA
| | - Todd Hager
- Amgen Research, Department of Translational Safety & Bioanalytical Sciences, Thousand Oaks, CA, USA
| | - Veena A Thomas
- Amgen Research, Department of Pharmacokinetics and Drug Metabolism, South San Francisco, CA, USA
| | - Malhar Ambhaikar
- Pre-pivotal Drug Substance Technologies, Amgen, Thousand Oaks, CA, USA
| | | | - Yineng Zhu
- Amgen Early Development, Amgen, Thousand Oaks, CA, USA
| | - Vamsi Kurra
- Amgen Research, Department of Translational Safety & Bioanalytical Sciences, Thousand Oaks, CA, USA
| | - Rohini Jeswani
- Amgen Research, Department of Translational Safety & Bioanalytical Sciences, Thousand Oaks, CA, USA
| | | | - Jane R Parnes
- Amgen Early Development, Amgen, Thousand Oaks, CA, USA
| | | | - Joel Neutel
- Orange County Research Center, Tustin, CA, USA
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11
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Meeks KAC, Bentley AR, Assimes TL, Franceschini N, Adeyemo AA, Rotimi CN, Doumatey AP. Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes. Genome Med 2023; 15:108. [PMID: 38049854 PMCID: PMC10694992 DOI: 10.1186/s13073-023-01263-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 11/21/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses. METHODS We used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones). RESULTS Circulating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S β = - 0.67, P-value = 1.88 × 10-6 and HOMA-B β = 0.59, P-value = 1.88 × 10-5; IL-1RA ~ HOMA-S β = - 0.51, P-value = 8.49 × 10-5 and HOMA-B β = 0.48, P-value = 5.71 × 10-4). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P-value = 9.79 × 10-6), though these associations were not consistent in all sensitivity analyses. CONCLUSIONS The findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP's effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.
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Affiliation(s)
- Karlijn A C Meeks
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, 12 South Drive Bldg 12A ste 1025, Bethesda, MD, 20892-5611, USA.
| | - Amy R Bentley
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, 12 South Drive Bldg 12A ste 1025, Bethesda, MD, 20892-5611, USA
| | - Themistocles L Assimes
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- VA Palo Alto Healthcare System, Palo Alto, CA, USA
| | - Nora Franceschini
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
| | - Adebowale A Adeyemo
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, 12 South Drive Bldg 12A ste 1025, Bethesda, MD, 20892-5611, USA
| | - Charles N Rotimi
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, 12 South Drive Bldg 12A ste 1025, Bethesda, MD, 20892-5611, USA
| | - Ayo P Doumatey
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, 12 South Drive Bldg 12A ste 1025, Bethesda, MD, 20892-5611, USA.
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12
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Ruck L, Wiegand S, Kühnen P. Relevance and consequence of chronic inflammation for obesity development. Mol Cell Pediatr 2023; 10:16. [PMID: 37957462 PMCID: PMC10643747 DOI: 10.1186/s40348-023-00170-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Increasing prevalence of morbid obesity accompanied by comorbidities like type 2 diabetes mellitus (T2DM) led to a demand for improving therapeutic strategies and pharmacological intervention options. Apart from genetics, inflammation processes have been hypothesized to be of importance for the development of obesity and related aspects like insulin resistance. MAIN TEXT Within this review, we provide an overview of the intricate interplay between chronic inflammation of the adipose tissue and the hypothalamus and the development of obesity. Further understanding of this relationship might improve the understanding of the underlying mechanism and may be of relevance for the establishment of new treatment strategies.
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Affiliation(s)
- Lisa Ruck
- Klinik Für Pädiatrische Endokrinologie und Diabetologie, Charité Universitätsmedizin, Berlin, Germany.
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Charitéplatz 1, 10117, Berlin, Germany.
| | - Susanna Wiegand
- Abteilung Interdisziplinär, Sozial-Pädiatrisches Zentrum, Charité Universitätsmedizin, Berlin, Germany
| | - Peter Kühnen
- Klinik Für Pädiatrische Endokrinologie und Diabetologie, Charité Universitätsmedizin, Berlin, Germany
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13
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Campbell JE, Müller TD, Finan B, DiMarchi RD, Tschöp MH, D'Alessio DA. GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications. Cell Metab 2023; 35:1519-1529. [PMID: 37591245 PMCID: PMC10528201 DOI: 10.1016/j.cmet.2023.07.010] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/09/2023] [Accepted: 07/21/2023] [Indexed: 08/19/2023]
Abstract
The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1), which have cognate receptors (GIPR and GLP-1R) on islet β cells as well as in other tissues. Pharmacologic engagement of the GLP-1R is a proven strategy for treating hyperglycemia in diabetes and reducing body weight. Tirzepatide is the first monomeric peptide with dual activity at both incretin receptors now available for clinical use, and in clinical trials it has shown unprecedented effects to reduce blood glucose and body weight. Here, we discuss the foundational science that led to the development of monomeric multi-incretin receptor agonists, culminating in the development of tirzepatide. We also look to the future of this field and comment on how the concept of multi-receptor agonists will continue to progress for the treatment of metabolic disease.
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Affiliation(s)
- 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.
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Brian Finan
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | | | - Matthias H Tschöp
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technical University of München, Munich, Germany; Helmholtz Munich, Neuherberg, Germany.
| | - David A D'Alessio
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA
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14
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Cataldi S, Aprile M, Perfetto C, Angot B, Cormont M, Ciccodicola A, Tanti JF, Costa V. GIPR expression is induced by thiazolidinediones in a PPARγ-independent manner and repressed by obesogenic stimuli. Eur J Cell Biol 2023; 102:151320. [PMID: 37130450 DOI: 10.1016/j.ejcb.2023.151320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 04/24/2023] [Accepted: 04/25/2023] [Indexed: 05/04/2023] Open
Abstract
Adipose tissue (AT) dysfunctions are associated with the onset of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). Targeting glucose-dependent insulinotropic peptide receptor (GIPR) is a valid option to increase the efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists in T2DM treatment. Nevertheless, the therapeutic potential of targeting the GIP/GIPR axis and its effect on the AT are controversial. In this work, we explored the expression and regulation of GIPR in precursor cells and mature adipocytes, investigating if and how obesogenic stimuli and thiazolidinediones perturb GIPR expression. Using publicly available gene expression datasets, we assessed that, among white adipose tissue (WAT) cells, adipocytes express lower levels of GIPR compared to cells of mesothelial origin, pericytes, dendritic and NK/T cells. However, we report that GIPR levels markedly increase during the in vitro differentiation of both murine and human adipocytes, from 3T3-L1 and human mesenchymal precursor cells (MSCs), respectively. Notably, we demonstrated that thiazolidinediones - ie. synthetic PPARγ agonists widely used as anti-diabetic drugs and contained in the adipogenic mix - markedly induce GIPR expression. Moreover, using multiple in vitro systems, we assessed that thiazolidinediones induce GIPR in a PPARγ-independent manner. Our results support the hypothesis that PPARγ synthetic agonists may be used to increase GIPR levels in AT, potentially affecting in turn the targeting of GIP system in patients with metabolic dysfunctions. Furthermore, we demonstrate in vitro and in vivo that proinflammatory stimuli, and especially the TNFα, represses GIPR both in human and murine adipocytes, even though discordant results were obtained between human and murine cellular systems for other cytokines. Finally, we demonstrated that GIPR is negatively affected also by the excessive lipid engulfment. Overall, we report that obesogenic stimuli - ie. pro-inflammatory cytokines and the increased lipid accumulation - and PPARγ synthetic ligands oppositely modulate GIPR expression, possibly influencing the effectiveness of GIP agonists.
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Affiliation(s)
- Simona Cataldi
- Institute of Genetics and Biophysics ''Adriano Buzzati-Traverso'', CNR, Via P. Castellino 111, 80131 Naples, Italy
| | - Marianna Aprile
- Institute of Genetics and Biophysics ''Adriano Buzzati-Traverso'', CNR, Via P. Castellino 111, 80131 Naples, Italy
| | - Caterina Perfetto
- Institute of Genetics and Biophysics ''Adriano Buzzati-Traverso'', CNR, Via P. Castellino 111, 80131 Naples, Italy
| | - Brice Angot
- Université Côte d'Azur, Inserm UMR1065, C3M, Team Cellular and Molecular Pathophysiology of Obesity, 06204 Nice, France
| | - Mireille Cormont
- Université Côte d'Azur, Inserm UMR1065, C3M, Team Cellular and Molecular Pathophysiology of Obesity, 06204 Nice, France
| | - Alfredo Ciccodicola
- Institute of Genetics and Biophysics ''Adriano Buzzati-Traverso'', CNR, Via P. Castellino 111, 80131 Naples, Italy; Department of Science and Technology, University of Naples ''Parthenope'', Naples, Italy
| | - Jean-Francois Tanti
- Université Côte d'Azur, Inserm UMR1065, C3M, Team Cellular and Molecular Pathophysiology of Obesity, 06204 Nice, France.
| | - Valerio Costa
- Institute of Genetics and Biophysics ''Adriano Buzzati-Traverso'', CNR, Via P. Castellino 111, 80131 Naples, Italy; NBFC, National Biodiversity Future Center, Palermo 90133, Italy.
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15
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Hansen MS, Søe K, Christensen LL, Fernandez-Guerra P, Hansen NW, Wyatt RA, Martin C, Hardy RS, Andersen TL, Olesen JB, Hartmann B, Rosenkilde MM, Kassem M, Rauch A, Gorvin CM, Frost M. GIP reduces osteoclast activity and improves osteoblast survival in primary human bone cells. Eur J Endocrinol 2023; 188:6987865. [PMID: 36747334 DOI: 10.1093/ejendo/lvac004] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/26/2022] [Accepted: 11/19/2022] [Indexed: 01/18/2023]
Abstract
OBJECTIVE Drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) are emerging as treatments for type-2 diabetes and obesity. GIP acutely decreases serum markers of bone resorption and transiently increases bone formation markers in short-term clinical investigations. However, it is unknown whether GIP acts directly on bone cells to mediate these effects. Using a GIPR-specific antagonist, we aimed to assess whether GIP acts directly on primary human osteoclasts and osteoblasts. METHODS Osteoclasts were differentiated from human CD14+ monocytes and osteoblasts from human bone. GIPR expression was determined using RNA-seq in primary human osteoclasts and in situ hybridization in human femoral bone. Osteoclastic resorptive activity was assessed using microscopy. GIPR signaling pathways in osteoclasts and osteoblasts were assessed using LANCE cAMP and AlphaLISA phosphorylation assays, intracellular calcium imaging and confocal microscopy. The bioenergetic profile of osteoclasts was evaluated using Seahorse XF-96. RESULTS GIPR is robustly expressed in mature human osteoclasts. GIP inhibits osteoclastogenesis, delays bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways (Src, cAMP, Akt, p38, Akt, NFκB) to impair nuclear translocation of nuclear factor of activated T cells-1 (NFATc1) and nuclear factor-κB (NFκB). Osteoblasts also expressed GIPR, and GIP improved osteoblast survival. Decreased bone resorption and improved osteoblast survival were also observed after GIP treatment of osteoclast-osteoblast co-cultures. Antagonizing GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoclasts and osteoblasts. CONCLUSIONS GIP inhibits bone resorption and improves survival of human osteoblasts, indicating that drugs targeting GIPR may impair bone resorption, whilst preserving bone formation.
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Affiliation(s)
- Morten S Hansen
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark
- Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, United Kingdom
- Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham B15 2TT, United Kingdom
| | - Kent Søe
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark
- Clinical Cell Biology, Department of Pathology, Odense University Hospital, Odense C DK-5000, Denmark
- Department of Molecular Medicine, University of Southern Denmark, Odense C DK-5000, Denmark
| | - Line L Christensen
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark
| | - Paula Fernandez-Guerra
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark
| | - Nina W Hansen
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark
| | - Rachael A Wyatt
- Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, United Kingdom
- Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham B15 2TT, United Kingdom
| | - Claire Martin
- Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Rowan S Hardy
- Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Thomas L Andersen
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark
- Clinical Cell Biology, Department of Pathology, Odense University Hospital, Odense C DK-5000, Denmark
- Department of Molecular Medicine, University of Southern Denmark, Odense C DK-5000, Denmark
| | - Jacob B Olesen
- Clinical Cell Biology, Department of Pathology, Odense University Hospital, Odense C DK-5000, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark
| | - Moustapha Kassem
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark
| | - Alexander Rauch
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark
- Steno Diabetes Centre Odense, Odense University Hospital, Odense C DK-5000, Denmark
| | - Caroline M Gorvin
- Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, United Kingdom
- Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham B15 2TT, United Kingdom
| | - Morten Frost
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Odense C DK-5000, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C DK-5000, Denmark
- Steno Diabetes Centre Odense, Odense University Hospital, Odense C DK-5000, Denmark
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16
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Obesity-associated mesenteric lymph leakage impairs the trafficking of lipids, lipophilic drugs and antigens from the intestine to mesenteric lymph nodes. Eur J Pharm Biopharm 2022; 180:319-331. [DOI: 10.1016/j.ejpb.2022.10.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/06/2022] [Accepted: 10/19/2022] [Indexed: 11/23/2022]
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17
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An analysis of intestinal morphology and incretin-producing cells using tissue optical clearing and 3-D imaging. Sci Rep 2022; 12:17530. [PMID: 36266531 PMCID: PMC9584944 DOI: 10.1038/s41598-022-22511-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 10/17/2022] [Indexed: 01/13/2023] Open
Abstract
Tissue optical clearing permits detailed evaluation of organ three-dimensional (3-D) structure as well as that of individual cells by tissue staining and autofluorescence. In this study, we evaluated intestinal morphology, intestinal epithelial cells (IECs), and enteroendocrine cells, such as incretin-producing cells, in reporter mice by intestinal 3-D imaging. 3-D intestinal imaging of reporter mice using optical tissue clearing enabled us to evaluate both detailed intestinal morphologies and cell numbers, villus length and crypt depth in the same samples. In disease mouse model of lipopolysaccharide (LPS)-injected mice, the results of 3-D imaging using tissue optical clearing in this study was consistent with those of 2-D imaging in previous reports and could added the new data of intestinal morphology. In analysis of incretin-producing cells of reporter mice, we could elucidate the number, the percentage, and the localization of incretin-producing cells in intestine and the difference of those between L cells and K cells. Thus, we established a novel method of intestinal analysis using tissue optical clearing and 3-D imaging. 3-D evaluation of intestine enabled us to clarify not only detailed intestinal morphology but also the precise number and localization of IECs and incretin-producing cells in the same samples.
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18
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Lednovich KR, Nnyamah C, Gough S, Priyadarshini M, Xu K, Wicksteed B, Mishra S, Jain S, Zapater JL, Yadav H, Layden BT. Intestinal FFA3 mediates obesogenic effects in mice on a Western diet. Am J Physiol Endocrinol Metab 2022; 323:E290-E306. [PMID: 35858247 PMCID: PMC9448285 DOI: 10.1152/ajpendo.00016.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 01/05/2023]
Abstract
Free fatty acid receptor 3 (FFA3) is a recently-deorphanized G-protein-coupled receptor. Its ligands are short-chain fatty acids (SCFAs), which are key nutrients derived from the gut microbiome fermentation process that play diverse roles in the regulation of metabolic homeostasis and glycemic control. FFA3 is highly expressed within the intestine, where its role and its effects on physiology and metabolism are unclear. Previous in vivo studies involving this receptor have relied on global knockout mouse models, making it difficult to isolate intestine-specific roles of FFA3. To overcome this challenge, we generated an intestine-specific knockout mouse model for FFA3, Villin-Cre-FFA3 (Vil-FFA3). Model validation and general metabolic assessment of male mice fed a standard chow diet revealed no major congenital defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, an obesogenic challenge was performed on male Vil-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar "Western diet" (WD) compared with a low-fat control diet (CD). Vil-FFA3 mice versus FFA3fl/fl controls on WD, but not CD, were protected from the development of diet-induced obesity and exhibited significantly less fat mass as well as smaller adipose depositions and adipocytes. Although overall glycemic control was unchanged in the WD-fed Vil-FFA3 group, fasted glucose levels trended lower. Intestinal inflammation was significantly reduced in the WD-fed Vil-FFA3 mice, supporting protection from obesogenic effects. Furthermore, we observed lower levels of gastric inhibitory protein (GIP) in the WD-fed Vil-FFA3 mice, which may contribute to phenotypic changes. Our findings suggest a novel role of intestinal FFA3 in promoting the metabolic consequences of a WD, including the development of obesity and inflammation. Moreover, these data support an intestine-specific role of FFA3 in whole body metabolic homeostasis and in the development of adiposity.NEW & NOTEWORTHY Here, we generated a novel intestine-specific knockout mouse model for FFA3 (Vil-FFA3) and performed a comprehensive metabolic characterization of mice in response to an obesogenic challenge. We found that Vil-FFA3 mice fed with a Western diet were largely protected from obesity, exhibiting significantly lower levels of fat mass, lower intestinal inflammation, and altered expression of intestinal incretin hormones. Results support an important role of intestinal FFA3 in contributing to metabolism and in the development of diet-induced obesity.
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Affiliation(s)
- Kristen R Lednovich
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Chioma Nnyamah
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Sophie Gough
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Medha Priyadarshini
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Kai Xu
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Barton Wicksteed
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Sidharth Mishra
- USF Center for Microbiome Research, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Shalini Jain
- USF Center for Microbiome Research, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Joseph L Zapater
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Hariom Yadav
- USF Center for Microbiome Research, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Brian T Layden
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
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19
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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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20
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Campbell JE, Beaudry JL, Svendsen B, Baggio LL, Gordon AN, Ussher JR, Wong CK, Gribble FM, D’Alessio DA, Reimann F, Drucker DJ. GIPR Is Predominantly Localized to Nonadipocyte Cell Types Within White Adipose Tissue. Diabetes 2022; 71:1115-1127. [PMID: 35192688 PMCID: PMC7612781 DOI: 10.2337/db21-1166] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/16/2022] [Indexed: 02/02/2023]
Abstract
The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) augments glucose-dependent insulin secretion through its receptor expressed on islet β-cells. GIP also acts on adipose tissue; yet paradoxically, both enhanced and reduced GIP receptor (GIPR) signaling reduce adipose tissue mass and attenuate weight gain in response to nutrient excess. Moreover, the precise cellular localization of GIPR expression within white adipose tissue (WAT) remains uncertain. We used mouse genetics to target Gipr expression within adipocytes. Surprisingly, targeting Cre expression to adipocytes using the adiponectin (Adipoq) promoter did not produce meaningful reduction of WAT Gipr expression in Adipoq-Cre:Giprflx/flx mice. In contrast, adenoviral expression of Cre under the control of the cytomegalovirus promoter, or transgenic expression of Cre using nonadipocyte-selective promoters (Ap2/Fabp4 and Ubc) markedly attenuated WAT Gipr expression. Analysis of single-nucleus RNA-sequencing, adipose tissue data sets localized Gipr/GIPR expression predominantly to pericytes and mesothelial cells rather than to adipocytes. Together, these observations reveal that adipocytes are not the major GIPR+ cell type within WAT-findings with mechanistic implications for understanding how GIP and GIP-based co-agonists control adipose tissue biology.
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Affiliation(s)
- Jonathan E. Campbell
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada
- Duke Molecular Physiology Institute, Duke University, Durham, NC
- Department of Medicine, Division of Endocrinology, Duke University, Durham, NC
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC
- Corresponding authors: Jonathan E. Campbell, , or Daniel J. Drucker,
| | - Jacqueline L. Beaudry
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada
| | - Berit Svendsen
- Duke Molecular Physiology Institute, Duke University, Durham, NC
| | - Laurie L. Baggio
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada
| | - Andrew N. Gordon
- Duke Molecular Physiology Institute, Duke University, Durham, NC
| | - John R. Ussher
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada
| | - Chi Kin Wong
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada
| | - Fiona M. Gribble
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, U.K
| | - David A. D’Alessio
- Duke Molecular Physiology Institute, Duke University, Durham, NC
- Department of Medicine, Division of Endocrinology, Duke University, Durham, NC
| | - Frank Reimann
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, U.K
| | - Daniel J. Drucker
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Corresponding authors: Jonathan E. Campbell, , or Daniel J. Drucker,
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21
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Takahashi H, Nakajima A, Matsumoto Y, Mori H, Inoue K, Yamanouchi H, Tanaka K, Tomiga Y, Miyahara M, Yada T, Iba Y, Matsuda Y, Watanabe K, Anzai K. Administration of Jerusalem artichoke reduces the postprandial plasma glucose and glucose-dependent insulinotropic polypeptide (GIP) concentrations in humans. Food Nutr Res 2022; 66:7870. [PMID: 35440936 PMCID: PMC8985572 DOI: 10.29219/fnr.v66.7870] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 02/26/2022] [Accepted: 02/28/2022] [Indexed: 01/19/2023] Open
Abstract
Background The consumption of Jerusalem artichoke has multiple beneficial effects against diabetes and obesity. Objective The aim of this study was to determine the effect of a single administration of Jerusalem artichoke tubers on postprandial glycemia and the concentrations of incretin hormones in humans. Method Grated Jerusalem artichoke was administered prior to a meal (Trial 1; white rice for prediabetic participants, n = 10). Dose-dependent effect of Jerusalem artichoke (Trial 2; white rice for prediabetic participants, n = 4) and effect prior to the fat-rich meal were also investigated (Trial 3; healthy participants, n = 5) in this pilot study. Circulating glucose, insulin, triglyceride, glucagon, active glucagon-like peptide-1 (GLP-1), and active glucose-dependent insulinotropic polypeptide (GIP) concentrations were subsequently measured in all the trials. Results Jerusalem artichoke significantly reduced the glucose and GIP concentrations after the consumption of either meal in Trial 1 and Trial 3, whereas there were no differences in the insulin, glucagon, and active GLP-1 concentrations. Also, there was no significant difference in the triglyceride concentration after the ingestion of the fat-rich meal in Trial 3. The glucose and GIP-lowering effects were dose-dependent, and the consumption of at least 100 g of Jerusalem artichoke was required to have these effects in Trial 2. Conclusion This study demonstrates that a single administration of Jerusalem artichoke tubers reduces postprandial glucose and active GIP concentrations in prediabetic and healthy individuals.
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Affiliation(s)
- Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan
| | - Akane Nakajima
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Center of Nutritional Education, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan
| | - Yuichi Matsumoto
- Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, Karatsu, Saga, Japan
| | - Hitoe Mori
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Kanako Inoue
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Hiroko Yamanouchi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Yuki Tomiga
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Maki Miyahara
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Tomomi Yada
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan
| | - Yumiko Iba
- Center of Nutritional Education, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan
| | - Yayoi Matsuda
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keiichi Watanabe
- Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, Karatsu, Saga, Japan
| | - Keizo Anzai
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
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22
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The transcription factor hepatocyte nuclear factor 4A acts in the intestine to promote white adipose tissue energy storage. Nat Commun 2022; 13:224. [PMID: 35017517 PMCID: PMC8752770 DOI: 10.1038/s41467-021-27934-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 12/23/2021] [Indexed: 12/13/2022] Open
Abstract
The transcription factor hepatocyte nuclear factor 4 A (HNF4A) controls the metabolic features of several endodermal epithelia. Both HNF4A and HNF4G are redundant in the intestine and it remains unclear whether HNF4A alone controls intestinal lipid metabolism. Here we show that intestinal HNF4A is not required for intestinal lipid metabolism per se, but unexpectedly influences whole-body energy expenditure in diet-induced obesity (DIO). Deletion of intestinal HNF4A caused mice to become DIO-resistant with a preference for fat as an energy substrate and energetic changes in association with white adipose tissue (WAT) beiging. Intestinal HNF4A is crucial for the fat-induced release of glucose-dependent insulinotropic polypeptide (GIP), while the reintroduction of a stabilized GIP analog rescues the DIO resistance phenotype of the mutant mice. Our study provides evidence that intestinal HNF4A plays a non-redundant role in whole-body lipid homeostasis and points to a non-cell-autonomous regulatory circuit for body-fat management. HNF4A is a nuclear receptor that regulates liver lipid homeostasis. Here the authors show that HNF4A is not required for intestinal lipid metabolism but controls energy expenditure under diet induced obesity through the fat-induced release of glucose-dependent insulinotropic polypeptide.
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23
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Wang C, Chen J, Wang P, Qing S, Li W, Lu J. Endogenous Protective Factors and Potential Therapeutic Agents for Diabetes-Associated Atherosclerosis. Front Endocrinol (Lausanne) 2022; 13:821028. [PMID: 35557850 PMCID: PMC9086429 DOI: 10.3389/fendo.2022.821028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 03/21/2022] [Indexed: 11/30/2022] Open
Abstract
The complications of macrovascular atherosclerosis are the leading cause of disability and mortality in patients with diabetes. It is generally believed that the pathogenesis of diabetic vascular complications is initiated by the imbalance between injury and endogenous protective factors. Multiple endogenous protective factors secreted by endothelium, liver, skeletal muscle and other tissues are recognized of their importance in combating injury factors and maintaining the homeostasis of vasculatures in diabetes. Among them, glucagon-like peptide-1 based drugs were clinically proven to be effective and recommended as the first-line medicine for the treatment of type 2 diabetic patients with high risks or established arteriosclerotic cardiovascular disease (CVD). Some molecules such as irisin and lipoxins have recently been perceived as new protective factors on diabetic atherosclerosis, while the protective role of HDL has been reinterpreted since the failure of several clinical trials to raise HDL therapy on cardiovascular events. The current review aims to summarize systemic endogenous protective factors for diabetes-associated atherosclerosis and discuss their mechanisms and potential therapeutic strategy or their analogues. In particular, we focus on the existing barriers or obstacles that need to be overcome in developing new therapeutic approaches for macrovascular complications of diabetes.
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Affiliation(s)
- Chaoqun Wang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jin Chen
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Pin Wang
- Department of Pharmacology, Naval Medical University, Shanghai, China
| | - Shengli Qing
- Department of Pharmacology, Naval Medical University, Shanghai, China
| | - Wenwen Li
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Naval Medical University, Shanghai, China
- *Correspondence: Jin Lu, ; Wenwen Li,
| | - Jin Lu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Naval Medical University, Shanghai, China
- *Correspondence: Jin Lu, ; Wenwen Li,
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24
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Abstract
The enteroendocrine system coordinates the physiological response to food intake by regulating rates of digestion, nutrient absorption, insulin secretion, satiation and satiety. Gut hormones with important anorexigenic and/or insulinotropic roles include glucagon-like peptide 1 (GLP-1), peptide YY (PYY3-36), cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP). High BMI or obesogenic diets do not markedly disrupt this enteroendocrine system, which represents a critical target for inducing weight loss and treating co-morbidities in individuals with obesity.
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25
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Kiyobayashi S, Murakami T, Harada N, Fujimoto H, Murata Y, Fujita N, Hamamatsu K, Ikeguchi-Ogura E, Hatoko T, Lu X, Yamane S, Inagaki N. Noninvasive Evaluation of GIP Effects on β-Cell Mass Under High-Fat Diet. Front Endocrinol (Lausanne) 2022; 13:921125. [PMID: 35909510 PMCID: PMC9326491 DOI: 10.3389/fendo.2022.921125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 05/23/2022] [Indexed: 12/22/2022] Open
Abstract
Pancreatic β-cell mass (BCM) has an importance in the pathophysiology of diabetes mellitus. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged as a promising tool for BCM evaluation. While glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is known to be involved in high-fat diet (HFD)-induced obesity, the effect of GIP on BCM is still controversial. In this study, we investigated indium 111 (111In)-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) single-photon emission computed tomography/computed tomography (SPECT/CT) as a tool for evaluation of longitudinal BCM changes in HFD-induced obese mice, at the same time we also investigated the effects of GIP on BCM in response to HFD using GIP-knockout (GIP-/-) mice. 111In-exendin-4 SPECT/CT was able to distinguish control-fat diet (CFD)-fed mice from HFD-fed mice and the pancreatic uptake values replicated the BCM measured by conventional histological methods. Furthermore, BCM expansions in HFD-fed mice were demonstrated by time-course changes of the pancreatic uptake values. Additionally, 111In-exendin-4 SPECT/CT demonstrated the distinct changes in BCM between HFD-fed GIP-/- (GIP-/-+HFD) and wild-type (WT+HFD) mice; the pancreatic uptake values of GIP-/-+HFD mice became significantly lower than those of WT+HFD mice. The different changes in the pancreatic uptake values between the two groups preceded those in fat accumulation and insulin resistance. Taken together with the finding of increased β-cell apoptosis in GIP-/-+HFD mice compared with WT+HFD mice, these data indicated that GIP has preferable effects on BCM under HFD. Therefore, 111In-exendin-4 SPECT/CT can be useful for evaluating increasing BCM and the role of GIP in BCM changes under HFD conditions.
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Affiliation(s)
- Sakura Kiyobayashi
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takaaki Murakami
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Fujimoto
- Radioisotope Research Center, Agency of Health, Safety and Environment, Kyoto University, Kyoto, Japan
| | - Yuki Murata
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Naotaka Fujita
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keita Hamamatsu
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Eri Ikeguchi-Ogura
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomonobu Hatoko
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Xuejing Lu
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shunsuke Yamane
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- *Correspondence: Nobuya Inagaki,
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26
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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: 32] [Impact Index Per Article: 10.7] [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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27
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Lindquist P, Gasbjerg LS, Mokrosinski J, Holst JJ, Hauser AS, Rosenkilde MM. The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection. Front Endocrinol (Lausanne) 2022; 13:891586. [PMID: 35846282 PMCID: PMC9277503 DOI: 10.3389/fendo.2022.891586] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/04/2022] [Indexed: 11/16/2022] Open
Abstract
The intestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is involved in important physiological functions, including postprandial blood glucose homeostasis, bone remodeling, and lipid metabolism. While mutations leading to physiological changes can be identified in large-scale sequencing, no systematic investigation of GIP missense variants has been performed. Here, we identified 168 naturally occurring missense variants in the human GIP genes from three independent cohorts comprising ~720,000 individuals. We examined amino acid changing variants scattered across the pre-pro-GIP peptide using in silico effect predictions, which revealed that the sequence of the fully processed GIP hormone is more protected against mutations than the rest of the precursor protein. Thus, we observed a highly species-orthologous and population-specific conservation of the GIP peptide sequence, suggestive of evolutionary constraints to preserve the GIP peptide sequence. Elucidating the mutational landscape of GIP variants and how they affect the structural and functional architecture of GIP can aid future biological characterization and clinical translation.
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Affiliation(s)
- Peter Lindquist
- Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lærke Smidt Gasbjerg
- Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jacek Mokrosinski
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, United States
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alexander Sebastian Hauser
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Alexander Sebastian Hauser, ; Mette Marie Rosenkilde,
| | - Mette Marie Rosenkilde
- Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Alexander Sebastian Hauser, ; Mette Marie Rosenkilde,
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28
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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: 10] [Impact Index Per Article: 2.5] [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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29
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Morrow NM, Hanson AA, Mulvihill EE. Distinct Identity of GLP-1R, GLP-2R, and GIPR Expressing Cells and Signaling Circuits Within the Gastrointestinal Tract. Front Cell Dev Biol 2021; 9:703966. [PMID: 34660576 PMCID: PMC8511495 DOI: 10.3389/fcell.2021.703966] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 08/16/2021] [Indexed: 12/17/2022] Open
Abstract
Enteroendocrine cells directly integrate signals of nutrient content within the gut lumen with distant hormonal responses and nutrient disposal via the production and secretion of peptides, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2). Given their direct and indirect control of post-prandial nutrient uptake and demonstrated translational relevance for the treatment of type 2 diabetes, malabsorption and cardiometabolic disease, there is significant interest in the locally engaged circuits mediating these metabolic effects. Although several specific populations of cells in the intestine have been identified to express endocrine receptors, including intraepithelial lymphocytes (IELs) and αβ and γδ T-cells (Glp1r+) and smooth muscle cells (Glp2r+), the definitive cellular localization and co-expression, particularly in regards to the Gipr remain elusive. Here we review the current state of the literature and evaluate the identity of Glp1r, Glp2r, and Gipr expressing cells within preclinical and clinical models. Further elaboration of our understanding of the initiating G-protein coupled receptor (GPCR) circuits engaged locally within the intestine and how they become altered with high-fat diet feeding can offer insight into the dysregulation observed in obesity and diabetes.
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Affiliation(s)
- Nadya M Morrow
- Energy Substrate Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Antonio A Hanson
- Energy Substrate Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Erin E Mulvihill
- Energy Substrate Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Montreal Diabetes Research Center CRCHUM-Pavillion R, Montreal, QC, Canada.,Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
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30
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Murata Y, Harada N, Kishino S, Iwasaki K, Ikeguchi-Ogura E, Yamane S, Kato T, Kanemaru Y, Sankoda A, Hatoko T, Kiyobayashi S, Ogawa J, Hirasawa A, Inagaki N. Medium-chain triglycerides inhibit long-chain triglyceride-induced GIP secretion through GPR120-dependent inhibition of CCK. iScience 2021; 24:102963. [PMID: 34466786 PMCID: PMC8382997 DOI: 10.1016/j.isci.2021.102963] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 01/14/2021] [Accepted: 08/05/2021] [Indexed: 12/13/2022] Open
Abstract
Long-chain triglycerides (LCTs) intake strongly stimulates GIP secretion from enteroendocrine K cells and induces obesity and insulin resistance partly due to GIP hypersecretion. In this study, we found that medium-chain triglycerides (MCTs) inhibit GIP secretion after single LCT ingestion and clarified the mechanism underlying MCT-induced inhibition of GIP secretion. MCTs reduced the CCK effect after single LCT ingestion in wild-type (WT) mice, and a CCK agonist completely reversed MCT-induced inhibition of GIP secretion. In vitro studies showed that medium-chain fatty acids (MCFAs) inhibit long-chain fatty acid (LCFA)-stimulated CCK secretion and increase in intracellular Ca2+ concentrations through inhibition of GPR120 signaling. Long-term administration of MCTs reduced obesity and insulin resistance in high-LCT diet-fed WT mice, but not in high-LCT diet-fed GIP-knockout mice. Thus, MCT-induced inhibition of GIP hypersecretion reduces obesity and insulin resistance under high-LCT diet feeding condition.
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Affiliation(s)
- Yuki Murata
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shigenobu Kishino
- Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Kanako Iwasaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Eri Ikeguchi-Ogura
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shunsuke Yamane
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tomoko Kato
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yoshinori Kanemaru
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Akiko Sankoda
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tomonobu Hatoko
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Sakura Kiyobayashi
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Jun Ogawa
- Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Akira Hirasawa
- Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
- Corresponding author
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31
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Abstract
Glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) is a hormone produced in the upper gut and secreted to the circulation in response to the ingestion of foods, especially fatty foods. Growing evidence supports the physiological and pharmacological relevance of GIP in obesity. In an obesity setting, inhibition of endogenous GIP or its receptor leads to decreased energy intake, increased energy expenditure, or both, eventually causing weight loss. Further, supraphysiological dosing of exogenous long-lasting GIP agonists alters energy balance and has a marked antiobesity effect. This remarkable yet paradoxical antiobesity effect is suggested to occur primarily via the brain. The brain is capable of regulating both energy intake and expenditure and plays a critical role in human obesity. In addition, the GIP receptor is widely distributed throughout the brain, including areas responsible for energy homeostasis. Recent studies have uncovered previously underappreciated roles of the GIP receptor in the brain in the context of obesity. This article highlights how the GIP receptor expressed by the brain impacts obesity-related pathogenesis.
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Affiliation(s)
- Makoto Fukuda
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX
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Nogueiras R. MECHANISMS IN ENDOCRINOLOGY: The gut-brain axis: regulating energy balance independent of food intake. Eur J Endocrinol 2021; 185:R75-R91. [PMID: 34260412 PMCID: PMC8345901 DOI: 10.1530/eje-21-0277] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022]
Abstract
Obesity is a global pandemic with a large health and economic burden worldwide. Bodyweight is regulated by the ability of the CNS, and especially the hypothalamus, to orchestrate the function of peripheral organs that play a key role in metabolism. Gut hormones play a fundamental role in the regulation of energy balance, as they modulate not only feeding behavior but also energy expenditure and nutrient partitioning. This review examines the recent discoveries about hormones produced in the stomach and gut, which have been reported to regulate food intake and energy expenditure in preclinical models. Some of these hormones act on the hypothalamus to modulate thermogenesis and adiposity in a food intake-independent fashion. Finally, the association of these gut hormones to eating, energy expenditure, and weight loss after bariatric surgery in humans is discussed.
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Affiliation(s)
- Ruben Nogueiras
- Department of Physiology, CIMUS, USC, CIBER Fisiopatología Obesidad y Nutrición (CiberOBN), Instituto Salud Carlos III, Galician Agency of Innovation, Xunta de Galicia, Santiago de Compostela, Spain
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Cooked Black Turtle Beans Ameliorate Insulin Resistance and Restore Gut Microbiota in C57BL/6J Mice on High-Fat Diets. Foods 2021; 10:foods10081691. [PMID: 34441468 PMCID: PMC8393191 DOI: 10.3390/foods10081691] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/07/2021] [Accepted: 07/19/2021] [Indexed: 01/06/2023] Open
Abstract
Colored common beans are associated with health promoting and chronic disease prevention effects. Male C57BL/6J mice were fed high-fat (HF) diets supplemented with cooked black turtle beans (HFB) to prevent obesity related insulin resistance. Mice on both HF and HFB were obese compared to mice fed a low-fat (LF) diet. Plasma low density lipoprotein (LDL) and triglyceride concentrations of mice fed HFB diet were 28% and 36.6% lower than those on HF diet. Homeostatic model assessment of insulin resistance (HOMA-IR) index of mice fed HFB diet was 87% lower than that of mice fed HF diet. Diabetes related biomarkers, gastric inhibitory polypeptide (GIP), leptin, glucagon, and inflammatory cytokines interleukin 4 (IL-4) and IL-5, 10 and 12, IFN-g and TNF-α were significantly affected by HFB diet. Pparα, Cyp7a1 and Fasn were down-regulated by HFB diet while LDL-R, Srebp-2, Adipoq and Slc2a4 were up-regulated by HFB diet. The ratio of Firmicutes/Bacteroidetes (F/B) was also decreased 64.1% by HFB diet compared to HF diet. The results indicated that cooked black turtle bean consumption could ameliorate insulin resistance and lower plasma LDL in mice fed HF diet through glucose signaling pathway and JNK/c-Jun pathway. Meanwhile, cooked black turtle bean consumption restored the gut microbiome.
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Takashima M, Tanaka W, Matsuyama H, Tajiri H, Sakakibara H. Maternal Quercetin Consumption during Pregnancy May Help Regulate Total Cholesterol/HDL-Cholesterol Ratio without Effect on Cholesterol Levels in Male Progeny Consuming High-Fat Diet. Nutrients 2021; 13:1242. [PMID: 33918820 PMCID: PMC8069367 DOI: 10.3390/nu13041242] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/02/2021] [Accepted: 04/06/2021] [Indexed: 01/14/2023] Open
Abstract
Quercetin has been shown to have anti-obesity effects, but it is unknown whether these effects can be transmitted from mothers to their progeny. In this study, we investigated whether maternal quercetin consumption during pregnancy has a protective effect on high-fat diet-induced hyper lipid levels and overweight in progeny. Female mice consumed a control diet or a diet containing 1.0% quercetin during breeding. The male progeny were then divided into four groups that were (1) sacrificed at postnatal day 3; (2) born to dams fed the control diet and also fed the control diet (C-C), (3) born to dams fed the control diet and then fed a 30% high-fat diet (C-HF), or (4) born to dams fed the Q-diet and then fed the HF diet (Q-HF). Maternal consumption of quercetin did not affect body weight or blood lipid parameters in either dams or neonates at postnatal day 3. After 13 weeks, the Q-HF group exhibited greater body and liver weights, and higher blood cholesterol levels than the C-HF group. However, the total cholesterol/ high density lipoprotein (HDL)-cholesterol ratios in the Q-HF and C-C groups remained similar. In conclusion, maternal quercetin consumption does not appear to protect the next generation from high-fat diet-induced hyper cholesterol level in the blood and liver, and consequently overweight, but may help regulate the total cholesterol/HDL-cholesterol ratio.
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Affiliation(s)
| | | | | | | | - Hiroyuki Sakakibara
- Graduate School of Agriculture, University of Miyazaki, 1-1 Gakuen-kibanadai Nishi, Miyazaki 889-2192, Japan; (M.T.); (W.T.); (H.M.); (H.T.)
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Boer GA, Keenan SN, Miotto PM, Holst JJ, Watt MJ. GIP receptor deletion in mice confers resistance to high-fat diet-induced obesity via alterations in energy expenditure and adipose tissue lipid metabolism. Am J Physiol Endocrinol Metab 2021; 320:E835-E845. [PMID: 33645252 DOI: 10.1152/ajpendo.00646.2020] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) is best known as an incretin hormone that is secreted from K-cells of the proximal intestine, but evidence also implicates a role for GIP in regulating lipid metabolism and adiposity. It is well-established that GIP receptor knockout (GIPR KO) mice are resistant to diet-induced obesity; however, the factors mediating this effect remain unresolved. Accordingly, we aimed to elucidate the mechanisms leading to adiposity resistance in GIPR KO mice with a focus on whole-body energy balance and lipid metabolism in adipose tissues. Studies were conducted in age-matched male GIPR KO and wild-type (WT) mice fed a high-fat diet for 10 weeks. GIPR KO mice gained less body weight and fat mass compared to WT littermates, and this was associated with increased energy expenditure but no differences in food intake or fecal energy loss. Upon an oral lipid challenge, fatty acid storage in inguinal adipose tissue was significantly increased in GIPR KO compared with WT mice. This was not related to differential expression of lipoprotein lipase in adipose tissue. Adipose tissue lipolysis was increased in GIPR KO compared with WT mice, particularly following β-adrenergic stimulation, and could explain why GIPR KO mice gain less adipose tissue despite increased rates of fatty acid storage in inguinal adipose tissue. Taken together, these results suggest that the GIPR is required for normal maintenance of body weight and adipose tissue mass by regulating energy expenditure and lipolysis.NEW & NOTEWORTHY GIPR KO mice fed a high-fat diet have reduced adiposity despite transporting more ingested lipids into adipose tissue. This can be partly explained by accelerated adipose tissue lipolysis and increased energy expenditure in GIPR KO mice. These new insights rationalize targeting the GIPR as part of a weight management strategy in obesity.
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Affiliation(s)
- Geke Aline Boer
- 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
| | - Stacey N Keenan
- Department of Anatomy and Physiology, School of Biomedical Sciences, University of Melbourne, Melbourne, Victoria, Australia
| | - Paula M Miotto
- Department of Anatomy and Physiology, School of Biomedical Sciences, University of Melbourne, Melbourne, Victoria, Australia
| | - Jens Juul 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
| | - Matthew J Watt
- Department of Anatomy and Physiology, School of Biomedical Sciences, University of Melbourne, Melbourne, Victoria, Australia
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West JA, Tsakmaki A, Ghosh SS, Parkes DG, Grønlund RV, Pedersen PJ, Maggs D, Rajagopalan H, Bewick GA. Chronic peptide-based GIP receptor inhibition exhibits modest glucose metabolic changes in mice when administered either alone or combined with GLP-1 agonism. PLoS One 2021; 16:e0249239. [PMID: 33788878 PMCID: PMC8011784 DOI: 10.1371/journal.pone.0249239] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/13/2021] [Indexed: 12/04/2022] Open
Abstract
Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3–30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5–42)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.
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Affiliation(s)
- Jason A. West
- Fractyl Laboratories Inc, Lexington, MA, United States of America
| | - Anastasia Tsakmaki
- Diabetes Research Group, School of Life Course Sciences, Faculty of Life Science and Medicine, King’s College London, London, England, United Kingdom
| | | | | | | | | | - David Maggs
- Fractyl Laboratories Inc, Lexington, MA, United States of America
| | | | - Gavin A. Bewick
- Diabetes Research Group, School of Life Course Sciences, Faculty of Life Science and Medicine, King’s College London, London, England, United Kingdom
- * E-mail:
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Sokołowska E, Sadowska A, Sawicka D, Kotulska-Bąblińska I, Car H. A head-to-head comparison review of biological and toxicological studies of isomaltulose, d-tagatose, and trehalose on glycemic control. Crit Rev Food Sci Nutr 2021; 62:5679-5704. [PMID: 33715524 DOI: 10.1080/10408398.2021.1895057] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Diabetes mellitus is the most common metabolic disorder contributing to significant morbidity and mortality in humans. Different preventive and therapeutic agents, as well as various pharmacological strategies or non-pharmacological tools, improve the glycemic profile of diabetic patients. Isomaltulose, d-tagatose, and trehalose are naturally occurring, low glycemic sugars that are not synthesized by humans but widely used in food industries. Various studies have shown that these carbohydrates can regulate glucose metabolism and provide support in maintaining glucose homeostasis in patients with diabetes, but also can improve insulin response, subsequently leading to better control of hyperglycemia. In this review, we discussed the anti-hyperglycemic effects of isomaltulose, D-tagatose, and trehalose, comparing their properties with other known sweeteners, and highlighting their importance for the development of the pharmaceutical and food industries.
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Affiliation(s)
- Emilia Sokołowska
- Department of Experimental Pharmacology, Medical University of Bialystok, Bialystok, Poland
| | - Anna Sadowska
- Department of Experimental Pharmacology, Medical University of Bialystok, Bialystok, Poland
| | - Diana Sawicka
- Department of Experimental Pharmacology, Medical University of Bialystok, Bialystok, Poland
| | | | - Halina Car
- Department of Experimental Pharmacology, Medical University of Bialystok, Bialystok, Poland
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Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective. Nutrients 2021; 13:nu13020351. [PMID: 33503878 PMCID: PMC7910956 DOI: 10.3390/nu13020351] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.
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Chen J, Zheng S, Hu Y, Mou X, Wang H. Chronic treatment with anti-GIPR mAb alone and combined with DPP-4 inhibitor correct obesity, dyslipidemia and nephropathy in rodent animals. Life Sci 2021; 269:119038. [PMID: 33453239 DOI: 10.1016/j.lfs.2021.119038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/18/2020] [Accepted: 01/01/2021] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Glucose-dependent insulinotropic polypeptide receptor (GIPR) has been identified as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). Therefore, we developed the anti-GIPR antagonistic monoclonal antibody (mAb) alone and in combination with DPP-4 inhibitor as potential therapeutic strategy for treating obesity and dyslipidemia based on this genetic evidence. METHODS Fully neutralized GIPR activity of GIPR-monoclonal antibody (mAb) was assessed by regulating the in vitro production of cAMP in the mouse GIPR stably expressing cells. Chronic efficacies of GIPR-mAb alone and in combination with DPP-4 inhibitor Sitagliptin in diabetic or DIO mice were both investigated. Multiple metabolic parameters including body weight, glucose level, fat mass, lipid metabolism-related indicators as well as H&E staining and immunohistochemical analysis were performed. Role of GIPR in pancreatic cells on regulating fat metabolism was explored in GIPR β-cell knockout mouse model. RESULTS Chronic treatment of GIPR-mAb improved body weight control, glucose metabolism, and was associated with reduced fat mass, enhanced pancreatic function and exchange ratio of the resting respiratory in diabetic mice. In addition, further study of anti-GIPR mAb combined with Sitagliptin in DIO mice demonstrated significantly improved weight loss compare to the both monomer treatment. Furthermore, we demonstrated important role of GIPR in β-cell in regulating the fat mass and response to antagonistic GIPR-mAb in a conditional GIPR-knockout mouse. CONCLUSION Chronic treatment with anti-GIPR mAb alone and combined with DPP-4 inhibitor provide preclinical therapeutic approaches to treat obesity.
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Affiliation(s)
- Jiawei Chen
- Hangzhou Red Cross Hospital, Xiacheng District, Hangzhou City 310003, Zhejiang Province, PR China.
| | - Songsong Zheng
- Hangzhou Red Cross Hospital, Xiacheng District, Hangzhou City 310003, Zhejiang Province, PR China
| | - Yongbin Hu
- Hangzhou Red Cross Hospital, Xiacheng District, Hangzhou City 310003, Zhejiang Province, PR China
| | - Xin Mou
- Hangzhou Red Cross Hospital, Xiacheng District, Hangzhou City 310003, Zhejiang Province, PR China
| | - Huiyang Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Binjiang District, Hangzhou City 310051, Zhejiang Province, PR China
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Campbell JE. Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms. Mol Metab 2020; 46:101139. [PMID: 33290902 PMCID: PMC8085569 DOI: 10.1016/j.molmet.2020.101139] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/24/2020] [Accepted: 12/02/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP's biology was quickly outpaced by research focusing on the other incretin hormone, glucagon-like peptide 1 (GLP-1). Early work on GIP produced the theory that GIP is obesogenic, limiting interest in developing GIPR agonists to treat type 2 diabetes. A resurgence of GIP research has occurred in the last five years, reinvigorating interest in this peptide. Two independent approaches have emerged for treating obesity, one promoting GIPR agonism and the other antagonism. In this report, evidence supporting both cases is discussed and hypotheses are presented to reconcile this apparent paradox. SCOPE OF THE REVIEW This review presents evidence to support targeting GIPR to reduce obesity. Most of the focus is on the effect of singly targeting the GIPR using both a gain- and loss-of-function approach, with additional sections that discuss co-targeting of the GIPR and GLP-1R. MAJOR CONCLUSIONS There is substantial evidence to support that GIPR agonism and antagonism can positively impact body weight. The long-standing theory that GIP drives weight gain is exclusively derived from loss-of-function studies, with no evidence to support that GIPR agonisms increases adiposity or body weight. There is insufficient evidence to reconcile the paradoxical observations that both GIPR agonism and antagonism can reduce body weight; however, two independent hypotheses centered on GIPR antagonism are presented based on new data in an effort to address this question. The first discusses the compensatory relationship between incretin receptors and how antagonism of the GIPR may enhance GLP-1R activity. The second discusses how chronic GIPR agonism may produce desensitization and ultimately loss of GIPR activity that mimics antagonism. Overall, it is clear that a deeper understanding of GIP biology is required to understand how modulating this system impacts metabolic homeostasis.
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Affiliation(s)
- 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.
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English A, Craig SL, Flatt PR, Irwin N. Individual and combined effects of GIP and xenin on differentiation, glucose uptake and lipolysis in 3T3-L1 adipocytes. Biol Chem 2020; 401:1293-1303. [PMID: 32769216 DOI: 10.1515/hsz-2020-0195] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 08/04/2020] [Indexed: 02/07/2023]
Abstract
The incretin hormone glucose-dependent insulinotropic polypeptide (GIP), released postprandially from K-cells, has established actions on adipocytes and lipid metabolism. In addition, xenin, a related peptide hormone also secreted from K-cells after a meal, has postulated effects on energy regulation and lipid turnover. The current study has probed direct individual and combined effects of GIP and xenin on adipocyte function in 3T3-L1 adipocytes, using enzyme-resistant peptide analogues, (d-Ala2)GIP and xenin-25-Gln, and knockdown (KD) of receptors for both peptides. (d-Ala2)GIP stimulated adipocyte differentiation and lipid accumulation in 3T3-L1 adipocytes over 96 h, with xenin-25-Gln evoking similar effects. Combined treatment significantly countered these individual adipogenic effects. Individual receptor KD impaired lipid accumulation and adipocyte differentiation, with combined receptor KD preventing differentiation. (d-Ala2)GIP and xenin-25-Gln increased glycerol release from 3T3-L1 adipocytes, but this lipolytic effect was significantly less apparent with combined treatment. Key adipogenic and lipolytic genes were upregulated by (d-Ala2)GIP or xenin-25-Gln, but not by dual peptide culture. Similarly, both (d-Ala2)GIP and xenin-25-Gln stimulated insulin-induced glucose uptake in 3T3-L1 adipocytes, but this effect was annulled by dual treatment. In conclusion, GIP and xenin possess direct, comparable, lipogenic and lipolytic actions in 3T3-L1 adipocytes. However, effects on lipid metabolism are significantly diminished by combined administration.
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Affiliation(s)
- Andrew English
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
| | - Sarah L Craig
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
| | - Peter R Flatt
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
| | - Nigel Irwin
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
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Killion EA, Chen M, Falsey JR, Sivits G, Hager T, Atangan L, Helmering J, Lee J, Li H, Wu B, Cheng Y, Véniant MM, Lloyd DJ. Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism. Nat Commun 2020; 11:4981. [PMID: 33020469 PMCID: PMC7536395 DOI: 10.1038/s41467-020-18751-8] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 09/09/2020] [Indexed: 12/30/2022] Open
Abstract
Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.
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Affiliation(s)
- Elizabeth A Killion
- Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - Michelle Chen
- Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - James R Falsey
- Amgen Research, Department of Selection and Modality Engineering, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - Glenn Sivits
- Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - Todd Hager
- Amgen Research, Department of Translational Safety & Bioanalytical Sciences, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - Larissa Atangan
- Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - Joan Helmering
- Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - Jae Lee
- Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - Hongyan Li
- Amgen Research, Department of Translational Safety & Bioanalytical Sciences, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - Bin Wu
- Amgen Research, Department of Selection and Modality Engineering, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - Yuan Cheng
- Amgen Research, Department of Selection and Modality Engineering, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - Murielle M Véniant
- Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA
| | - David J Lloyd
- Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA.
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Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Mol Metab 2020; 46:101090. [PMID: 32987188 PMCID: PMC8085566 DOI: 10.1016/j.molmet.2020.101090] [Citation(s) in RCA: 173] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/13/2020] [Accepted: 09/17/2020] [Indexed: 12/21/2022] Open
Abstract
Background Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved to treat type 2 diabetes and obesity. They elicit robust improvements in glycemic control and weight loss, combined with cardioprotection in individuals at risk of or with pre-existing cardiovascular disease. These attributes make GLP-1 a preferred partner for next-generation therapies exhibiting improved efficacy yet retaining safety to treat diabetes, obesity, non-alcoholic steatohepatitis, and related cardiometabolic disorders. The available clinical data demonstrate that the best GLP-1R agonists are not yet competitive with bariatric surgery, emphasizing the need to further improve the efficacy of current medical therapy. Scope of review In this article, we discuss data highlighting the physiological and pharmacological attributes of potential peptide and non-peptide partners, exemplified by amylin, glucose-dependent insulinotropic polypeptide (GIP), and steroid hormones. We review the progress, limitations, and future considerations for translating findings from preclinical experiments to competitive efficacy and safety in humans with type 2 diabetes and obesity. Major conclusions Multiple co-agonist combinations exhibit promising clinical efficacy, notably tirzepatide and investigational amylin combinations. Simultaneously, increasing doses of GLP-1R agonists such as semaglutide produces substantial weight loss, raising the bar for the development of new unimolecular co-agonists. Collectively, the available data suggest that new co-agonists with robust efficacy should prove superior to GLP-1R agonists alone to treat metabolic disorders.
GLP-1 is a preferred partner for co-agonist development. Co-agonist combinations must exhibit improved weight loss beyond GLP-1 alone. Unimolecular coagonists must exhibit retained or improved cardioprotection. Obesity represents an optimal condition for the development of new GLP-1 co-agonists.
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Affiliation(s)
- Laurie L Baggio
- Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mt. Sinai Hospital, Toronto, Ontario, M5G 1X5 Canada
| | - Daniel J Drucker
- Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mt. Sinai Hospital, Toronto, Ontario, M5G 1X5 Canada.
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Fu Y, Kaneko K, Lin HY, Mo Q, Xu Y, Suganami T, Ravn P, Fukuda M. Gut Hormone GIP Induces Inflammation and Insulin Resistance in the Hypothalamus. Endocrinology 2020; 161:5865317. [PMID: 32603429 PMCID: PMC7410368 DOI: 10.1210/endocr/bqaa102] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 06/24/2020] [Indexed: 02/08/2023]
Abstract
The hypothalamus plays a critical role in controlling energy balance. High-fat diet (HFD) feeding increases the gene expression of proinflammatory mediators and decreases insulin actions in the hypothalamus. Here, we show that a gut-derived hormone, glucose-dependent insulinotropic polypeptide (GIP), whose levels are elevated during diet-induced obesity, promotes and mediates hypothalamic inflammation and insulin resistance during HFD-induced obesity. Unbiased ribonucleic acid sequencing of GIP-stimulated hypothalami revealed that hypothalamic pathways most affected by intracerebroventricular (ICV) GIP stimulation were related to inflammatory-related responses. Subsequent analysis demonstrated that GIP administered either peripherally or centrally, increased proinflammatory-related factors such as Il-6 and Socs3 in the hypothalamus, but not in the cortex of C57BL/6J male mice. Consistently, hypothalamic activation of IκB kinase-β inflammatory signaling was induced by ICV GIP. Further, hypothalamic levels of proinflammatory cytokines and Socs3 were significantly reduced by an antagonistic GIP receptor (GIPR) antibody and by GIPR deficiency. Additionally, centrally administered GIP reduced anorectic actions of insulin in the brain and diminished insulin-induced phosphorylation of Protein kinase B and Glycogen synthase kinase 3β in the hypothalamus. Collectively, these findings reveal a previously unrecognized role for brain GIP signaling in diet-induced inflammation and insulin resistance in the hypothalamus.
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Affiliation(s)
- Yukiko Fu
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Kentaro Kaneko
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Hsiao-Yun Lin
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Qianxing Mo
- Dan L Duncan Cancer Center and Center for Cell Gene & Therapy, Baylor College of Medicine, Houston, Texas
- Present address: Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612
| | - Yong Xu
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Takayoshi Suganami
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Peter Ravn
- AstraZeneca, R&D BioPharmaceuticals Unit, Department of Antibody Discovery and Protein Engineering, Cambridge, UK
| | - Makoto Fukuda
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Correspondence: Makoto Fukuda, Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. E-mail:
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Gobron B, Bouvard B, Vyavahare S, Blom LV, Pedersen KK, Windeløv JA, Boer GA, Harada N, Zhang S, Shimazu-Kuwahara S, Wice B, Inagaki N, Legrand E, Flatt PR, Chappard D, Hartmann B, Holst JJ, Rosenkilde MM, Irwin N, Mabilleau G. Enteroendocrine K Cells Exert Complementary Effects to Control Bone Quality and Mass in Mice. J Bone Miner Res 2020; 35:1363-1374. [PMID: 32155286 DOI: 10.1002/jbmr.4004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/27/2020] [Accepted: 03/04/2020] [Indexed: 12/11/2022]
Abstract
The involvement of a gut-bone axis in controlling bone physiology has been long suspected, although the exact mechanisms are unclear. We explored whether glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine K cells were involved in this process. The bone phenotype of transgenic mouse models lacking GIP secretion (GIP-GFP-KI) or enteroendocrine K cells (GIP-DT) was investigated. Mice deficient in GIP secretion exhibited lower bone strength, trabecular bone mass, trabecular number, and cortical thickness, notably due to higher bone resorption. Alterations of microstructure, modifications of bone compositional parameters, represented by lower collagen cross-linking, were also apparent. None of these alterations were observed in GIP-DT mice lacking enteroendocrine K cells, suggesting that another K-cell secretory product acts to counteract GIP action. To assess this, stable analogues of the known K-cell peptide hormones, xenin and GIP, were administered to mature NIH Swiss male mice. Both were capable of modulating bone strength mostly by altering bone microstructure, bone gene expression, and bone compositional parameters. However, the two molecules exhibited opposite actions on bone physiology, with evidence that xenin effects are mediated indirectly, possibly via neural networks. Our data highlight a previously unknown interaction between GIP and xenin, which both moderate gut-bone connectivity. © 2020 American Society for Bone and Mineral Research.
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Affiliation(s)
- Benoît Gobron
- Groupe Études Remodelage Osseux et Biomatériaux, GEROM, SFR 42-08, Université d'Angers, Institut de Biologie en Santé, CHU d'Angers, Angers, France.,Service de Rhumatologie, CHU d'Angers, Angers, France
| | - Béatrice Bouvard
- Groupe Études Remodelage Osseux et Biomatériaux, GEROM, SFR 42-08, Université d'Angers, Institut de Biologie en Santé, CHU d'Angers, Angers, France.,Service de Rhumatologie, CHU d'Angers, Angers, France
| | - Sagar Vyavahare
- School of Biomedical Sciences, University of Ulster, Coleraine, UK
| | - Liv Vv Blom
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kristian K Pedersen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Johanne A Windeløv
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Geke A Boer
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Norio Harada
- Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Sheng Zhang
- Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Saint Louis, MO, USA
| | - Satoko Shimazu-Kuwahara
- Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Burton Wice
- Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Saint Louis, MO, USA
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Erick Legrand
- Groupe Études Remodelage Osseux et Biomatériaux, GEROM, SFR 42-08, Université d'Angers, Institut de Biologie en Santé, CHU d'Angers, Angers, France.,Service de Rhumatologie, CHU d'Angers, Angers, France
| | - Peter R Flatt
- School of Biomedical Sciences, University of Ulster, Coleraine, UK
| | - Daniel Chappard
- Groupe Études Remodelage Osseux et Biomatériaux, GEROM, SFR 42-08, Université d'Angers, Institut de Biologie en Santé, CHU d'Angers, Angers, France.,Service Commun D'imageries et d'Analyses Microscopiques, SCIAM, SFR 42-08, Université d'Angers, Institut de Biologie en Santé, CHU d'Angers, Angers, France.,Bone Pathology Unit, CHU d'Angers, Angers, France
| | - Bolette Hartmann
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nigel Irwin
- School of Biomedical Sciences, University of Ulster, Coleraine, UK
| | - Guillaume Mabilleau
- Groupe Études Remodelage Osseux et Biomatériaux, GEROM, SFR 42-08, Université d'Angers, Institut de Biologie en Santé, CHU d'Angers, Angers, France.,Service Commun D'imageries et d'Analyses Microscopiques, SCIAM, SFR 42-08, Université d'Angers, Institut de Biologie en Santé, CHU d'Angers, Angers, France.,Bone Pathology Unit, CHU d'Angers, Angers, France
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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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Kanemaru Y, Harada N, Shimazu-Kuwahara S, Yamane S, Ikeguchi E, Murata Y, Kiyobayashi S, Hatoko T, Inagaki N. Absence of GIP secretion alleviates age-related obesity and insulin resistance. J Endocrinol 2020; 245:13-20. [PMID: 31977316 PMCID: PMC7040458 DOI: 10.1530/joe-19-0477] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 01/23/2020] [Indexed: 12/25/2022]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body weight gain and insulin sensitivity remains unclear. In the present study, we investigated the effect of GIP on age-related body weight gain and insulin resistance using GIP-knockout homozygous (GIP-/-) and heterozygous (GIP+/-) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Under 12% fat-containing normal diet feeding condition, body weight was significantly lower in GIP-/- mice compared to that in WT and GIP+/- mice from 38 weeks of age, while there was no significant difference between WT and GIP+/- mice. Visceral and s.c. fat mass were also significantly lower in GIP-/- mice compared to those in WT and GIP+/- mice. During oral glucose tolerance test, blood glucose levels did not differ among the three groups. Insulin levels were significantly lower in GIP-/- mice than those in WT and GIP+/- mice. During insulin tolerance test, GIP-/- mice showed higher insulin sensitivity than that of WT and GIP+/- mice. Adiponectin mRNA levels were increased and leptin mRNA levels tended to be decreased in adipose tissue of GIP-/- mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydrate-based diet feeding condition.
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Affiliation(s)
- Yoshinori Kanemaru
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoko Shimazu-Kuwahara
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Preemptive Medicine and Lifestyle Related Disease Research Center, Kyoto University Hospital, Kyoto, Japan
| | - Shunsuke Yamane
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Eri Ikeguchi
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuki Murata
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Sakura Kiyobayashi
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomonobu Hatoko
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Correspondence should be addressed to N Inagaki:
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Ceddia RP, Collins S. A compendium of G-protein-coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure. Clin Sci (Lond) 2020; 134:473-512. [PMID: 32149342 PMCID: PMC9137350 DOI: 10.1042/cs20190579] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 02/17/2020] [Accepted: 02/24/2020] [Indexed: 12/15/2022]
Abstract
With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand-receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein-coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.
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Affiliation(s)
- Ryan P Ceddia
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, U.S.A
| | - Sheila Collins
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, U.S.A
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49
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Holst JJ, Rosenkilde MM. Recent advances of GIP and future horizons. Peptides 2020; 125:170230. [PMID: 31838219 DOI: 10.1016/j.peptides.2019.170230] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 12/12/2022]
Abstract
Recently GIP-GLP-1 co-agonists with powerful effects on glycemic control and body weight in patients with type 2 diabetes have been described. While such effects are the expected ones from a glucagonlike peptide-1 receptor agonist, similar contributions from the GIP component of the co-agonist would be surprising and contrast to the existing literature. Conventionally, GIP is thought of as an important incretin hormone regulating postprandial insulin secretion in glucose tolerant individuals, but such effects are weak or absent in patients with type 2 diabetes, and GIP has been proposed to an obesity-promoting hormone, rather than the opposite. Recent studies with a GIP receptor antagonist suitable for human studies have confirmed these concepts regarding the actions of endogenous GIP and point to potential beneficial metabolic effects of GIP receptor antagonists rather than agonist in the treatment of obesity and type 2 diabetes. So how is it possible that apparently similar results can be obtained with GIP receptor agonists and antagonists? Maybe the explanation should be sought in GIP receptor dynamics, where the agonists clearly elicit beta-arrestin mediated receptor internalization, rendering the target tissues unresponsive, whereas antagonists block the internalization and increase receptor expression on the cell surfaces. This may explain that both antagonists and agonists show efficacy in obesity and type 2 diabetes.
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Affiliation(s)
- Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health Sciences, The Panum Institute, University of Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health Sciences, The Panum Institute, University of Copenhagen, Denmark.
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Health Sciences, The Panum Institute, University of 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: 72] [Impact Index Per Article: 14.4] [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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