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Kim YJ, Ihrie VM, Shi P, Ihrie MD, Womble JT, Meares AH, Granek JA, Gunsch CK, Ingram JL. Glucagon-Like Peptide 1 Receptor ( Glp1r) Deficiency Does Not Appreciably Alter Airway Inflammation or Gut-Lung Microbiome Axis in a Mouse Model of Obese Allergic Airways Disease and Bariatric Surgery. J Asthma Allergy 2025; 18:285-305. [PMID: 40046174 PMCID: PMC11880686 DOI: 10.2147/jaa.s478329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 01/22/2025] [Indexed: 03/09/2025] Open
Abstract
Purpose High body mass index (≥30 kg/m2) is associated with asthma severity, and nearly 40% of asthma patients exhibit obesity. Furthermore, over 40% of patients with obesity and asthma that receive bariatric surgery no longer require asthma medication. Increased levels of glucagon-like peptide 1 (GLP-1) occur after bariatric surgery, and recent studies suggest that GLP-1 receptor (GLP-1R) signaling may regulate the gut microbiome and have anti-inflammatory properties in the lung. Thus, we hypothesized that increased GLP-1R signaling following metabolic surgery in obese and allergen-challenged mice leads to gut/lung microbiome alterations, which together contribute to improved features of allergic airways disease. Methods Male and female Glp1r-deficient (Glp1r-/- ) and replete (Glp1r+/+) mice were administered high fat diet (HFD) to induce obesity with simultaneous intranasal challenge with house dust mite (HDM) allergen to model allergic airway disease with appropriate controls. Mice on HFD received either no surgery, sham surgery, or vertical sleeve gastrectomy (VSG) on week 10 and were sacrificed on week 13. Data were collected with regard to fecal and lung tissue microbiome, lung histology, metabolic markers, and respiratory inflammation. Results HFD led to metabolic imbalance characterized by lower GLP-1 and higher leptin levels, increased glucose intolerance, and alterations in gut microbiome composition. Prevalence of bacteria associated with short chain fatty acid (SCFA) production, namely Bifidobacterium, Lachnospiraceae UCG-001, and Parasutterella, was reduced in mice fed HFD and positively associated with serum GLP-1 levels. Intranasal HDM exposure induced airway inflammation. While Glp1r-/- genotype affected fecal microbiome beta diversity metrics, its effect was limited. Conclusion Herein, GLP-1R deficiency had surprisingly little effect on host gut and lung microbiomes and health, despite recent studies suggesting that GLP-1 receptor agonists are protective against lung inflammation.
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Affiliation(s)
- Yeon Ji Kim
- Department of Civil and Environmental Engineering, Pratt School of Engineering, DukeUniversity, Durham, NC, USA
| | - Victoria M Ihrie
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Pixu Shi
- Biostatistics and Bioinformatics, Division of Integrative Genomics, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Mark D Ihrie
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Jack T Womble
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Anna Hill Meares
- Department of Civil and Environmental Engineering, Pratt School of Engineering, DukeUniversity, Durham, NC, USA
| | - Joshua A Granek
- Biostatistics and Bioinformatics, Division of Integrative Genomics, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Claudia K Gunsch
- Department of Civil and Environmental Engineering, Pratt School of Engineering, DukeUniversity, Durham, NC, USA
| | - Jennifer L Ingram
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA
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Shishani R, Wang A, Lyo V, Nandakumar R, Cummings BP. Vertical Sleeve Gastrectomy Reduces Gut Luminal Deoxycholic Acid Concentrations in Mice. Obes Surg 2024; 34:2483-2491. [PMID: 38777944 PMCID: PMC11217124 DOI: 10.1007/s11695-024-07288-0] [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: 01/09/2024] [Revised: 05/13/2024] [Accepted: 05/13/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Bariatric surgery alters bile acid metabolism, which contributes to post-operative improvements in metabolic health. However, the mechanisms by which bariatric surgery alters bile acid metabolism are incompletely defined. In particular, the role of the gut microbiome in the effects of bariatric surgery on bile acid metabolism is incompletely understood. Therefore, we sought to define the changes in gut luminal bile acid composition after vertical sleeve gastrectomy (VSG). METHODS Bile acid profile was determined by UPLC-MS/MS in serum and gut luminal samples from VSG and sham-operated mice. Sham-operated mice were divided into two groups: one was fed ad libitum, while the other was food-restricted to match their body weight to the VSG-operated mice. RESULTS VSG decreased gut luminal secondary bile acids, which was driven by a decrease in gut luminal deoxycholic acid concentrations and abundance. However, gut luminal cholic acid (precursor for deoxycholic acid) concentration and abundance did not differ between groups. Therefore, the observed decrease in gut luminal deoxycholic acid abundance after VSG was not due to a reduction in substrate availability. CONCLUSION VSG decreased gut luminal deoxycholic acid abundance independently of body weight, which may be driven by a decrease in gut bacterial bile acid metabolism.
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Affiliation(s)
- Rahaf Shishani
- Department of Surgery, Division of Foregut, Metabolic, and General Surgery, Center for Alimentary and Metabolic Sciences, School of Medicine, University of California - Davis, Sacramento, CA, 95817, USA
- Department of Molecular Biosciences, School of Veterinary Medicine, University of CA - Davis, Davis, CA, 95616, USA
| | - Annie Wang
- Department of Surgery, Division of Foregut, Metabolic, and General Surgery, Center for Alimentary and Metabolic Sciences, School of Medicine, University of California - Davis, Sacramento, CA, 95817, USA
| | - Victoria Lyo
- Department of Surgery, Division of Foregut, Metabolic, and General Surgery, Center for Alimentary and Metabolic Sciences, School of Medicine, University of California - Davis, Sacramento, CA, 95817, USA
| | - Renu Nandakumar
- Biomarkers Core Laboratory, Irving Institute for Clinical and Translational Research, Columbia University Irving Medical Center, Columbia University, New York, NY, 10032, USA
| | - Bethany P Cummings
- Department of Surgery, Division of Foregut, Metabolic, and General Surgery, Center for Alimentary and Metabolic Sciences, School of Medicine, University of California - Davis, Sacramento, CA, 95817, USA.
- Department of Molecular Biosciences, School of Veterinary Medicine, University of CA - Davis, Davis, CA, 95616, USA.
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Allard C, Cota D, Quarta C. Poly-Agonist Pharmacotherapies for Metabolic Diseases: Hopes and New Challenges. Drugs 2024; 84:127-148. [PMID: 38127286 DOI: 10.1007/s40265-023-01982-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2023] [Indexed: 12/23/2023]
Abstract
The use of glucagon-like peptide-1 (GLP-1) receptor-based multi-agonists in the treatment of type 2 diabetes and obesity holds great promise for improving glycaemic control and weight management. Unimolecular dual and triple agonists targeting multiple gut hormone-related pathways are currently in clinical trials, with recent evidence supporting their efficacy. However, significant knowledge gaps remain regarding the biological mechanisms and potential adverse effects associated with these multi-target agents. The mechanisms underlying the therapeutic efficacy of GLP-1 receptor-based multi-agonists remain somewhat mysterious, and hidden threats may be associated with the use of gut hormone-based polyagonists. In this review, we provide a critical analysis of the benefits and risks associated with the use of these new drugs in the management of obesity and diabetes, while also exploring new potential applications of GLP-1-based pharmacology beyond the field of metabolic disease.
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Affiliation(s)
- Camille Allard
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 33000, Bordeaux, France
| | - Daniela Cota
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 33000, Bordeaux, France
| | - Carmelo Quarta
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 33000, Bordeaux, France.
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Liu FS, Wang S, Guo XS, Ye ZX, Zhang HY, Li Z. State of art on the mechanisms of laparoscopic sleeve gastrectomy in treating type 2 diabetes mellitus. World J Diabetes 2023; 14:632-655. [PMID: 37383590 PMCID: PMC10294061 DOI: 10.4239/wjd.v14.i6.632] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 04/01/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
Obesity and type-2 diabetes mellitus (T2DM) are metabolic disorders. Obesity increases the risk of T2DM, and as obesity is becoming increasingly common, more individuals suffer from T2DM, which poses a considerable burden on health systems. Traditionally, pharmaceutical therapy together with lifestyle changes is used to treat obesity and T2DM to decrease the incidence of comorbidities and all-cause mortality and to increase life expectancy. Bariatric surgery is increasingly replacing other forms of treatment of morbid obesity, especially in patients with refractory obesity, owing to its many benefits including good long-term outcomes and almost no weight regain. The bariatric surgery options have markedly changed recently, and laparoscopic sleeve gastrectomy (LSG) is gradually gaining popularity. LSG has become an effective and safe treatment for type-2 diabetes and morbid obesity, with a high cost-benefit ratio. Here, we review the me-chanism associated with LSG treatment of T2DM, and we discuss clinical studies and animal experiments with regard to gastrointestinal hormones, gut microbiota, bile acids, and adipokines to clarify current treatment modalities for patients with obesity and T2DM.
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Affiliation(s)
- Fa-Shun Liu
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Song Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Xian-Shan Guo
- Department of Endocrinology, Xinxiang Central Hospital, Xinxiang 453000, Henan Province, China
| | - Zhen-Xiong Ye
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Hong-Ya Zhang
- Central Laboratory, Yangpu District Control and Prevention Center, Shanghai 200090, China
| | - Zhen Li
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
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Zeng R, Zeng Y, Wang Q, Li X, Liu J, Li B, Zhang G, Hu S. Sleeve gastrectomy decreased hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway. Biochem Biophys Res Commun 2023; 653:115-125. [PMID: 36868075 DOI: 10.1016/j.bbrc.2023.02.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 02/27/2023]
Abstract
This study was designed to investigate the roles of autophagy in the attenuation of hepatic lipid accumulation after sleeve gastrectomy (SG). Thirty-two rats were divided into normal control, obesity group, sham group, and SG group. Then serum glucagon-like polypeptide-1 (GLP-1) and lipid accumulation were determined, followed by measuring the activity of autophagy based on immunohistochemistry (IHC) and Western blot analysis. Our data showed significant decrease in the lipid accumulation after SG compared with sham group. GLP-1 and autophagy showed significant increase in rats underwent SG compared with the sham group (P < 0.05). In vitro experiments were conducted to analyze the roles of GLP-1 in autophagy. We knock-downed the expression of Beclin-1 in HepG2, and then analyzed the expression of autophagy-related protein (i.e. LC3BII and LC3BI) and lipid droplet accumulation. In HepG2 cells, GLP-1 analog reduced lipid accumulation by activating autophagy through modulating the AMPK/mTOR signaling pathway. All these concluded that SG decreased hepatic lipid accumulation by inducing autophagy through modulating AMPK/mTOR pathway.
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Affiliation(s)
- Runzhi Zeng
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250014, China
| | - Yijia Zeng
- Department of Radiology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Qi Wang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, China
| | - Xinzhang Li
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250014, China
| | - Jize Liu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, China
| | - Bingjun Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, China
| | - Guangyong Zhang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250014, China
| | - Sanyuan Hu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250014, China.
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Sandoval DA, Patti ME. Glucose metabolism after bariatric surgery: implications for T2DM remission and hypoglycaemia. Nat Rev Endocrinol 2023; 19:164-176. [PMID: 36289368 PMCID: PMC10805109 DOI: 10.1038/s41574-022-00757-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/28/2022] [Indexed: 11/09/2022]
Abstract
Although promising therapeutics are in the pipeline, bariatric surgery (also known as metabolic surgery) remains our most effective strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Of the many available options, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are currently the most widely used procedures. RYGB and VSG have very different anatomical restructuring but both surgeries are effective, to varying degrees, at inducing weight loss and T2DM remission. Both weight loss-dependent and weight loss-independent alterations in multiple tissues (such as the intestine, liver, pancreas, adipose tissue and skeletal muscle) yield net improvements in insulin resistance, insulin secretion and insulin-independent glucose metabolism. In a subset of patients, post-bariatric hypoglycaemia can develop months to years after surgery, potentially reflecting the extreme effects of potent glucose reduction after surgery. This Review addresses the effects of bariatric surgery on glucose regulation and the potential mechanisms responsible for both the resolution of T2DM and the induction of hypoglycaemia.
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Affiliation(s)
- Darleen A Sandoval
- Department of Paediatrics, Section of Nutrition, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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Albaugh VL, He Y, Münzberg H, Morrison CD, Yu S, Berthoud HR. Regulation of body weight: Lessons learned from bariatric surgery. Mol Metab 2023; 68:101517. [PMID: 35644477 PMCID: PMC9938317 DOI: 10.1016/j.molmet.2022.101517] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 05/04/2022] [Accepted: 05/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bariatric or weight loss surgery is currently the most effective treatment for obesity and metabolic disease. Unlike dieting and pharmacology, its beneficial effects are sustained over decades in most patients, and mortality is among the lowest for major surgery. Because there are not nearly enough surgeons to implement bariatric surgery on a global scale, intensive research efforts have begun to identify its mechanisms of action on a molecular level in order to replace surgery with targeted behavioral or pharmacological treatments. To date, however, there is no consensus as to the critical mechanisms involved. SCOPE OF REVIEW The purpose of this non-systematic review is to evaluate the existing evidence for specific molecular and inter-organ signaling pathways that play major roles in bariatric surgery-induced weight loss and metabolic benefits, with a focus on Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), in both humans and rodents. MAJOR CONCLUSIONS Gut-brain communication and its brain targets of food intake control and energy balance regulation are complex and redundant. Although the relatively young science of bariatric surgery has generated a number of hypotheses, no clear and unique mechanism has yet emerged. It seems increasingly likely that the broad physiological and behavioral effects produced by bariatric surgery do not involve a single mechanism, but rather multiple signaling pathways. Besides a need to improve and better validate surgeries in animals, advanced techniques, including inducible, tissue-specific knockout models, and the use of humanized physiological traits will be necessary. State-of-the-art genetically-guided neural identification techniques should be used to more selectively manipulate function-specific pathways.
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Affiliation(s)
- Vance L Albaugh
- Translational and Integrative Gastrointestinal and Endocrine Research Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Yanlin He
- Brain Glycemic and Metabolism Control Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Heike Münzberg
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Christopher D Morrison
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Sangho Yu
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Hans-Rudolf Berthoud
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA.
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Barron M, Hayes H, Fernando DG, Geurts AM, Kindel TL. Sleeve Gastrectomy Improves High-Fat Diet-Associated Hepatic Steatosis Independent of the Glucagon-like-Petpide-1 Receptor in Rats. J Gastrointest Surg 2022; 26:1607-1618. [PMID: 35618993 PMCID: PMC9444920 DOI: 10.1007/s11605-022-05361-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 05/14/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is increased after sleeve gastrectomy (SG). Rat and clinical studies support, while mouse studies refute, a role for GLP-1R signaling after SG. Therefore, we developed a global GLP-1R knockout (KO) rat to test the hypothesis that a functional GLP-1R is critical to induce weight loss and metabolic disease improvement after SG. METHODOLOGY A 4 bp deletion was created in exon 2 of the GLP-1R gene on a Lewis strain background to create a global GLP-1R KO rat. KO and Lewis rats were placed on a high-fat or low-fat diet and phenotyped followed by SG or Sham surgery and assessed for the effect of GLP-1R KO on surgical and metabolic efficacy. RESULTS Loss of the GLP-1R created an obesity-prone rodent without changes in energy expenditure. Both male and female KO rats had significantly greater insulin concentrations after an oral glucose gavage, augmented by a high-fat diet, compared to Lewis rats despite similar glucose concentrations. GLP-1R KO caused hepatomegaly and increased triglyceride deposition compared to Lewis rats. We found no difference between SG GLP-1R KO and Lewis groups when considering efficacy on body weight, glucose tolerance, and a robustly preserved improvement in fatty liver disease. CONCLUSIONS Loss of the GLP-1R in rats resulted in increased adiposity, insulin resistance, and severe steatosis. A functional GLP-1R is not critical to the metabolic efficacy of SG in Lewis rats, similar to mouse studies, but importantly including steatosis, supporting a GLP-1R-independent mechanism for the improvement in fatty liver disease after SG.
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Affiliation(s)
- Matthew Barron
- Department of Surgery, Division of Gastrointestinal and Minimally Invasive Surgery, Medical College of Wisconsin, 8900 W. Doyne Avenue, Milwaukee, WI, 53226, USA
| | - Hailey Hayes
- Medical College of Wisconsin School of Medicine, Medical College of Wisconsin, 8900 W. Doyne Avenue, Milwaukee, WI, 53226, USA
| | - Deemantha G Fernando
- Department of Surgery, Division of Gastrointestinal and Minimally Invasive Surgery, Medical College of Wisconsin, 8900 W. Doyne Avenue, Milwaukee, WI, 53226, USA
| | - Aron M Geurts
- Department of Physiology, Medical College of Wisconsin, 8900 W. Doyne Avenue, Milwaukee, WI, 53226, USA
| | - Tammy L Kindel
- Department of Surgery, Division of Gastrointestinal and Minimally Invasive Surgery, Medical College of Wisconsin, 8900 W. Doyne Avenue, Milwaukee, WI, 53226, USA.
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Holter MM, Phuong DJ, Lee I, Saikia M, Weikert L, Fountain S, Anderson ET, Fu Q, Zhang S, Sloop KW, Cummings BP. 14-3-3-zeta mediates GLP-1 receptor agonist action to alter α cell proglucagon processing. SCIENCE ADVANCES 2022; 8:eabn3773. [PMID: 35867787 PMCID: PMC9307243 DOI: 10.1126/sciadv.abn3773] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 06/08/2022] [Indexed: 06/15/2023]
Abstract
Recent studies demonstrate that α cells contribute to glucose-stimulated insulin secretion (GSIS). Glucagon-like peptide-1 receptor (GLP-1R) agonists potently potentiate GSIS, making these drugs useful for diabetes treatment. However, the role of α and β cell paracrine interactions in the effects of GLP-1R agonists is undefined. We previously found that increased β cell GLP-1R signaling activates α cell GLP-1 expression. Here, we characterized the bidirectional paracrine cross-talk by which α and β cells communicate to mediate the effects of the GLP-1R agonist, liraglutide. We find that the effect of liraglutide to enhance GSIS is blunted by α cell ablation in male mice. Furthermore, the effect of β cell GLP-1R signaling to activate α cell GLP-1 is mediated by a secreted protein factor that is regulated by the signaling protein, 14-3-3-zeta, in mouse and human islets. These data refine our understanding of GLP-1 pharmacology and identify 14-3-3-zeta as a potential target to enhance α cell GLP-1 production.
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Affiliation(s)
- Marlena M. Holter
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
| | - Daryl J. Phuong
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
| | - Isaac Lee
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
| | - Mridusmita Saikia
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Ithaca, NY, USA
| | - Lisa Weikert
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
| | - Samantha Fountain
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
| | - Elizabeth T. Anderson
- Proteomics and Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA
| | - Qin Fu
- Proteomics and Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA
| | - Sheng Zhang
- Proteomics and Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA
| | - Kyle W. Sloop
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Bethany P. Cummings
- Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA
- Department of Surgery, Center for Alimentary and Metabolic Sciences, School of Medicine, University of California, Davis, Sacramento, CA, USA
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Holter MM, Saikia M, Cummings BP. Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion. Front Endocrinol (Lausanne) 2022; 13:934775. [PMID: 35957816 PMCID: PMC9360487 DOI: 10.3389/fendo.2022.934775] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/28/2022] [Indexed: 01/14/2023] Open
Abstract
As an incretin hormone, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels by enhancing glucose-stimulated insulin secretion from pancreatic beta-cells. Therapies targeting the GLP-1 receptor (GLP-1R) use the classical incretin model as a physiological framework in which GLP-1 secreted from enteroendocrine L-cells acts on the beta-cell GLP-1R. However, this model has come into question, as evidence demonstrating local, intra-islet GLP-1 production has advanced the competing hypothesis that the incretin activity of GLP-1 may reflect paracrine signaling of GLP-1 from alpha-cells on GLP-1Rs on beta-cells. Additionally, recent studies suggest that alpha-cell-derived glucagon can serve as an additional, albeit less potent, ligand for the beta-cell GLP-1R, thereby expanding the role of alpha-cells beyond that of a counterregulatory cell type. Efforts to understand the role of the alpha-cell in the regulation of islet function have revealed both transcriptional and functional heterogeneity within the alpha-cell population. Further analysis of this heterogeneity suggests that functionally distinct alpha-cell subpopulations display alterations in islet hormone profile. Thus, the role of the alpha-cell in glucose homeostasis has evolved in recent years, such that alpha-cell to beta-cell communication now presents a critical axis regulating the functional capacity of beta-cells. Herein, we describe and integrate recent advances in our understanding of the impact of alpha-cell paracrine signaling on insulin secretory dynamics and how this intra-islet crosstalk more broadly contributes to whole-body glucose regulation in health and under metabolic stress. Moreover, we explore how these conceptual changes in our understanding of intra-islet GLP-1 biology may impact our understanding of the mechanisms of incretin-based therapeutics.
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Affiliation(s)
- Marlena M. Holter
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
- *Correspondence: Marlena M. Holter,
| | - Mridusmita Saikia
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States
| | - Bethany P. Cummings
- School of Medicine, Department of Surgery, Center for Alimentary and Metabolic Sciences, University of California, Davis, Sacramento, CA, United States
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Pérez-Arana GM, Fernández-Vivero J, Camacho-Ramírez A, Díaz Gómez A, Bancalero de los Reyes J, Ribelles-García A, Almorza-Gomar D, Carrasco-Molinillo C, Prada-Oliveira JA. Sleeve Gastrectomy and Roux-En-Y Gastric Bypass. Two Sculptors of the Pancreatic Islet. J Clin Med 2021; 10:jcm10184217. [PMID: 34575329 PMCID: PMC8465472 DOI: 10.3390/jcm10184217] [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: 07/22/2021] [Revised: 09/10/2021] [Accepted: 09/14/2021] [Indexed: 01/10/2023] Open
Abstract
Several surgical procedures are performed for the treatment of obesity. A main outcome of these procedures is the improvement of type 2 diabetes mellitus. Trying to explain this, gastrointestinal hormone levels and their effect on organs involved in carbohydrate metabolism, such as liver, gut, muscle or fat, have been studied intensively after bariatric surgery. These effects on endocrine-cell populations in the pancreas have been less well studied. We gathered the existing data on these pancreatic-cell populations after the two most common types of bariatric surgery, the sleeve gastrectomy (SG) and the roux-en-Y gastric bypass (RYGB), with the aim to explain the pathophysiological mechanisms underlying these surgeries and to improve their outcome.
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Affiliation(s)
- Gonzalo-Martín Pérez-Arana
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Cadiz, 11003 Cadiz, Spain; (J.F.-V.); (A.C.-R.); (A.R.-G.); (C.C.-M.)
- Institute for Biomedical Science Research and Innovation (INIBICA), University of Cadiz, 11003 Cadiz, Spain;
- Asociación Gaditana de Apoyo al Investigador (AGAI), 11012 Cadiz, Spain
- Correspondence: (G.-M.P.-A.); (J.-A.P.-O.)
| | - José Fernández-Vivero
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Cadiz, 11003 Cadiz, Spain; (J.F.-V.); (A.C.-R.); (A.R.-G.); (C.C.-M.)
| | - Alonso Camacho-Ramírez
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Cadiz, 11003 Cadiz, Spain; (J.F.-V.); (A.C.-R.); (A.R.-G.); (C.C.-M.)
- Asociación Gaditana de Apoyo al Investigador (AGAI), 11012 Cadiz, Spain
- Surgery Unit, Puerta del Mar Universitary Hospital, University of Cadiz, 11003 Cadiz, Spain
| | | | | | - Antonio Ribelles-García
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Cadiz, 11003 Cadiz, Spain; (J.F.-V.); (A.C.-R.); (A.R.-G.); (C.C.-M.)
| | - David Almorza-Gomar
- Institute for Biomedical Science Research and Innovation (INIBICA), University of Cadiz, 11003 Cadiz, Spain;
- Operative Statistic and Research Department, University of Cadiz, 11003 Cadiz, Spain
| | - Carmen Carrasco-Molinillo
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Cadiz, 11003 Cadiz, Spain; (J.F.-V.); (A.C.-R.); (A.R.-G.); (C.C.-M.)
| | - José-Arturo Prada-Oliveira
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Cadiz, 11003 Cadiz, Spain; (J.F.-V.); (A.C.-R.); (A.R.-G.); (C.C.-M.)
- Institute for Biomedical Science Research and Innovation (INIBICA), University of Cadiz, 11003 Cadiz, Spain;
- Asociación Gaditana de Apoyo al Investigador (AGAI), 11012 Cadiz, Spain
- Correspondence: (G.-M.P.-A.); (J.-A.P.-O.)
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12
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Akhtar MF, Shagufta A, Saleem A, Baig MMFA, Sharif A, Rasul A, Abdel-Daim MM. Tylophora hirsuta L. leaf extract attenuates alloxan-induced diabetes in mice by suppressing oxidative stress and α-amylase. Asian Pac J Trop Biomed 2021; 11:394-404. [DOI: 10.4103/2221-1691.321128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Objective:
To evaluate the antidiabetic potential of leaf extracts of Tylophora hirsuta (T. hirsuta).
Methods:
The methanolic and ethyl acetate extracts of T. hirsuta leaves were analyzed by high pressure liquid chromatography. In vitro antioxidant activity was determined by ferric ion reduction, 1, 1-diphenyl-2-picrylhydrazyl, and hydrogen peroxide scavenging methods. In vitro alpha amylase (α-amylase) inhibitory activity of the plant extracts was assessed. In vivo antidiabetic potential was determined in alloxan-induced diabetic mice to assess glycated hemoglobin (HbA1c), oral glucose tolerance, serum amylase, lipid profile, fasting blood glucose, and body weight. Histopathological lesions of the pancreas, liver and kidney were observed. Oxidative stress biomarkers such as superoxide dismutase, catalase and peroxidase were also determined.
Results:
Quercetin, chlorogenic acid, p-coumaric acid, and m-coumaric acid were found in the plant extracts. The methanolic plant extract exhibited higher in vitro antioxidant activities than the ethyl acetate extract. Moreover, methanolic plant extract exhibited (83.90±1.56)% α-amylase inhibitory activity at 3.2 mg/ mL concentration. Animal study showed that the methanolic extract of T. hirsuta improved the levels of fasting blood glucose, HbA1c, serum α-amylase, lipid profile, liver function biomarkers, and kidney functions of diabetic mice. Moreover, the methanolic extract ameliorated diabetes-related oxidative stress by increasing superoxide dismutase and catalase activities and decreasing peroxidase and malondialdehyde levels. Histopathological examination showed that the plant extract had improved the integrity of pancreatic islets of Langerhans and reduced the pathological lesions in the liver and kidney of diabetic mice.
Conclusions:
The methanolic extract of T. hirsuta exhibits pronounced antidiabetic activity in mice through reduction of oxidative stress. The plant extract has several natural antioxidants such as phenolic acids. T. hirsuta extract could serve as a nutraceutical for managing diabetes mellitus.
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13
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Arora T, Vanslette AM, Hjorth SA, Bäckhed F. Microbial regulation of enteroendocrine cells. MED 2021; 2:553-570. [DOI: 10.1016/j.medj.2021.03.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/24/2021] [Accepted: 03/29/2021] [Indexed: 02/08/2023]
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14
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Saikia M, Holter MM, Donahue LR, Lee IS, Zheng QC, Wise JL, Todero JE, Phuong DJ, Garibay D, Coch R, Sloop KW, Garcia-Ocana A, Danko CG, Cummings BP. GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells. JCI Insight 2021; 6:141851. [PMID: 33554958 PMCID: PMC7934853 DOI: 10.1172/jci.insight.141851] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates glucose-stimulated insulin secretion. GLP-1 is classically produced by gut L cells; however, under certain circumstances α cells can express the prohormone convertase required for proglucagon processing to GLP-1, prohormone convertase 1/3 (PC1/3), and can produce GLP-1. However, the mechanisms through which this occurs are poorly defined. Understanding the mechanisms by which α cell PC1/3 expression can be activated may reveal new targets for diabetes treatment. Here, we demonstrate that the GLP-1 receptor (GLP-1R) agonist, liraglutide, increased α cell GLP-1 expression in a β cell GLP-1R-dependent manner. We demonstrate that this effect of liraglutide was translationally relevant in human islets through application of a new scRNA-seq technology, DART-Seq. We found that the effect of liraglutide to increase α cell PC1/3 mRNA expression occurred in a subcluster of α cells and was associated with increased expression of other β cell-like genes, which we confirmed by IHC. Finally, we found that the effect of liraglutide to increase bihormonal insulin+ glucagon+ cells was mediated by the β cell GLP-1R in mice. Together, our data validate a high-sensitivity method for scRNA-seq in human islets and identify a potentially novel GLP-1-mediated pathway regulating human α cell function.
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Affiliation(s)
- Mridusmita Saikia
- Department of Biomedical Sciences and
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York, USA
| | | | | | | | | | | | | | | | | | - Reilly Coch
- Cayuga Medical Center, Ithaca, New York, USA
| | - Kyle W Sloop
- Diabetes and Complications, Lilly Research Laboratories, Lilly, Indianapolis, Indiana, USA
| | | | - Charles G Danko
- Department of Biomedical Sciences and
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York, USA
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15
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Capozzi ME, Campbell JE. Could micro changes in β-cells enable major changes in metabolism? EBioMedicine 2020; 59:102936. [PMID: 32810821 PMCID: PMC7452372 DOI: 10.1016/j.ebiom.2020.102936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 07/17/2020] [Indexed: 11/18/2022] Open
Affiliation(s)
- Megan E Capozzi
- Department of Medicine, Division of Endocrinology, Department of Pharmacology and Cancer Biology, Duke Molecular Physiology Institute, Duke University, 300 N Duke St, 27701 Durham, NC, USA
| | - Jonathan E Campbell
- Department of Medicine, Division of Endocrinology, Department of Pharmacology and Cancer Biology, Duke Molecular Physiology Institute, Duke University, 300 N Duke St, 27701 Durham, NC, USA.
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16
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Moffett RC, Docherty NG, le Roux CW. The altered enteroendocrine reportoire following roux-en-Y-gastric bypass as an effector of weight loss and improved glycaemic control. Appetite 2020; 156:104807. [PMID: 32871202 DOI: 10.1016/j.appet.2020.104807] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 07/14/2020] [Accepted: 07/20/2020] [Indexed: 02/08/2023]
Abstract
The alarming rise in obesity and relative lack of pharmacotherapies to treat, what is becoming a global epidemic, has necessitated that an increasing number of bariatric procedures be performed. Several surgical techniques have been developed during the last 50 years and the advent of laparoscopic surgery has increased the safety and efficacy of these procedures. Bariatric surgery is by a substantial margin, the most efficacious means of achieving sustained weight loss maintenance in patients with obesity. Roux-en-Y gastric bypass surgery (RYGB) elicits the most favourable metabolic outcomes with attendant benefits for type 2 diabetes and, cardiovascular disease as well as endocrine disorders and cancers in females. RYGB is the most extensively studied bariatric procedure regarding mechanism of action. In this review we catalogue the multiple alterations in secretion of gut hormones (ghrelin, obestatin, cholecystokinin, GLP-1, PYY, GIP, oxyntomodulin, glicentin and GLP-2) occurring after RYGB and summarise evidence indicating that these changes play a role in the reduction of food intake and improvements in glucose homeostasis.
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Affiliation(s)
- R Charlotte Moffett
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK.
| | - Neil G Docherty
- Diabetes Complications Research Centre, Conway Institute, School of Medicine, University College Dublin, Ireland; Department of Gastrosurgical Research and Education, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Carel W le Roux
- Diabetes Complications Research Centre, Conway Institute, School of Medicine, University College Dublin, Ireland; Investigative Science, Imperial College London, UK
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17
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Abstract
Reviewed here are multiple mouse models of vertical sleeve gastrectomy (VSG) and Roux-en Y gastric bypass (RYGB) that have emerged over the past decade. These models use diverse approaches to both operative and perioperative procedures. Scrutinizing the benefits and pitfalls of each surgical model and what to expect in terms of post-operative outcomes will enhance our assessment of studies using mouse models, as well as advance our understanding of their translational potential. Two mouse models of bariatric surgery, VSG-lembert and RYGB-small pouch, demonstrate low mortality and most closely recapitulate the human forms of surgery. The use of liquid diets can be minimized, and in mice, RYGB demonstrates more reliable and longer lasting effects on weight loss compared to that of VSG.
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18
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TGR5 Protects Against Colitis in Mice, but Vertical Sleeve Gastrectomy Increases Colitis Severity. Obes Surg 2020; 29:1593-1601. [PMID: 30623320 DOI: 10.1007/s11695-019-03707-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Bariatric surgery, such as vertical sleeve gastrectomy (VSG), is the most effective long-term treatment for obesity. However, there are conflicting reports on the effect of bariatric surgery on inflammatory bowel disease (IBD). Bariatric surgery increases bile acid concentrations, which can decrease inflammation by signaling through the bile acid receptor, TGR5. TGR5 signaling protects against chemically induced colitis in mice. VSG increases circulating bile acid concentrations to increase TGR5 signaling, which contributes to improved metabolic regulation after VSG. Therefore, we investigated the effect of VSG on chemically induced colitis development and the role of TGR5 in this context. METHODS VSG or sham surgery was performed in high fat diet-fed male Tgr5+/+ and Tgr5-/- littermates. Sham-operated mice were food restricted to match their body weight to VSG-operated mice. Colitis was induced with 2.5% dextran sodium sulfate (DSS) in water post-operatively. Body weight, energy intake, fecal scoring, colon histopathology, colonic markers of inflammation, goblet cell counts, and colonic microRNA-21 levels were assessed. RESULTS VSG decreased body weight independently of genotype. Consistent with previous work, genetic ablation of TGR5 increased the severity of DSS-induced colitis. Notably, despite the effect of VSG to decrease body weight and increase TGR5 signaling, VSG increased the severity of DSS-induced colitis. VSG-induced increases in colitis were associated with increased colonic expression of TNF-α, IL-6, MCP-1, and microRNA-21. CONCLUSIONS While our data demonstrate that TGR5 protects against colitis, they also demonstrate that VSG potentiates chemically induced colitis in mice. These data suggest that individuals undergoing VSG may be at increased risk for developing colitis; however, further study is needed.
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19
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Li K, Zou J, Li S, Guo J, Shi W, Wang B, Han X, Zhang H, Zhang P, Miao Z, Li Y. Farnesoid X receptor contributes to body weight-independent improvements in glycemic control after Roux-en-Y gastric bypass surgery in diet-induced obese mice. Mol Metab 2020; 37:100980. [PMID: 32305491 PMCID: PMC7182762 DOI: 10.1016/j.molmet.2020.100980] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 03/12/2020] [Accepted: 03/12/2020] [Indexed: 02/08/2023] Open
Abstract
Objective Roux-en-Y gastric bypass surgery (RYGB) can achieve long-term remission of type 2 diabetes. However, the specific molecular mechanism through which this occurs has remained largely elusive. Bile acid signaling through the nuclear hormone receptor farnesoid X receptor (FXR) exerts beneficial effects after sleeve gastrectomy (VSG), which has similar effects to RYGB. Therefore, we investigated whether FXR signaling is necessary to mediate glycemic control after RYGB. Methods RYGB or sham surgery was performed in high-fat diet-induced obese FXR−/− (knockout) and FXR+/+ (wild type) littermates. Sham-operated mice were fed ad libitum (S-AL) or by weight matching (S-WM) to RYGB mice via caloric restriction. Body weight, body composition, food intake, energy expenditure, glucose tolerance tests, insulin tolerance tests, and homeostatic model assessment of insulin resistance were performed. Results RYGB surgery decreases body weight and fat mass in WT and FXR-KO mice. RYGB surgery has similar effects on food intake and energy expenditure independent of genotype. In addition, body weight-independent improvements in glucose control were attenuated in FXR −/− relative to FXR +/+ mice after RYGB. Furthermore, pharmacologic blockade of the glucagon-like peptide-1 receptor (GLP-1R) blunts the glucoregulatory effects of RYGB in FXR +/+ but not in FXR −/− mice at 4 weeks after surgery. Conclusions These results suggest that FXR signaling is not required for the weight loss up to 16 weeks after RYGB. Although most of the improvements in glucose homeostasis are secondary to RYGB-induced weight loss in wild type mice, FXR signaling contributes to glycemic control after RYGB in a body weight-independent manner, which might be mediated by an FXR-GLP-1 axis during the early postoperative period.
The reduction in body weight after RYGB is independent of FXR, which is mainly due to a decrease in net energy intake. RYGB prevents the weight loss-induced decrease observed in nonsurgical weight-matched mice in both genotypes. FXR signaling contributes to glycemic control after RYGB in a body weight-independent manner. The early body weight-independent improvements in glucose homeostasis after RYGB might be mediated by an FXR-GLP-1 axis.
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Affiliation(s)
- Kun Li
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China
| | - Jianan Zou
- Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, PR China
| | - Song Li
- School of Basic Medicine, Shandong First Medical University, Tai'an, 271000, PR China
| | - Jing Guo
- Discipline Planning Department, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China
| | - Wentao Shi
- Clinical Research Center, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China
| | - Bing Wang
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China
| | - Xiaodong Han
- Department of Metabolic & Bariatric Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, PR China
| | - Hongwei Zhang
- Department of Metabolic & Bariatric Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, PR China
| | - Pin Zhang
- Department of Metabolic & Bariatric Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, PR China
| | - Zengmin Miao
- School of Life Sciences, Shandong First Medical University, Tai'an, 271000, PR China.
| | - Yousheng Li
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China.
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20
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Davis EM, Sandoval DA. Glucagon‐Like Peptide‐1: Actions and Influence on Pancreatic Hormone Function. Compr Physiol 2020; 10:577-595. [DOI: 10.1002/cphy.c190025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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21
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Korakas E, Kountouri A, Raptis A, Kokkinos A, Lambadiari V. Bariatric Surgery and Type 1 Diabetes: Unanswered Questions. Front Endocrinol (Lausanne) 2020; 11:525909. [PMID: 33071965 PMCID: PMC7531037 DOI: 10.3389/fendo.2020.525909] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 08/20/2020] [Indexed: 01/19/2023] Open
Abstract
In recent decades there has been an alarming increase in the prevalence of obesity in patients with type 1 diabetes leading to the development of insulin resistance and cardiometabolic complications, with mechanisms poorly clarified. While bariatric surgery has long been considered an effective treatment option for patients with type 2 diabetes, the evidence regarding its benefits on weight loss and the prevention of complications in T1DM patients is scarce, with controversial outcomes. Bariatric surgery has been associated with a significant reduction in daily insulin requirement, along with a considerable reduction in body mass index, results which were sustained in the long term. Furthermore, studies suggest that bariatric surgery in type 1 diabetes results in the improvement of comorbidities related to obesity including hypertension and dyslipidemia. However, regarding glycemic control, the reduction of mean glycosylated hemoglobin was modest or statistically insignificant in most studies. The reasons for these results are yet to be elucidated; possible explanations include preservation of beta cell mass and increased residual function post-surgery, improvement in insulin action, altered GLP-1 function, timing of surgery, and association with residual islet cell mass. A number of concerns regarding safety issues have arisen due to the reporting of peri-operative and post-operative adverse events. The most significant complications are metabolic and include diabetic ketoacidosis, severe hypoglycemia and glucose fluctuations. Further prospective clinical studies are required to provide evidence for the effect of bariatric surgery on T1DM patients. The results may offer a better knowledge for the selection of people living with diabetes who will benefit more from a metabolic surgery.
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Affiliation(s)
- Emmanouil Korakas
- Second Department of Internal Medicine, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Aikaterini Kountouri
- Second Department of Internal Medicine, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios Raptis
- Second Department of Internal Medicine, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Vaia Lambadiari
- Second Department of Internal Medicine, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
- *Correspondence: Vaia Lambadiari
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22
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Holter MM, Garibay D, Lee SA, Saikia M, McGavigan AK, Ngyuen L, Moore ES, Daugherity E, Cohen P, Kelly K, Weiss RS, Cummings BP. Hepatocyte p53 ablation induces metabolic dysregulation that is corrected by food restriction and vertical sleeve gastrectomy in mice. FASEB J 2019; 34:1846-1858. [PMID: 31914635 DOI: 10.1096/fj.201902214r] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 11/20/2019] [Accepted: 11/26/2019] [Indexed: 12/17/2022]
Abstract
P53 has been implicated in the pathogenesis of obesity and diabetes; however, the mechanisms and tissue sites of action are incompletely defined. Therefore, we investigated the role of hepatocyte p53 in metabolic homeostasis using a hepatocyte-specific p53 knockout mouse model. To gain further mechanistic insight, we studied mice under two complementary conditions of restricted weight gain: vertical sleeve gastrectomy (VSG) or food restriction. VSG or sham surgery was performed in high-fat diet-fed male hepatocyte-specific p53 wild-type and knockout littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Hepatocyte-specific p53 ablation in sham-operated ad libitum-fed mice impaired glucose homeostasis, increased body weight, and decreased energy expenditure without changing food intake. The metabolic deficits induced by hepatocyte-specific p53 ablation were corrected, in part by food restriction, and completely by VSG. Unlike food restriction, VSG corrected the effect of hepatocyte p53 ablation to lower energy expenditure, resulting in a greater improvement in glucose homeostasis compared with food restricted mice. These data reveal an important new role for hepatocyte p53 in the regulation of energy expenditure and body weight and suggest that VSG can improve alterations in energetics associated with p53 dysregulation.
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Affiliation(s)
- Marlena M Holter
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Darline Garibay
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Seon A Lee
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Mridusmita Saikia
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Anne K McGavigan
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Lily Ngyuen
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA
| | - Elizabeth S Moore
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Erin Daugherity
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Paul Cohen
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA
| | - Kathleen Kelly
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Robert S Weiss
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Bethany P Cummings
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
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23
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Kim KS, Hutch CR, Wood L, Magrisso IJ, Seeley RJ, Sandoval DA. Glycemic effect of pancreatic preproglucagon in mouse sleeve gastrectomy. JCI Insight 2019; 4:129452. [PMID: 31619587 PMCID: PMC6824314 DOI: 10.1172/jci.insight.129452] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 09/18/2019] [Indexed: 02/06/2023] Open
Abstract
Intestinally derived glucagon-like peptide-1 (GLP-1), encoded by the preproglucagon (Gcg) gene, is believed to function as an incretin. However, our previous work questioned this dogma and demonstrated that pancreatic peptides rather than intestinal Gcg peptides, including GLP-1, are a primary regulator of glucose homeostasis in normal mice. The objective of these experiments was to determine whether changes in nutrition or alteration of gut hormone secretion by bariatric surgery would result in a larger role for intestinal GLP-1 in the regulation of insulin secretion and glucose homeostasis. Multiple transgenic models, including mouse models with intestine- or pancreas tissue-specific Gcg expression and a whole-body Gcg-null mouse model, were generated to study the role of organ-specific GLP-1 production on glucose homeostasis under dietary-induced obesity and after weight loss from bariatric surgery (vertical sleeve gastrectomy; VSG). Our findings indicated that the intestine is a major source of circulating GLP-1 after various nutrient and surgical stimuli. However, even with the 4-fold increase in intestinally derived GLP-1 with VSG, it is pancreatic peptides, not intestinal Gcg peptides, that are necessary for surgery-induced improvements in glucose homeostasis.
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24
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Douros JD, Tong J, D’Alessio DA. The Effects of Bariatric Surgery on Islet Function, Insulin Secretion, and Glucose Control. Endocr Rev 2019; 40:1394-1423. [PMID: 31241742 PMCID: PMC6749890 DOI: 10.1210/er.2018-00183] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 04/23/2019] [Indexed: 01/19/2023]
Abstract
Although bariatric surgery was developed primarily to treat morbid obesity, evidence from the earliest clinical observations to the most recent clinical trials consistently demonstrates that these procedures have substantial effects on glucose metabolism. A large base of research indicates that bariatric surgeries such as Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), and biliopancreatic diversion (BPD) improve diabetes in most patients, with effects frequently evident prior to substantial weight reduction. There is now unequivocal evidence from randomized controlled trials that the efficacy of surgery is superior to intensive life-style/medical management. Despite advances in the clinical understanding and application of bariatric surgery, there remains only limited knowledge of the mechanisms by which these procedures confer such large changes to metabolic physiology. The improvement of insulin sensitivity that occurs with weight loss (e.g., the result of diet, illness, physical training) also accompanies bariatric surgery. However, there is evidence to support specific effects of surgery on insulin clearance, hepatic glucose production, and islet function. Understanding the mechanisms by which surgery affects these parameters of glucose regulation has the potential to identify new targets for therapeutic discovery. Studies to distinguish among bariatric surgeries on key parameters of glucose metabolism are limited but would be of considerable value to assist clinicians in selecting specific procedures and investigators in delineating the resulting physiology. This review is based on literature related to factors governing glucose metabolism and insulin secretion after the commonly used RYGB and VSG, and the less frequently used BPD and adjustable gastric banding.
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Affiliation(s)
- Jonathan D Douros
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Jenny Tong
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - David A D’Alessio
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
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25
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Conversion from Prediabetes to Diabetes in Individuals with Obesity, 5-Years Post-Band, Sleeve, and Gastric Bypass Surgeries. Obes Surg 2019; 29:3901-3906. [PMID: 31313239 DOI: 10.1007/s11695-019-04090-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND Identifying risk factors for conversion to diabetes among individuals with obesity and prediabetes is important for preventing diabetes. PURPOSE We assessed conversion rates to diabetes 5 years after three types of metabolic surgery and examined predictors of diabetes development. METHODS We accessed data of individuals with prediabetes, defined as fasting glucose (FG) 100-125 mg/dL (5.6-6.9 mmol/L) or HbA1c 5.7-6.4% at baseline (preoperatively), who underwent metabolic surgeries in Clalit Health Services during 2002-2011. RESULTS Of 1,756 individuals with prediabetes, 819 underwent gastric banding (GB), 845 sleeve gastrectomy (SG), and 92 Roux-en-Y gastric bypass (RYGB). Mean age was 41.6 years and 73.5% were women. Five years post-surgery, 177 (10.1%) had developed diabetes. Conversion rates by type of surgery were 14.4%, 6.3%, and 6.5% for GB, SG, and RYGB, respectively (p < 0.001). Conversion was more rapid following GB than SG or RYGB (χ2(2) = 29.67, p < 0.005). In a multiple-logistic-regression model, predictors of diabetes development 5 years postoperatively were (1) weight loss during the first postoperative year and (2) preoperative levels of both FG and HbA1c within the prediabetes range. Baseline weight, age, and sex, were not associated with conversion to diabetes. Conversion rates were lower (4.7%) five years postoperatively for patients who lost > 25% of their baseline weight, compared to those who lost less than 15% of their weight during the first postoperative year: (14.0% < 0.001). CONCLUSIONS Our findings emphasize the importance of preoperative glycemic control and weight loss during the first year postoperatively, for the long-term prevention of diabetes in patients with prediabetes undergoing metabolic surgery.
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Prada-Oliveira JA, Camacho-Ramirez A, Salas-Alvarez J, Campos-Martinez FJ, Lechuga-Sancho AM, Almorza-Gomar D, Blandino-Rosano M, Perez-Arana GM. GLP-1 mediated improvement of the glucose tolerance in the T2DM GK rat model after massive jejunal resection. Ann Anat 2019; 223:1-7. [DOI: 10.1016/j.aanat.2019.01.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 01/04/2019] [Accepted: 01/23/2019] [Indexed: 12/25/2022]
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Sandoval DA. Mechanisms for the metabolic success of bariatric surgery. J Neuroendocrinol 2019; 31:e12708. [PMID: 30882956 PMCID: PMC9205614 DOI: 10.1111/jne.12708] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 03/11/2019] [Accepted: 03/13/2019] [Indexed: 12/14/2022]
Abstract
To date, bariatric surgery remains the most effective strategy for the treatment of obesity and its comorbidities. However, given the enormity of the obesity epidemic, and sometimes variable results, it is not a feasible strategy for the treatment of all obese patients. A simple PubMed search for 'bariatric surgery' reveals over 28 000 papers that have been published since the 1940s when the first bariatric surgeries were performed. However, there is still an incomplete understanding of the mechanisms for the weight loss and metabolic success of surgery. An understanding of the mechanisms is important because it may lead to greater understanding of the pathophysiology of obesity and thus surgery-alternative strategies for the treatment of all obese patients. In this review, the potential mechanisms that underlie the success of surgery are discussed, with a focus on the potential endocrine, neural and other circulatory factors (eg, bile acids) that have been proposed to play a role.
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Debédat J, Amouyal C, Aron-Wisnewsky J, Clément K. Impact of bariatric surgery on type 2 diabetes: contribution of inflammation and gut microbiome? Semin Immunopathol 2019; 41:461-475. [PMID: 31025085 DOI: 10.1007/s00281-019-00738-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 03/15/2019] [Indexed: 02/06/2023]
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Abstract
Gut hormones have many key roles in the control of metabolism, as they target diverse tissues involved in the control of intestinal function, insulin secretion, nutrient assimilation and food intake. Produced by scattered cells found along the length of the intestinal epithelium, gut hormones generate signals related to the rate of nutrient absorption, the composition of the luminal milieu and the integrity of the epithelial barrier. Gut hormones already form the basis for existing and developing therapeutics for type 2 diabetes mellitus and obesity, exemplified by the licensed glucagon-like peptide 1 (GLP1) mimetics and dipeptidyl peptidase inhibitors that enhance GLP1 receptor activation. Modulating the release of the endogenous stores of GLP1 and other gut hormones is thought to be a promising strategy to mimic bariatric surgery with its multifaceted beneficial effects on food intake, body weight and blood glucose levels. This Review focuses on the molecular mechanisms underlying the modulation of gut hormone release by food ingestion, obesity and the gut microbiota. Depending on the nature of the stimulus, release of gut hormones involves recruitment of a variety of signalling pathways, including G protein-coupled receptors, nutrient transporters and ion channels, which are targets for future therapeutics for diabetes mellitus and obesity.
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Affiliation(s)
- Fiona M Gribble
- Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
| | - Frank Reimann
- Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
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Douros JD, Niu J, Sdao S, Gregg T, Fisher-Wellman K, Bharadwaj M, Molina A, Arumugam R, Martin M, Petretto E, Merrins MJ, Herman MA, Tong J, Campbell J, D’Alessio D. Sleeve gastrectomy rapidly enhances islet function independently of body weight. JCI Insight 2019; 4:126688. [PMID: 30777938 PMCID: PMC6483064 DOI: 10.1172/jci.insight.126688] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/11/2019] [Indexed: 12/14/2022] Open
Abstract
Bariatric surgeries including vertical sleeve gastrectomy (VSG) ameliorate obesity and diabetes. Weight loss and accompanying increases to insulin sensitivity contribute to improved glycemia after surgery; however, studies in humans also suggest weight-independent actions of bariatric procedures to lower blood glucose, possibly by improving insulin secretion. To evaluate this hypothesis, we compared VSG-operated mice with pair-fed, sham-surgical controls (PF-Sham) 2 weeks after surgery. This paradigm yielded similar postoperative body weight and insulin sensitivity between VSG and calorically restricted PF-Sham animals. However, VSG improved glucose tolerance and markedly enhanced insulin secretion during oral nutrient and i.p. glucose challenges compared with controls. Islets from VSG mice displayed a unique transcriptional signature enriched for genes involved in Ca2+ signaling and insulin secretion pathways. This finding suggests that bariatric surgery leads to intrinsic changes within the islet that alter function. Indeed, islets isolated from VSG mice had increased glucose-stimulated insulin secretion and a left-shifted glucose sensitivity curve compared with islets from PF-Sham mice. Isolated islets from VSG animals showed corresponding increases in the pulse duration of glucose-stimulated Ca2+ oscillations. Together, these findings demonstrate a weight-independent improvement in glycemic control following VSG, which is, in part, driven by improved insulin secretion and associated with substantial changes in islet gene expression. These results support a model in which β cells play a key role in the adaptation to bariatric surgery and the improved glucose tolerance that is typical of these procedures.
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Affiliation(s)
- Jonathan D. Douros
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - Jingjing Niu
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - Sophia Sdao
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Trillian Gregg
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Kelsey Fisher-Wellman
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - Manish Bharadwaj
- Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Anthony Molina
- Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Ramamani Arumugam
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - MacKenzie Martin
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - Enrico Petretto
- Centre for Computational Biology, Duke-NUS Medical School, Singapore
| | - Matthew J. Merrins
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Mark A. Herman
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - Jenny Tong
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - Jonathan Campbell
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - David D’Alessio
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
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Larraufie P, Roberts GP, McGavigan AK, Kay RG, Li J, Leiter A, Melvin A, Biggs EK, Ravn P, Davy K, Hornigold DC, Yeo GSH, Hardwick RH, Reimann F, Gribble FM. Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery. Cell Rep 2019; 26:1399-1408.e6. [PMID: 30726726 PMCID: PMC6367566 DOI: 10.1016/j.celrep.2019.01.047] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 12/14/2018] [Accepted: 01/11/2019] [Indexed: 02/07/2023] Open
Abstract
Bariatric surgery is widely used to treat obesity and improves type 2 diabetes beyond expectations from the degree of weight loss. Elevated post-prandial concentrations of glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin are widely reported, but the importance of GLP-1 in post-bariatric physiology remains debated. Here, we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1Rs) post-gastrectomy in lean humans using Exendin-9 or in mice using an anti-GLP1R antibody. Transcriptomics and peptidomics analyses revealed that human and mouse enteroendocrine cells were unaltered post-surgery; instead, we found that elevated plasma GLP-1 and PYY correlated with increased nutrient delivery to the distal gut in mice. We conclude that increased GLP-1 secretion after bariatric surgery arises from rapid nutrient delivery to the distal gut and is a key driver of enhanced insulin secretion.
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Affiliation(s)
- Pierre Larraufie
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
| | - Geoffrey P Roberts
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
| | - Anne K McGavigan
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
| | - Richard G Kay
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
| | - Joyce Li
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Andrew Leiter
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Audrey Melvin
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
| | - Emma K Biggs
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
| | - Peter Ravn
- Department of Antibody Discovery and Protein Engineering, MedImmune, Granta Park, Cambridge CB21 6GH, UK
| | - Kathleen Davy
- Department of Cardiovascular and Metabolic Disease, MedImmune, Granta Park, Cambridge, UK
| | - David C Hornigold
- Department of Cardiovascular and Metabolic Disease, MedImmune, Granta Park, Cambridge, UK
| | - Giles S H Yeo
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
| | - Richard H Hardwick
- Cambridge Oesophago-gastric Centre, Addenbrooke's Hospital, Cambridge, UK
| | - Frank Reimann
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
| | - Fiona M Gribble
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
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Capozzi ME, DiMarchi RD, Tschöp MH, Finan B, Campbell JE. Targeting the Incretin/Glucagon System With Triagonists to Treat Diabetes. Endocr Rev 2018; 39:719-738. [PMID: 29905825 PMCID: PMC7263842 DOI: 10.1210/er.2018-00117] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 06/07/2018] [Indexed: 02/07/2023]
Abstract
Glucagonlike peptide 1 (GLP-1) receptor agonists have been efficacious for the treatment of type 2 diabetes due to their ability to reduce weight and attenuate hyperglycemia. However, the activity of glucagonlike peptide 1 receptor-directed strategies is submaximal, and the only potent, sustainable treatment of metabolic dysfunction is bariatric surgery, necessitating the development of unique therapeutics. GLP-1 is structurally related to glucagon and glucose-dependent insulinotropic peptide (GIP), allowing for the development of intermixed, unimolecular peptides with activity at each of their respective receptors. In this review, we discuss the range of tissue targets and added benefits afforded by the inclusion of each of GIP and glucagon. We discuss considerations for the development of sequence-intermixed dual agonists and triagonists, highlighting the importance of evaluating balanced signaling at the targeted receptors. Several multireceptor agonist peptides have been developed and evaluated, and the key preclinical and clinical findings are reviewed in detail. The biological activity of these multireceptor agonists are founded in the success of GLP-1-directed strategies; by including GIP and glucagon components, these multireceptor agonists are thought to enhance GLP-1's activities by broadening the tissue targets and synergizing at tissues that express multiple receptors, such at the brain and pancreatic islet β cells. The development and utility of balanced, unimolecular multireceptor agonists provide both a useful tool for querying the actions of incretins and glucagon during metabolic disease and a unique drug class to treat type 2 diabetes with unprecedented efficacy.
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Affiliation(s)
- Megan E Capozzi
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Richard D DiMarchi
- Department of Chemistry, Indiana University, Bloomington, Indiana
- Novo Nordisk Research Center, Indianapolis, Indiana
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany
| | - Brian Finan
- Novo Nordisk Research Center, Indianapolis, Indiana
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
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Douros JD, Lewis AG, Smith EP, Niu J, Capozzi M, Wittmann A, Campbell J, Tong J, Wagner C, Mahbod P, Seeley R, D'Alessio DA. Enhanced Glucose Control Following Vertical Sleeve Gastrectomy Does Not Require a β-Cell Glucagon-Like Peptide 1 Receptor. Diabetes 2018; 67:1504-1511. [PMID: 29759973 PMCID: PMC6054432 DOI: 10.2337/db18-0081] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 05/04/2018] [Indexed: 12/12/2022]
Abstract
Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell-specific Glp1r knockdown (Glp1rβ-cell-ko). Mice with VSG lost ∼20% of body weight over 30 days compared with sham-operated controls and had a ∼60% improvement in glucose tolerance. Isolated islets from VSG mice had significantly greater insulin responses to glucose than controls. Glp1r knockdown in β-cells caused glucose intolerance in diet-induced obese mice compared with obese controls, but VSG improved glycemic profiles to similar levels during oral and intraperitoneal glucose challenges in Glp1rβ-cell-ko and Glp1rWT mice. Therefore, even though the β-cell GLP-1R seems to be important for maintaining glucose tolerance in obese mice, in these experiments it is dispensable for the improvement in glucose tolerance after VSG. Moreover, the metabolic physiology activated by VSG can overcome the deficits in glucose regulation caused by lack of β-cell GLP-1 signaling in obesity.
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Affiliation(s)
- Jonathan D Douros
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
| | - Alfor G Lewis
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Eric P Smith
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
| | - JingJing Niu
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
| | - Megan Capozzi
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
| | - April Wittmann
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
| | - Jonathan Campbell
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
| | - Jenny Tong
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC
| | - Constance Wagner
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
| | - Parinaz Mahbod
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
| | - Randy Seeley
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - David A D'Alessio
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC
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GLP-2 receptor signaling controls circulating bile acid levels but not glucose homeostasis in Gcgr -/- mice and is dispensable for the metabolic benefits ensuing after vertical sleeve gastrectomy. Mol Metab 2018; 16:45-54. [PMID: 29937214 PMCID: PMC6157461 DOI: 10.1016/j.molmet.2018.06.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 06/04/2018] [Accepted: 06/06/2018] [Indexed: 02/06/2023] Open
Abstract
Objective Therapeutic interventions that improve glucose homeostasis such as attenuation of glucagon receptor (Gcgr) signaling and bariatric surgery share common metabolic features conserved in mice and humans. These include increased circulating levels of bile acids (BA) and the proglucagon-derived peptides (PGDPs), GLP-1 and GLP-2. Whether BA acting through TGR5 (Gpbar1) increases PGDP levels in these scenarios has not been examined. Furthermore, although the importance of GLP-1 action has been interrogated in Gcgr−/− mice and after bariatric surgery, whether GLP-2 contributes to the metabolic benefits of these interventions is not known. Methods To assess whether BA acting through Gpbar1 mediates improved glucose homeostasis in Gcgr−/− mice we generated and characterized Gcgr−/−:Gpbar1−/− mice. The contribution of GLP-2 receptor (GLP-2R) signaling to intestinal and metabolic adaptation arising following loss of the Gcgr was studied in Gcgr−/−:Glp2r−/− mice. The role of the GLP-2R in the metabolic improvements evident after bariatric surgery was studied in high fat-fed Glp2r−/− mice subjected to vertical sleeve gastrectomy (VSG). Results Circulating levels of BA were markedly elevated yet similar in Gcgr−/−:Gpbar1+/+ vs. Gcgr−/−:Gpbar1−/− mice. Loss of GLP-2R lowered levels of BA in Gcgr−/− mice. Gcgr−/−:Glp2r−/− mice also exhibited shifts in the proportion of circulating BA species. Loss of Gpbar1 did not impact body weight, intestinal mass, or glucose homeostasis in Gcgr−/− mice. In contrast, small bowel growth was attenuated in Gcgr−/−:Glp2r−/− mice. The improvement in glucose tolerance, elevated circulating levels of GLP-1, and glucose-stimulated insulin levels were not different in Gcgr−/−:Glp2r+/+ vs. Gcgr−/−:Glp2r−/− mice. Similarly, loss of the GLP-2R did not attenuate the extent of weight loss and improvement in glucose control after VSG. Conclusions These findings reveal that GLP-2R controls BA levels and relative proportions of BA species in Gcgr−/− mice. Nevertheless, the GLP-2R is not essential for i) control of body weight or glucose homeostasis in Gcgr−/− mice or ii) metabolic improvements arising after VSG in high fat-fed mice. Furthermore, despite elevations of circulating levels of BA, Gpbar1 does not mediate elevated levels of PGDPs or major metabolic phenotypes in Gcgr−/− mice. Collectively these findings refine our understanding of the relationship between Gpbar1, elevated levels of BA, PGDPs, and the GLP-2R in amelioration of metabolic derangements arising following loss of Gcgr signaling or after vertical sleeve gastrectomy.
GLP-2 receptor controls bile acid levels in Gcgr−/− mice. Gpbar1 is not required for the metabolic benefits or elevated levels of PGDPs in Gcgr−/− mice. GLP-2 regulates gut adaptation in Gcgr−/− mice. Bile acid profiles are altered in Gcgr−/− mice following loss of GLP-2R. GLP-2R is not required for improvements in glucose homeostasis or weight loss after VSG in mice.
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Smith EP, Polanco G, Yaqub A, Salehi M. Altered glucose metabolism after bariatric surgery: What's GLP-1 got to do with it? Metabolism 2018; 83:159-166. [PMID: 29113813 DOI: 10.1016/j.metabol.2017.10.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 10/20/2017] [Accepted: 10/25/2017] [Indexed: 01/20/2023]
Abstract
Bariatric surgery is an effective treatment for obesity. The two widely performed weight-loss procedures, Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG), alter postprandial glucose pattern and enhance gut hormone secretion immediately after surgery before significant weight loss. This weight-loss independent glycemic effects of GB has been attributed to an accelerated nutrient transit from stomach pouch to the gut and enhanced secretion of insulinotropic gut factors; in particular, glucagon-like peptide-1 (GLP-1). Meal-induced GLP-1 secretion is as much as tenfold higher in patients after GB compared to non-surgical individuals and inhibition of GLP-1 action during meals reduces postprandial hyperinsulinemia after GB two to three times more than that in persons without surgery. Moreover, in a subgroup of patients with the late complication of postprandial hyperinsulinemic hypoglycemia after GB, GLP1R blockade reverses hypoglycemia by reducing meal stimulated insulin secretion. The role of enteroinsular axis activity after SG, an increasingly popular alternative to GB, is less understood but, similar to GB, SG accelerates nutrient delivery to the intestine, improves glucose tolerance, and increases postprandial GLP-1 secretion. This review will focus on the current evidence for and against the role of GLP-1 on glycemic effects of GB and will also highlight differences between GB and SG.
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Affiliation(s)
- Eric P Smith
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
| | - Georgina Polanco
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Abid Yaqub
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Marzieh Salehi
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Garibay D, Lou J, Lee SA, Zaborska KE, Weissman MH, Sloma E, Donahue L, Miller AD, White AC, Michael MD, Sloop KW, Cummings BP. β Cell GLP-1R Signaling Alters α Cell Proglucagon Processing after Vertical Sleeve Gastrectomy in Mice. Cell Rep 2018; 23:967-973. [PMID: 29694904 PMCID: PMC5983903 DOI: 10.1016/j.celrep.2018.03.120] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 03/05/2018] [Accepted: 03/27/2018] [Indexed: 12/11/2022] Open
Abstract
Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes high rates of type 2 diabetes remission and remarkable increases in postprandial glucagon-like peptide-1 (GLP-1) secretion. GLP-1 plays a critical role in islet function by potentiating glucose-stimulated insulin secretion; however, the mechanisms remain incompletely defined. Therefore, we applied a murine VSG model to an inducible β cell-specific GLP-1 receptor (GLP-1R) knockout mouse model to investigate the role of the β cell GLP-1R in islet function. Our data show that loss of β cell GLP-1R signaling decreases α cell GLP-1 expression after VSG. Furthermore, we find a β cell GLP-1R-dependent increase in α cell expression of the prohormone convertase required for the production of GLP-1 after VSG. Together, the findings herein reveal two concepts. First, our data support a paracrine role for α cell-derived GLP-1 in the metabolic benefits observed after VSG. Second, we have identified a role for the β cell GLP-1R as a regulator of α cell proglucagon processing.
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Affiliation(s)
- Darline Garibay
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Jon Lou
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Seon A Lee
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Karolina E Zaborska
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Margot H Weissman
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Erica Sloma
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Leanne Donahue
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Andrew D Miller
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Andrew C White
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - M Dodson Michael
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Kyle W Sloop
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Bethany P Cummings
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
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Abstract
Glucagon-like peptide-1 (GLP-1) released from gut enteroendocrine cells controls meal-related glycemic excursions through augmentation of insulin and inhibition of glucagon secretion. GLP-1 also inhibits gastric emptying and food intake, actions maximizing nutrient absorption while limiting weight gain. Here I review the circuits engaged by endogenous versus pharmacological GLP-1 action, highlighting key GLP-1 receptor (GLP-1R)-positive cell types and pathways transducing metabolic and non-glycemic GLP-1 signals. The role(s) of GLP-1 in the benefits and side effects associated with bariatric surgery are discussed and actions of GLP-1 controlling islet function, appetite, inflammation, and cardiovascular pathophysiology are highlighted. Refinement of the risk-versus-benefit profile of GLP-1-based therapies for the treatment of diabetes and obesity has stimulated development of orally bioavailable agonists, allosteric modulators, and unimolecular multi-agonists, all targeting the GLP-1R. This review highlights established and emerging concepts, unanswered questions, and future challenges for development and optimization of GLP-1R agonists in the treatment of metabolic disease.
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Affiliation(s)
- Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, 600 University Avenue, Mailbox 39, Toronto, ON M5G 1X5, Canada.
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Hankir MK, Seyfried F, Miras AD, Cowley MA. Brain Feeding Circuits after Roux-en-Y Gastric Bypass. Trends Endocrinol Metab 2018; 29:218-237. [PMID: 29475578 DOI: 10.1016/j.tem.2018.01.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 01/17/2018] [Accepted: 01/25/2018] [Indexed: 12/12/2022]
Abstract
Metabolic surgical procedures, such as Roux-en-Y gastric bypass (RYGB), uniquely reprogram feeding behavior and body weight in obese subjects. Clinical neuroimaging and animal studies are only now beginning to shed light on some of the underlying central mechanisms. We present here the roles of key brain neurotransmitter/neuromodulator systems in food choice, value, and intake at various stages after RYGB. In doing so, we elaborate on how known signals emanating from the reorganized gut, including peptide hormones and microbiota products, impinge on newly mapped homeostatic and hedonic brain feeding circuits. Continued progress in the rapidly evolving field of metabolic surgery will inform the design of more effective weight-loss compounds.
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Affiliation(s)
- Mohammed K Hankir
- Department of Experimental Surgery, University Hospital Wuerzburg, Wuerzburg, Bavaria 97080, Germany; German Research Foundation Collaborative Research Center in Obesity Mechanisms, University of Leipzig, Leipzig, Saxony 04103, Germany.
| | - Florian Seyfried
- Department of Experimental Surgery, University Hospital Wuerzburg, Wuerzburg, Bavaria 97080, Germany
| | - Alexander D Miras
- Department of Investigative Science, Imperial College London Academic Healthcare Centre, London W12 0NN, UK
| | - Michael A Cowley
- Metabolic Disease and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Physiology, Monash University, Victoria 3800, Australia
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Briere DA, Bueno AB, Gunn EJ, Michael MD, Sloop KW. Mechanisms to Elevate Endogenous GLP-1 Beyond Injectable GLP-1 Analogs and Metabolic Surgery. Diabetes 2018; 67:309-320. [PMID: 29203510 DOI: 10.2337/db17-0607] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 11/16/2017] [Indexed: 11/13/2022]
Abstract
Therapeutic engineering of glucagon-like peptide 1 (GLP-1) has enabled development of new medicines to treat type 2 diabetes. These injectable analogs achieve robust glycemic control by increasing concentrations of "GLP-1 equivalents" (∼50 pmol/L). Similar levels of endogenous GLP-1 occur after gastric bypass surgery, and mechanistic studies indicate glucose lowering by these procedures is driven by GLP-1. Therefore, because of the remarkable signaling and secretory capacity of the GLP-1 system, we sought to discover mechanisms that increase GLP-1 pharmacologically. To study active GLP-1, glucose-dependent insulinotropic polypeptide receptor (Gipr)-deficient mice receiving background dipeptidyl peptidase 4 (DPP4) inhibitor treatment were characterized as a model for evaluating oral agents that increase circulating GLP-1. A somatostatin receptor 5 antagonist, which blunts inhibition of GLP-1 release, and agonists for TGR5 and GPR40, which stimulate GLP-1 secretion, were investigated alone and in combination with the DPP4 inhibitor sitagliptin; these only modestly increased GLP-1 (∼5-30 pmol/L). However, combining molecules to simultaneously intervene at multiple regulatory nodes synergistically elevated active GLP-1 to unprecedented concentrations (∼300-400 pmol/L), drastically reducing glucose in Gipr null and Leprdb/db mice in a GLP-1 receptor-dependent manner. Our studies demonstrate that complementary pathways can be engaged to robustly increase GLP-1 without invasive surgical or injection regimens.
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MESH Headings
- Administration, Oral
- Animals
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Dipeptidyl-Peptidase IV Inhibitors/administration & dosage
- Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
- Drug Design
- Drug Evaluation, Preclinical
- Drug Resistance
- Drug Synergism
- Drug Therapy, Combination
- Drugs, Investigational/administration & dosage
- Drugs, Investigational/therapeutic use
- Glucagon-Like Peptide 1/administration & dosage
- Glucagon-Like Peptide 1/analogs & derivatives
- Glucagon-Like Peptide 1/blood
- Glucagon-Like Peptide 1/therapeutic use
- Hyperglycemia/prevention & control
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Mutant Strains
- Models, Biological
- Proof of Concept Study
- Receptors, G-Protein-Coupled/agonists
- Receptors, G-Protein-Coupled/metabolism
- Receptors, Gastrointestinal Hormone/genetics
- Receptors, Gastrointestinal Hormone/metabolism
- Sitagliptin Phosphate/therapeutic use
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Affiliation(s)
- Daniel A Briere
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
| | - Ana B Bueno
- Centro de Investigación Lilly, Eli Lilly and Company, Alcobendas, Spain
| | | | - M Dodson Michael
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
| | - Kyle W Sloop
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
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40
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Paternoster S, Falasca M. Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1. Front Endocrinol (Lausanne) 2018; 9:584. [PMID: 30364192 PMCID: PMC6193070 DOI: 10.3389/fendo.2018.00584] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 09/14/2018] [Indexed: 12/11/2022] Open
Abstract
An aging world population exposed to a sedentary life style is currently plagued by chronic metabolic diseases, such as type-2 diabetes, that are spreading worldwide at an unprecedented rate. One of the most promising pharmacological approaches for the management of type 2 diabetes takes advantage of the peptide hormone glucagon-like peptide-1 (GLP-1) under the form of protease resistant mimetics, and DPP-IV inhibitors. Despite the improved quality of life, long-term treatments with these new classes of drugs are riddled with serious and life-threatening side-effects, with no overall cure of the disease. New evidence is shedding more light over the complex physiology of GLP-1 in health and metabolic diseases. Herein, we discuss the most recent advancements in the biology of gut receptors known to induce the secretion of GLP-1, to bridge the multiple gaps into our understanding of its physiology and pathology.
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Abstract
Bariatric surgery, such as vertical sleeve gastrectomy (VSG), is a surgery of the gastrointestinal tract that is performed for the purpose of weight loss. Bariatric surgery is currently the most effective long-term treatment for obesity. In addition to weight loss, bariatric surgery produces additional health benefits such as remission of type 2 diabetes, remission of hypertension, and decreased risk of developing certain types of cancer. The mechanisms beyond weight loss for these benefits remain incompletely defined. Therefore, animal models of bariatric surgery are being developed and validated to identify the mechanisms leading to these benefits, with the goal of improving understanding of gastrointestinal physiology and identifying new therapeutic targets. VSG has become the most commonly performed bariatric procedure in the clinic in the United States because it is highly effective at producing weight loss and metabolic improvement, and is simpler to perform than other bariatric procedures. Therefore, we have developed and validated a murine model of VSG. This murine VSG model recapitulates many of the effects of VSG seen in humans, including improved glucose and blood pressure regulation. The method is based on isolation of the stomach, ligation of gastric vessels, and removal of 70% of the stomach by transecting along the greater curvature of the stomach. We have successfully applied this surgical protocol to various genetically modified mouse lines to define the mechanistic contributors to the benefits of VSG. Furthermore, this murine VSG model has been combined with other surgical techniques, to achieve deeper mechanistic insight. Therefore, this is a simple and versatile model for studying gastrointestinal physiology and the health benefits of bariatric surgery.
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Hutch CR, Sandoval D. The Role of GLP-1 in the Metabolic Success of Bariatric Surgery. Endocrinology 2017; 158:4139-4151. [PMID: 29040429 PMCID: PMC5711387 DOI: 10.1210/en.2017-00564] [Citation(s) in RCA: 160] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 10/04/2017] [Indexed: 12/15/2022]
Abstract
Two of the most popular bariatric procedures, vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), are commonly considered metabolic surgeries because they are thought to affect metabolism in a weight loss-independent manner. In support of this classification, improvements in glucose homeostasis, insulin sensitivity, and even discontinuation of type 2 diabetes mellitus (T2DM) medication can occur before substantial postoperative weight loss. The mechanisms that underlie this effect are unknown. However, one of the common findings after VSG and RYGB in both animal models and humans is the sharp postprandial rise in several gut peptides, including the incretin and satiety peptide glucagonlike peptide-1 (GLP-1). The increase in endogenous GLP-1 signaling has been considered a primary pathway leading to postsurgical weight loss and improvements in glucose metabolism. However, the degree to which GLP-1 and other gut peptides are responsible for the metabolic successes after bariatric surgery is continually debated. In this review we discuss the mechanisms underlying the increase in GLP-1 and its potential role in the metabolic improvements after bariatric surgery, including remission of T2DM. Understanding the role of changes in gut peptides, or lack thereof, will be crucial in understanding the critical factors necessary for the metabolic success of bariatric surgery.
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Affiliation(s)
- Chelsea R. Hutch
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109
| | - Darleen Sandoval
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109
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43
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Windeløv JA, Wewer Albrechtsen NJ, Kuhre RE, Jepsen SL, Hornburg D, Pedersen J, Jensen EP, Galsgaard KD, Winther-Sørensen M, Ørgaard A, Deacon CF, Mann M, Kissow H, Hartmann B, Holst JJ. Why is it so difficult to measure glucagon-like peptide-1 in a mouse? Diabetologia 2017; 60:2066-2075. [PMID: 28669086 DOI: 10.1007/s00125-017-4347-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 05/19/2017] [Indexed: 02/08/2023]
Abstract
AIMS/HYPOTHESIS In humans, glucagon-like peptide-1 (GLP-1) is rapidly degraded by dipeptidyl peptidase-4 to a relatively stable metabolite, GLP-1(9-36)NH2, which allows measurement of GLP-1 secretion. However, little is known about the kinetics of the GLP-1 metabolite in mice. We hypothesised that the GLP-1 metabolite is rapidly degraded in this species by neutral endopeptidase(s) (NEP[s]). METHODS We administered glucose, mixed meal or water orally to 256 mice, and took blood samples before and 2, 6, 10, 20, 30, 60 or 90 min after stimulation. To study the metabolism of the GLP-1 metabolite, i.v. GLP-1(9-36)NH2 (800 fmol) or saline (154 mmol/l NaCl) was administered to 160 mice, some of which had a prior injection of a selective NEP 24.11 ± inhibitor (candoxatril, 5 mg/kg) or saline. Blood was collected before and 1, 2, 4 and 12 min after GLP-1/saline injection. Plasma GLP-1 levels were analysed using a customised single-site C-terminal ELISA, two different two-site ELISAs and MS. RESULTS GLP-1 secretion profiles after oral glucose administration differed markedly when assayed by C-terminal ELISA compared with sandwich ELISAs, with the former showing a far higher peak value and AUC. In mice injected with GLP-1(9-36)NH2, immunoreactive GLP-1 plasma levels peaked at approximately 75 pmol/l at 1 min when measured with sandwich ELISAs, returning to baseline (~20 pmol/l) after 12 min, but remained elevated using the C-terminal ELISA (~90 pmol/l at 12 min). NEP 24.11 inhibition by candoxatril significantly attenuated GLP-1(9-36)NH2 degradation in vivo and in vitro. MS identified GLP-1 fragments consistent with NEP 24.11 degradation. CONCLUSIONS/INTERPRETATION In mice, the GLP-1 metabolite is eliminated within a few minutes owing to endoproteolytic cleavage by NEP 24.11. Therefore, accurate measurement of GLP-1 secretion in mice requires assays for NEP 24.11 metabolites. Conventional sandwich ELISAs are inadequate because of endoproteolytic cleavage of the dipeptidyl peptidase-4-generated metabolite.
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Affiliation(s)
- Johanne A Windeløv
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Rune E Kuhre
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sara L Jepsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Daniel Hornburg
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Jens Pedersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Elisa P Jensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Katrine D Galsgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marie Winther-Sørensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anne Ørgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carolyn F Deacon
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Matthias Mann
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Hannelouise Kissow
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
- NNF 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, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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44
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Young CN. Endoplasmic reticulum stress in the pathogenesis of hypertension. Exp Physiol 2017; 102:869-884. [PMID: 28605068 DOI: 10.1113/ep086274] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 06/09/2017] [Indexed: 01/05/2025]
Abstract
What is the topic of this review? This review highlights the emerging role of disruptions in endoplasmic reticulum (ER) function, namely ER stress, as a contributor to hypertension. What advances does it highlight? This review presents an integrative view of ER stress in cardiovascular control systems, including systems within the brain, kidney and peripheral vasculature, as related to development of hypertension. The endoplasmic reticulum (ER) is a cellular organelle specialized in the synthesis, folding, assembly and modification of proteins. In situations of increased protein demand, complex signalling pathways, termed the unfolded protein response, influence a series of cellular feedback loops to control ER function strictly. Although this is initially a compensatory attempt to maintain cellular homeostasis, chronic activation of the unfolded protein response, known as ER stress, leads to sustained changes in cellular function. A growing body of literature points to ER stress in diverse cardioregulatory systems, including the brain, kidney and vasculature, as central to the development of hypertension. Here, these recent findings from essential and obesity-related forms of hypertension are highlighted in an integrative manner, with discussion of the potential upstream causes and downstream consequences of ER stress. Given that hypertension is a leading medical and socio-economic global challenge, emerging findings suggest that targeting ER stress might represent a viable strategy for the treatment of hypertensive disease.
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Affiliation(s)
- Colin N Young
- Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA
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45
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Wismann P, Barkholt P, Secher T, Vrang N, Hansen HB, Jeppesen PB, Baggio LL, Koehler JA, Drucker DJ, Sandoval DA, Jelsing J. The endogenous preproglucagon system is not essential for gut growth homeostasis in mice. Mol Metab 2017; 6:681-692. [PMID: 28702324 PMCID: PMC5485241 DOI: 10.1016/j.molmet.2017.04.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 04/21/2017] [Accepted: 04/24/2017] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE The prevalence of obesity and related co-morbidities is reaching pandemic proportions. Today, the most effective obesity treatments are glucagon-like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut; however, intestinotrophic mechanisms associated with or secondary to medical or surgical obesity therapies are poorly understood. Therefore, the objective of this study was to assess the local basal endogenous and pharmacological intestinotrophic effects of glucagon-like peptides and bariatric surgery in mice. METHODS We used in situ hybridization to provide a detailed and comparative anatomical map of the local distribution of GLP-1 receptor (Glp1r), GLP-2 receptor (Glp2r), and preproglucagon (Gcg) mRNA expression throughout the mouse gastrointestinal tract. Gut development in GLP-1R-, GLP-2R-, or GCG-deficient mice was compared to their corresponding wild-type controls, and intestinotrophic effects of GLP-1 and GLP-2 analogs were assessed in wild-type mice. Lastly, gut volume was determined in a mouse model of vertical sleeve gastrectomy (VSG). RESULTS Comparison of Glp1r, Glp2r, and Gcg mRNA expression indicated a widespread, but distinct, distribution of these three transcripts throughout all compartments of the mouse gastrointestinal tract. While mice null for Glp1r or Gcg showed normal intestinal morphology, Glp2r-/- mice exhibited a slight reduction in small intestinal mucosa volume. Pharmacological treatment with GLP-1 and GLP-2 analogs significantly increased gut volume. In contrast, VSG surgery had no effect on intestinal morphology. CONCLUSION The present study indicates that the endogenous preproglucagon system, exemplified by the entire GCG gene and the receptors for GLP-1 and GLP-2, does not play a major role in normal gut development in the mouse. Furthermore, elevation in local intestinal and circulating levels of GLP-1 and GLP-2 achieved after VSG has limited impact on intestinal morphometry. Hence, although exogenous treatment with GLP-1 and GLP-2 analogs enhances gut growth, the contributions of endogenously-secreted GLP-1 and GLP-2 to gut growth may be more modest and highly context-dependent.
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Affiliation(s)
| | | | - Thomas Secher
- Gubra Aps, Hørsholm Kongevej 11B, DK-2970 Hørsholm, Denmark
| | - Niels Vrang
- Gubra Aps, Hørsholm Kongevej 11B, DK-2970 Hørsholm, Denmark
| | | | | | - Laurie L. Baggio
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G1X5, Canada
| | - Jacqueline A. Koehler
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G1X5, Canada
| | - Daniel J. Drucker
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G1X5, Canada
| | | | - Jacob Jelsing
- Gubra Aps, Hørsholm Kongevej 11B, DK-2970 Hørsholm, Denmark
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Cavin JB, Bado A, Le Gall M. Intestinal Adaptations after Bariatric Surgery: Consequences on Glucose Homeostasis. Trends Endocrinol Metab 2017; 28:354-364. [PMID: 28209316 DOI: 10.1016/j.tem.2017.01.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 01/16/2017] [Accepted: 01/17/2017] [Indexed: 12/25/2022]
Abstract
The gastrointestinal (GI) tract can play a direct role in glucose homeostasis by modulating the digestion and absorption of carbohydrates and by producing the incretin hormones. In recent years, numerous studies have focused on intestinal adaptation following bariatric surgeries. Changes in the number of incretin (glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide) producing cells have been reported, which could result in the modified hormonal response seen after surgery. In addition, the rate of absorption and the intestinal regions exposed to sugars may affect the time course of appearance of glucose in the blood. This review gives new insights into the direct role of the GI tract in the metabolic outcomes of bariatric surgery, in the context of glucose homeostasis.
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Affiliation(s)
- Jean-Baptiste Cavin
- Inserm UMR 1149, UFR de Médecine Paris Diderot, Université Paris Diderot, Sorbonne Paris Cité, DHU Unity AP-HP, F-75890 Paris, France
| | - André Bado
- Inserm UMR 1149, UFR de Médecine Paris Diderot, Université Paris Diderot, Sorbonne Paris Cité, DHU Unity AP-HP, F-75890 Paris, France
| | - Maude Le Gall
- Inserm UMR 1149, UFR de Médecine Paris Diderot, Université Paris Diderot, Sorbonne Paris Cité, DHU Unity AP-HP, F-75890 Paris, France.
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McGavigan AK, Henseler ZM, Garibay D, Butler SD, Jayasinghe S, Ley RE, Davisson RL, Cummings BP. Vertical sleeve gastrectomy reduces blood pressure and hypothalamic endoplasmic reticulum stress in mice. Dis Model Mech 2017; 10:235-243. [PMID: 28093508 PMCID: PMC5374323 DOI: 10.1242/dmm.027474] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 01/04/2017] [Indexed: 12/13/2022] Open
Abstract
Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes remarkable improvements in cardiometabolic health, including hypertension remission. However, the mechanisms responsible remain undefined and poorly studied. Therefore, we developed and validated the first murine model of VSG that recapitulates the blood pressure-lowering effect of VSG using gold-standard radiotelemetry technology. We used this model to investigate several potential mechanisms, including body mass, brain endoplasmic reticulum (ER) stress signaling and brain inflammatory signaling, which are all critical contributors to the pathogenesis of obesity-associated hypertension. Mice fed on a high-fat diet underwent sham or VSG surgery and radiotelemeter implantation. Sham mice were fed ad libitum or were food restricted to match their body mass to VSG-operated mice to determine the role of body mass in the ability of VSG to lower blood pressure. Blood pressure was then measured in freely moving unstressed mice by radiotelemetry. VSG decreased energy intake, body mass and fat mass. Mean arterial blood pressure (MAP) was reduced in VSG-operated mice compared with both sham-operated groups. VSG-induced reductions in MAP were accompanied by a body mass-independent decrease in hypothalamic ER stress, hypothalamic inflammation and sympathetic nervous system tone. Assessment of gut microbial populations revealed VSG-induced increases in the relative abundance of Gammaproteobacteria and Enterococcus, and decreases in Adlercreutzia. These results suggest that VSG reduces blood pressure, but this is only partly due to the reduction in body weight. VSG-induced reductions in blood pressure may be driven by a decrease in hypothalamic ER stress and inflammatory signaling, and shifts in gut microbial populations. Summary: Vertical sleeve gastrectomy in mice decreases blood pressure independent of body mass, which may be due to a decrease in hypothalamic ER stress.
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Affiliation(s)
- Anne K McGavigan
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Zachariah M Henseler
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.,Department of Microbiome Science, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany
| | - Darline Garibay
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Scott D Butler
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Sisitha Jayasinghe
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Ruth E Ley
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.,Department of Microbiome Science, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany
| | - Robin L Davisson
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.,Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
| | - Bethany P Cummings
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
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Leung M, Wong VW, Durmush E, Phan V, Xie M, Leung DY. Cardiac dysfunction in type II diabetes: a bittersweet, weighty problem, or both? Acta Diabetol 2017; 54:91-100. [PMID: 27696068 PMCID: PMC5263192 DOI: 10.1007/s00592-016-0911-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 09/01/2016] [Indexed: 11/30/2022]
Abstract
AIMS Weight loss in obese patients leads to improved left ventricular (LV) function. It is unclear whether improving glycaemic control has additional benefits to weight loss alone in patients with type 2 diabetes, or if benefits of weight loss are mediated through improving glycaemic control. This case-control study examined the incremental impact of these approaches on LV function. METHODS Three groups of age, gender, and baseline HbA1c-matched patients with type 2 diabetes and suboptimal glycaemic control were followed-up for 12 months. Group 1 patients did not improve HbA1c ≥ 1 % (10.9 mmol/mol) or lose weight. Group 2 improved HbA1c ≥ 1 % but did not lose weight. Group 3 improved HbA1c ≥ 1 % (10.9 mmol/mol) and lost weight. All patients underwent transthoracic echocardiogram at baseline and at follow-up. RESULTS At baseline, three groups were comparable in all clinical and metabolic parameters except Group 3 had highest body mass index. The three groups had similar echocardiographic parameters except Group 3 had the worst LV systolic function [global longitudinal strain (GLS)]. At follow-up, LV ejection fraction and diastolic function improved with a reduction in filling pressures in Group 2 and more so in Group 3. LV filling pressures in Group 1 increased. There was a significant improvement in GLS in Group 2 and more so in Group 3. Despite GLS being the worst in Group 3 at baseline, this was comparable between Groups 2 and 3 at follow-up. CONCLUSIONS In overweight patients with type 2 diabetes, weight loss and improved glycaemic control had additive beneficial effects on improving LV systolic and diastolic function.
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Affiliation(s)
- Melissa Leung
- Department of Cardiology, Liverpool Hospital, South Western Sydney Clinical School, University of New South Wales, Locked Bag 7103, Liverpool BC, NSW, 1871, Australia.
- Ingham Institute for Applied Medical Research, Sydney, NSW, Australia.
- Leiden University Medical Centre, Leiden, The Netherlands.
| | - Vincent W Wong
- Ingham Institute for Applied Medical Research, Sydney, NSW, Australia
- Liverpool Diabetes Collaborative Research Unit, South Western Sydney Clinical School, University of New South Wales, Locked Bag 7103, Liverpool BC, NSW, 1871, Australia
| | | | - Victoria Phan
- Department of Cardiology, Liverpool Hospital, South Western Sydney Clinical School, University of New South Wales, Locked Bag 7103, Liverpool BC, NSW, 1871, Australia
- Ingham Institute for Applied Medical Research, Sydney, NSW, Australia
| | - Mikey Xie
- Department of Cardiology, Liverpool Hospital, South Western Sydney Clinical School, University of New South Wales, Locked Bag 7103, Liverpool BC, NSW, 1871, Australia
- Ingham Institute for Applied Medical Research, Sydney, NSW, Australia
| | - Dominic Y Leung
- Department of Cardiology, Liverpool Hospital, South Western Sydney Clinical School, University of New South Wales, Locked Bag 7103, Liverpool BC, NSW, 1871, Australia
- Ingham Institute for Applied Medical Research, Sydney, NSW, Australia
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Major P, Wysocki M, Pędziwiatr M, Małczak P, Pisarska M, Budzyński A. Laparoscopic sleeve gastrectomy for the treatment of diabetes mellitus type 2 patients-single center early experience. Gland Surg 2016; 5:465-472. [PMID: 27867860 DOI: 10.21037/gs.2016.09.04] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND In recent years, laparoscopic sleeve gastrectomy (LSG) has become one of the most commonly used primary bariatric procedures for morbid obesity. While laparoscopic Roux-en-Y gastric bypass (LRYGB) has well documented positive clinical influence on type 2 diabetes, the role of LSG in diabetes treatment is debatable. The main aim of this study is to present our early experience in LSG as a method of bariatric treatment in patients with type 2 diabetes or abnormalities in glucose homeostasis. METHODS Prospectively collected data of patients operated for morbid obesity at the 2nd Department of Surgery. The study was designed to assess the influence of LSG on type 2 diabetes and glucose homeostasis. The primary endpoint was the diabetes type 2 remission. Secondary endpoint was the change of glucose metabolism parameters after LSG. Patients were assessed preoperatively and allocated to two groups: group 1-with any preoperative abnormalities in glucose homeostasis (prediabetes, diabetes) and group 2-with non-elevated fasting glucose level. During follow-up (6 months after surgery) all glucose homeostasis parameters were analyzed again. One hundred and thirty-six patients after LSG were enrolled in the study (90 females, 46 males; mean age 40.5±9.9 years). Preoperative abnormalities in glucose homeostasis were confirmed in 64 (47%) patients. Twenty (15%) patients in this group had diabetes. RESULTS We observed significant reduction of body mass index (BMI) after surgery. Mean percent of EBMIL for all groups after 6 months from surgery was 59.90% (46.75-69.28%). There were no full remissions after surgery in patients with preoperative diabetes. We found significant improvement in biochemical markers of glucose homeostasis. We observed significant reduction of HbA1c% after surgery in both groups. The level of postoperative HbA1c% was related to BMI loss after surgery. CONCLUSIONS LSG leads to significant improvement in biochemical glucose homeostasis and can be considered as a method of treatment in morbidly obese patients with glucose metabolism abnormalities. LSG as a method of treatment for patients with clinical type 2 diabetes still needs some further observation.
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Affiliation(s)
- Piotr Major
- 2nd Department of General Surgery, Jagiellonian University Medical College, Kraków, Poland
| | - Michal Wysocki
- Students' Scientific Group at 2nd Department of Surgery, Jagiellonian University Medical College, Kraków, Poland
| | - Michał Pędziwiatr
- 2nd Department of General Surgery, Jagiellonian University Medical College, Kraków, Poland
| | - Piotr Małczak
- 2nd Department of General Surgery, Jagiellonian University Medical College, Kraków, Poland
| | - Magdalena Pisarska
- 2nd Department of General Surgery, Jagiellonian University Medical College, Kraków, Poland
| | - Andrzej Budzyński
- 2nd Department of General Surgery, Jagiellonian University Medical College, Kraków, Poland
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