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Jeerawattanawart S, Angkasekwinai P. Intestinal IL-25 prevents high-fat diet-induced obesity by modulating the cholesterol transporter NPC1L1 expression in the intestinal epithelial cells. Sci Rep 2025; 15:10445. [PMID: 40140439 PMCID: PMC11947149 DOI: 10.1038/s41598-025-95516-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 03/21/2025] [Indexed: 03/28/2025] Open
Abstract
The intestine is essential for digestion and nutrient absorption, and its altered function contributes to metabolic dysregulation and obesity-induced intestinal inflammation. Intestinal immune responses have been associated with the regulation of metabolic dysfunction during obesity. Given that the epithelial cell-derived cytokine IL-25 has been demonstrated to regulate metabolic disorders, we sought to examine the role of intestinal IL-25 in modulating a high-fat diet (HFD)-induced obesity. We found that mice on a high-fat diet exhibited decreased IL-25 expression in the small intestine. Intestinal IL-25 mRNA levels displayed an inverse association with plasma triglycerides, total cholesterol, glucose levels, and the expression of the cholesterol transporter Npc1l1 in the intestine. In HFD-induced obesity, transgenic mice overexpressing IL-25 in the intestinal epithelial cells demonstrated diminished mRNA expression of intestinal genes related to glucose, cholesterol, and fat absorption, along with chylomicron production, while also systemically decreasing plasma glucose, total cholesterol, and triglyceride levels, fat accumulation, and weight gain. In vitro, IL-25 treatment of human intestinal Caco-2 cells directly decreased cholesterol uptake and downregulated the expression of NPC1L1 and its transcriptional regulator, SREBP2. These findings highlight IL-25 as a potential modulator in the intestine that regulates intestinal cholesterol absorption and systemic metabolism in obesity.
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Affiliation(s)
- Siranart Jeerawattanawart
- Department of Medical Technology, Faculty of Allied Health Sciences, Thammasat University, Pathum Thani, 12120, Thailand
- Faculty of Medical Technology, Rangsit University, Pathum Thani, 12000, Thailand
| | - Pornpimon Angkasekwinai
- Department of Medical Technology, Faculty of Allied Health Sciences, Thammasat University, Pathum Thani, 12120, Thailand.
- Research Unit in Molecular Pathogenesis and Immunology of Infectious Diseases, Thammasat University, Pathum Thani, 12120, Thailand.
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Ribeiro FM, Arnaldo L, P Milhomem L, S Aguiar S, Franco OL. The intricate relationship between circadian rhythms and gastrointestinal peptides in obesity. Peptides 2025; 185:171356. [PMID: 39929256 DOI: 10.1016/j.peptides.2025.171356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 02/03/2025] [Accepted: 02/04/2025] [Indexed: 02/17/2025]
Abstract
There are different molecular pathways that regulate appetite, particularly the role of the hypothalamus, circadian rhythms, and gastrointestinal peptides. The hypothalamus integrates signals from orexigenic peptides like neuropeptide Y (NPY) and agouti-related protein (AgRP), which stimulate appetite, and anorexigenic peptides such as pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), which promote satiety. These signals are influenced by peripheral hormones like leptin, ghrelin, insulin, and cortisol, as well as gut peptides including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK). The circadian rhythm, regulated by proteins like circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1), modulates the secretion of these peptides, aligning feeding behaviors with the sleep-wake cycle. In obesity, these regulatory systems are disrupted, leading to leptin resistance, increased ghrelin sensitivity, and altered gut peptide secretion. This results in heightened appetite and impaired satiety, contributing to overeating and metabolic dysfunction. Additionally, circadian disruptions further impair metabolic processes, exacerbating obesity. The present article underscores the importance of understanding the molecular interplay between circadian rhythms and gastrointestinal peptides, particularly in the context of obesity. While some molecular interactions, such as the regulation of GLP-1 and PYY by reverberation of circadian rhythm α (REV-ERBα) and retinoic acid-related orphan receptor α (RORα), are well-established, clinical studies are scarce. Future research is expected to explore these pathways in obesity management, especially with the rise of incretin-based treatments like semaglutide. A deeper understanding of hypothalamic molecular mechanisms could lead to novel pharmacological and non-pharmacological therapies for obesity.
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Affiliation(s)
- Filipe M Ribeiro
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, DF, Brazil
| | - Luiz Arnaldo
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, DF, Brazil; Postgraduate Program in Molecular Pathology, University of Brasília, Brasília, DF, Brazil
| | - Lana P Milhomem
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, DF, Brazil
| | - Samuel S Aguiar
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, DF, Brazil
| | - Octavio L Franco
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, DF, Brazil; Postgraduate Program in Molecular Pathology, University of Brasília, Brasília, DF, Brazil; S-Inova Biotech, Catholic University Dom Bosco, Biotechnology Program, Campo Grande, MS, Brazil.
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Sellami E, Evangelista-Silva PH, Jordão Teixeira C, Diop K, Mitchell P, Forato Anhê F. High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice. Mol Metab 2025; 93:102101. [PMID: 39855562 PMCID: PMC11830333 DOI: 10.1016/j.molmet.2025.102101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/07/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
OBJECTIVE Increased fructose consumption contributes to type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms are ill-defined. Gut nutrient sensing involves enterohormones like Glucagon-like peptide (Glp)2, which regulates the absorptive capacity of luminal nutrients. While glucose is the primary dietary energy source absorbed in the gut, it is unknown whether excess fructose alters gut glucose sensing to impair blood glucose regulation and liver homeostasis. METHODS Mice were fed diets where carbohydrates were either entirely glucose (70 %Kcal) or glucose partially replaced with fructose (8.5 %Kcal). Glp2 receptor (Glp2r) was inhibited with Glp2 (3-33) injections. Glucose tolerance, insulin sensitivity, and gut glucose absorption were concomitantly assessed, and enteric sugar transporters and absorptive surface were quantified by RT-qPCR and histological analysis, respectively. RESULTS High fructose feeding led to impairment of blood glucose disposal, ectopic fat accumulation in the liver, and hepatic (but not muscle or adipose tissue) insulin resistance independent of changes in fat mass. This was accompanied by increased gut glucose absorption, which preceded glucose intolerance and liver steatosis. Fructose upregulated glucose transporters and enlarged the gut surface, but these effects were prevented by Glp2r inhibition. Blocking Glp2r prevented fructose-induced impairments in glucose disposal and hepatic lipid handling. CONCLUSION Excess fructose impairs blood glucose and liver homeostasis by rewiring gut glucose sensing and exacerbating gut glucose absorption. Our findings are positioned to inform novel early diagnostic tools and treatments tailored to counter high fructose-induced metabolic derangements predisposing to T2D and MASLD.
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Affiliation(s)
- Eya Sellami
- Québec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Department of Medicine, Faculty of Medicine, Université Laval - 1050, Av. de la Médecine, Québec, QC, G1V 0A6, Canada; Institute of Nutrition and Functional Foods, Université Laval - 2440 Bd. Hochelaga, Québec, QC, G1V 0A6, Canada
| | - Paulo Henrique Evangelista-Silva
- Québec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo - 1524, Av. Prof. Lineu Prestes, Sao Paulo, SP, 05508-000, Brazil
| | - Caio Jordão Teixeira
- Québec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo - 1524, Av. Prof. Lineu Prestes, Sao Paulo, SP, 05508-000, Brazil
| | - Khoudia Diop
- Québec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Institute of Nutrition and Functional Foods, Université Laval - 2440 Bd. Hochelaga, Québec, QC, G1V 0A6, Canada
| | - Patricia Mitchell
- Québec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada
| | - Fernando Forato Anhê
- Québec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Department of Medicine, Faculty of Medicine, Université Laval - 1050, Av. de la Médecine, Québec, QC, G1V 0A6, Canada; Institute of Nutrition and Functional Foods, Université Laval - 2440 Bd. Hochelaga, Québec, QC, G1V 0A6, Canada.
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Badurdeen DS, Li Z, Lee JH, Ma T, Bhagwate AV, Latanich R, Dogiparthi A, Ordog T, Kovbasnjuk O, Kumbhari V, Foulke-Abel J. Dysregulated intestinal nutrient absorption in obesity is associated with epigenomic alterations in epithelia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.05.06.591758. [PMID: 38766131 PMCID: PMC11100618 DOI: 10.1101/2024.05.06.591758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Obesity is an epidemic with myriad health effects, but little is understood regarding individual obese phenotypes and how they may respond to therapy. Epigenetic changes associated with obesity have been detected in blood, liver, pancreas, and adipose tissues. Previous work using human organoids found that dietary glucose hyperabsorption is a steadfast trait in cultures derived from some obese subjects, but detailed transcriptional or epigenomic features of the intestinal epithelia associated with this persistent phenotype are unknown. This study evaluated differentially expressed genes and relative chromatin accessibility in intestinal organoids established from donors classified as non-obese, obese, or obese hyperabsorptive by body mass index and glucose transport assays. Transcriptomic analysis indicated that obese hyperabsorptive subject organoids have significantly upregulated dietary nutrient absorption transcripts and downregulated type I interferon targets. Chromatin accessibility and transcription factor footprinting predicted that enhanced HNF4G binding may promote the obese hyperabsorption phenotype. Quantitative RT-PCR assessment in organoids representing a larger subject cohort suggested that intestinal epithelial expression of CUBN, GIP, SLC5A11, and SLC2A5 were highly correlated with hyperabsorption. Thus, the obese hyperabsorption phenotype was characterized by transcriptional changes that support increased nutrient uptake by intestinal epithelia, potentially driven by differentially accessible chromatin. Recognizing unique intestinal phenotypes in obesity provides a new perspective in considering therapeutic targets and options to manage the disease.
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Affiliation(s)
- Dilhana S Badurdeen
- Division of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Zhen Li
- Division of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Jeong-Heon Lee
- Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine, and Pathology, and Center for Cell Signaling in Gastroenterology (C-SiG), Mayo Clinic, Rochester, MN 55905, USA
| | - Tao Ma
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Rachel Latanich
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Arjit Dogiparthi
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Tamas Ordog
- Department of Physiology and Biomedical Engineering, and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Olga Kovbasnjuk
- National Institute for General Medical Sciences, Bethesda, MD 20892, USA
| | - Vivek Kumbhari
- Division of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Jennifer Foulke-Abel
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Sibthorpe PEM, Fitzgerald DM, Sillence MN, de Laat MA. Studies in vitro of equine intestinal glucagon-like peptide-2 secretion. J Equine Vet Sci 2024; 142:105179. [PMID: 39197558 DOI: 10.1016/j.jevs.2024.105179] [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: 01/28/2024] [Revised: 05/29/2024] [Accepted: 08/25/2024] [Indexed: 09/01/2024]
Abstract
Equine insulin dysregulation (ID) is a significant metabolic problem because the hyperinsulinaemia that develops increases the animal's risk of developing laminitis, a debilitating foot condition. The role of gastrointestinal factors, such as incretin hormones, in the pathogenesis of ID and hyperinsulinaemia in horses is poorly understood, particularly in comparison to other species. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic peptide released from L cells in the gastrointestinal tract and is implicated in metabolic dysfunction in other species. The aim of this study in vitro was to establish basic physiological understanding about intestinal secretion of GLP-2 in horses. Basal and glucose-stimulated GLP-2 secretion was measured in post-mortem tissue samples from the duodenum, jejunum, and ileum. We observed that GLP-2 secretion was minimal in samples from the duodenum compared to the jejunum and ileum (5-9-fold higher; P < 0.05). Furthermore, GLP-2 secretion was not responsive to glucose stimulation in the ileum or duodenum but was responsive to glucose in the jejunum. This effect in the jejunum was inhibited by 30 % (P = 0.02) using phlorizin, a selective sodium-glucose cotransporter-1 (SGLT-1) inhibitor, and by 38 % (P = 0.04) using phloretin, a non-selective SGLT-1/GLUT-2 inhibitor. The localisation of glucose-responsive GLP-2 secretion in the jejunum might be relevant to the development of post-prandial hyperinsulinaemia. This study has provided data on GLP-2 secretion from the equine small intestine that will enable more complex and dynamic studies on the pathogenesis of ID.
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Affiliation(s)
- P E M Sibthorpe
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - D M Fitzgerald
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - M N Sillence
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - M A de Laat
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia.
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Boškoski I, Gualtieri L, Matteo MV. Small Bowel Therapies for Metabolic Disease and Obesity. Gastrointest Endosc Clin N Am 2024; 34:715-732. [PMID: 39277300 DOI: 10.1016/j.giec.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/17/2024]
Abstract
The small bowel has a crucial role in metabolic homeostasis. Small bowel endoscopic bariatric metabolic treatments (EBMTs) include several devices aimed at providing minimally invasive approaches for the management of metabolic disorders. The aim of this review is to provide an updated and exhaustive overview of the EBMTs targeting the small bowel developed to date, including the duodenal mucosa resurfacing, the duodenal-jejunal bypass liners, gastro-jejunal bypass sleeve, and the incisioneless magnetic anastomosis system, as well as to mention the future perspectives in the field.
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Affiliation(s)
- Ivo Boškoski
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy; Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Loredana Gualtieri
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy; Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Maria Valeria Matteo
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy; Università Cattolica del Sacro Cuore, Roma 00168, Italy.
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Tlais AZA, Polo A, Granehäll L, Filannino P, Vincentini O, De Battistis F, Di Cagno R, Gobbetti M. Sugar lowering in fermented apple-pear juice orchestrates a promising metabolic answer in the gut microbiome and intestinal integrity. Curr Res Food Sci 2024; 9:100833. [PMID: 39290653 PMCID: PMC11406026 DOI: 10.1016/j.crfs.2024.100833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/29/2024] [Accepted: 08/29/2024] [Indexed: 09/19/2024] Open
Abstract
Excessive sugar consumption in young people, who are the major consumers of sugary drinks, combined with limited physical activity, is an important determinant of obesity. Despite their natural appeal, fruit juices have a similar sugar content to that of sugary drinks and once metabolized, they may induce the same biological response. This study aimed to verify whether fermentation processes can make juice consumption healthier and whether reduced-sugar juices have a specific impact on intestinal function. We designed a tailored fermentation of apple-pear juices with lactic acid bacteria and yeasts, which resulted in a reduction of sugar content (27-66%) and caloric intake, and an increase in mannitol content. The impact of newly developed apple-pear juices on gut microbiome composition and functionality was evaluated in vitro using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). Promising changes were found in the gut microbiota and its metabolic responses and functionality, targeting pathways related to obesity and weight loss (lipopolysaccharide and secondary metabolite biosynthesis, polycyclic aromatic hydrocarbon degradation, and amino sugar and nucleotide sugar metabolism). Additionally, the fermented apple-pear juices positively modulated the intestinal epithelial features. While the simulation of the study simplifies the complex in vivo conditions, it suggests that low-sugar fermented apple-pear juices can elicit targeted responses in the gut ecosystem, contributing to healthier alternatives to traditional fruit juices.
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Affiliation(s)
- Ali Zein Alabiden Tlais
- Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano-Bozen, 39100, Bolzano, Italy
- International Center on Food Fermentation, 39100, Bolzano, Italy
| | - Andrea Polo
- Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano-Bozen, 39100, Bolzano, Italy
- International Center on Food Fermentation, 39100, Bolzano, Italy
| | - Lena Granehäll
- Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano-Bozen, 39100, Bolzano, Italy
| | - Pasquale Filannino
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, 70121, Bari, Italy
- International Center on Food Fermentation, 39100, Bolzano, Italy
| | - Olimpia Vincentini
- U.O Alimentazione, Nutrizione e Salute, Dipartimento Sicurezza Alimentare, Nutrizione e Sanità Pubblica Veterinaria, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Francesca De Battistis
- U.O Alimentazione, Nutrizione e Salute, Dipartimento Sicurezza Alimentare, Nutrizione e Sanità Pubblica Veterinaria, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Raffaella Di Cagno
- Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano-Bozen, 39100, Bolzano, Italy
- International Center on Food Fermentation, 39100, Bolzano, Italy
| | - Marco Gobbetti
- Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano-Bozen, 39100, Bolzano, Italy
- International Center on Food Fermentation, 39100, Bolzano, Italy
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Socha-Banasiak A, Sakowicz A, Gaj Z, Kolejwa M, Gach A, Czkwianianc E. Intestinal fructose transporters GLUT5 and GLUT2 in children and adolescents with obesity and metabolic disorders. Adv Med Sci 2024; 69:349-355. [PMID: 39059468 DOI: 10.1016/j.advms.2024.07.008] [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: 03/11/2024] [Revised: 06/19/2024] [Accepted: 07/23/2024] [Indexed: 07/28/2024]
Abstract
PURPOSE The excessive fructose intake including high-fructose corn syrup (HFCS) may be responsible for increase of obesity occurrence. This study was designed to find potential differences in duodenal fructose transporters on mRNA and protein levels between obese and normal weight children and adolescents. MATERIALS/METHODS We performed a cross-sectional study on a group of 106 hospitalized patients aged 12 to 18. Glucose transporter 2 (GLUT2) and glucose transporter 5 (GLUT5) mRNA as well as protein levels (ELISA and Western blot methods) were assessed in duodenal mucosa biopsies of the patients categorized as obese or normal weight. Additionally, the expression of the aforementioned transporters was analyzed in patients based on the presence of insulin resistance (IR) and metabolic syndrome (MS). RESULTS In children with obesity, increased duodenal protein levels of GLUT5 (Relative protein GLUT5 expression/ACTB) (0.027 ± 0.009 vs. 0.011 ± 0.006, p < 0.05) but not GLUT2 as compared with the normal weight group, were revealed. No significant differences in duodenal relative GLUT2 and GLUT5 genes expression between the studied groups were found. There was no relationship between the presence of IR or MS and intestinal mRNA GLUT2 and GLUT5 as well as GLUT2 protein expression. CONCLUSION The upregulation of the duodenal GLUT5 may contribute to obesity occurrence in children and adolescents.
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Affiliation(s)
- Anna Socha-Banasiak
- Department of Gastroenterology, Allergology and Pediatrics, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland.
| | - Agata Sakowicz
- Department of Medical Biotechnology, Medical University of Lodz, Lodz, Poland
| | - Zuzanna Gaj
- Center of Medical Laboratory Diagnostics and Screening, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
| | - Michał Kolejwa
- Department of Gastroenterology, Allergology and Pediatrics, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
| | - Agnieszka Gach
- Department of Genetics, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
| | - Elżbieta Czkwianianc
- Department of Gastroenterology, Allergology and Pediatrics, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
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Xia S, Jing R, Shi M, Yang Y, Feng M, Deng L, Luo L. BBR affects macrophage polarization via inhibition of NF-κB pathway to protect against T2DM-associated periodontitis. J Periodontal Res 2024; 59:728-737. [PMID: 38501225 DOI: 10.1111/jre.13246] [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: 05/30/2023] [Revised: 02/01/2024] [Accepted: 02/05/2024] [Indexed: 03/20/2024]
Abstract
BACKGROUND AND OBJECTIVE Periodontitis is intimately associated with the development of various systemic diseases, among which type 2 diabetes mellitus (T2DM) has a bidirectional relationship with the pathogenesis of periodontitis. The objective of the present work was to investigate the role of berberine (BBR) in periodontitis with T2DM and related mechanisms. METHODS The mRNA expression of macrophage polarization-related factors in the microenvironment of periodontal inflammation was detected using real-time quantitative PCR (RT-qPCR). The experimental periodontitis model was constructed in wild-type (WT) and T2DM (db/db) mice, which were administered BBR after 7 days of modeling. Alveolar bone loss (ABL) in each group of mice was measured utilizing micro-computed tomography images. RT-qPCR was performed to analyze the levels of macrophage polarization-related factors in mouse gingiva. Lastly, using western blotting and RT-qPCR, the signaling pathway of BBR affecting macrophage polarization in the microenvironment of periodontitis was explored. RESULTS BBR inhibited M1 polarization and stimulated M2 polarization in the periodontitis microenvironment. BBR decreased ABL in the WT and T2DM periodontitis models. And BBR reduced the production of proinflammatory cytokines and increased anti-inflammatory cytokine expression in the gingiva of WT and T2DM model mice. Ultimately, BBR mediates its anti-inflammatory effects on periodontitis through inhibition of the NF-κB pathway. CONCLUSIONS BBR had a therapeutic effect on T2DM-associated periodontitis via inhibiting the NF-κB pathway to affect macrophage polarization, which may have implications for the new pharmacological treatment of T2DM-associated periodontitis.
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Affiliation(s)
- Siying Xia
- Department of Periodontology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Rui Jing
- Department of Periodontology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Mingyan Shi
- Department of Periodontology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Yanan Yang
- Department of Periodontology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Meiting Feng
- Department of Periodontology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Li Deng
- Department of Periodontology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Lijun Luo
- Department of Periodontology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
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10
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Tao T, Shu Q, Zhao Y, Guo W, Wang J, Shi Y, Jia S, Zhai H, Chen H, Wang C, Xu G. Mechanical regulation of lipid and sugar absorption by Piezo1 in enterocytes. Acta Pharm Sin B 2024; 14:3576-3590. [PMID: 39220873 PMCID: PMC11365390 DOI: 10.1016/j.apsb.2024.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 09/04/2024] Open
Abstract
Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid. Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients. The response of intestinal epithelial cells to mechanical stimulation is not fully understood. Piezo1, a mechanosensitive ion channel, is widely expressed throughout the digestive tract. However, its function in intestinal nutrient absorption is not yet clear. In our study, excessive lipid deposition was observed in the duodenum of obese patients, while duodenal Piezo1-CaMKK2-AMPKα was decreased when compared to normal-weight individuals. Under high-fat diet condition, the Piezo1 iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver. These phenotypes were mainly caused by the inhibition of duodenal CaMKK2-AMPKα and the upregulation of SGLT1 and DGAT2. In contrast, Yoda1, a Piezo1 agonist, was found to reduce intestinal lipid absorption in diet induced obese mice. Overexpression of Piezo1, stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1, whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells. Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity.
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Affiliation(s)
- Tian Tao
- Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China
- Department of Metabolic and Bariatric Surgery, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Qing Shu
- Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Yawen Zhao
- Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Wenying Guo
- Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Jinting Wang
- Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Yuhao Shi
- Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Shiqi Jia
- Department of Metabolic and Bariatric Surgery, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Hening Zhai
- Endoscopy Center, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Hui Chen
- Biotherapy Center; Cell-gene Therapy Translational Medicine Research Center, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Cunchuan Wang
- Department of Metabolic and Bariatric Surgery, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Geyang Xu
- Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China
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Ribeiro FM, Anderson M, Aguiar S, Gabriela E, Petriz B, Franco OL. Systematic review and meta-analysis of gut peptides expression during fasting and postprandial states in individuals with obesity. Nutr Res 2024; 127:27-39. [PMID: 38843565 DOI: 10.1016/j.nutres.2024.04.007] [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: 02/01/2024] [Revised: 04/28/2024] [Accepted: 04/28/2024] [Indexed: 07/28/2024]
Abstract
Gut peptides play a role in signaling appetite control in the hypothalamus. Limited knowledge exists regarding the release of these peptides in individuals with obesity before and during external stimuli. We hypothesize that the expression of gut peptides is different in the fasting and postprandial states in the scenario of obesity. PubMed/MEDLINE, Scopus, and Science Direct electronic databases were searched. The meta-analysis was performed using Review Manager Software. Randomized controlled trials that measured gut peptides in both obese and lean subjects were included in the analysis. A total of 552 subjects with obesity were enrolled in 25 trials. The gut peptide profile did not show any significant difference between obese and lean subjects for glucagon-like peptide 1 (95% confidence interval [CI], -1.21 to 0.38; P = .30), peptide YY (95% CI, -1.47 to 0.18; P = .13), and cholecystokinin (95% CI, -1.25 to 1.28; P = .98). Gut peptides are decreased by an increased high-fat, high-carbohydrate diet and by decreased chewing. There is no statistically significant difference in gut peptides between individuals with obesity and leanness in a fasting state. However, the release of gut peptides is affected in individuals with obesity following external stimuli, such as dietary interventions and chewing. Further studies are necessary to investigate the relationship between various stimuli and the release of gut peptides, as well as their impact on appetite regulation in subjects with obesity.
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Affiliation(s)
- Filipe M Ribeiro
- Postgraduate Program in Physical Education, Catholic University of Brasilia, Brasilia, DF, Brazil; Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, DF, Brazil; Laboratory of Molecular Exercise Physiology - University Center - UDF, Brasilia, DF, Brazil
| | - Maycon Anderson
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, DF, Brazil; Laboratory of Molecular Exercise Physiology - University Center - UDF, Brasilia, DF, Brazil
| | - Samuel Aguiar
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, DF, Brazil; Laboratory of Molecular Exercise Physiology - University Center - UDF, Brasilia, DF, Brazil
| | - Elza Gabriela
- Laboratory of Molecular Exercise Physiology - University Center - UDF, Brasilia, DF, Brazil
| | - Bernardo Petriz
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, DF, Brazil; Laboratory of Molecular Exercise Physiology - University Center - UDF, Brasilia, DF, Brazil
| | - Octavio L Franco
- Postgraduate Program in Physical Education, Catholic University of Brasilia, Brasilia, DF, Brazil; Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, DF, Brazil; S-Inova Biotech, Catholic University Dom Bosco, Biotechnology Program, Campo Grande, MS, Brazil.
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12
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Peschard S, Raverdy V, Bauvin P, Goutchtat R, Touche V, Derudas B, Gheeraert C, Dubois-Chevalier J, Caiazzo R, Baud G, Marciniak C, Verkindt H, Oukhouya Daoud N, Le Roux CW, Lefebvre P, Staels B, Lestavel S, Pattou F. Genetic Evidence of Causal Relation Between Intestinal Glucose Absorption and Early Postprandial Glucose Response: A Mendelian Randomization Study. Diabetes 2024; 73:983-992. [PMID: 38498375 PMCID: PMC11109783 DOI: 10.2337/db23-0805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 03/01/2024] [Indexed: 03/20/2024]
Abstract
The postprandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium-glucose cotransporter 1 (SGLT1). This study uses Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1,547 subjects with class II/III obesity from the Atlas Biologique de l'Obésité Sévère cohort, the study uses SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype serves as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-min postload glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results show that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of -0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study links a 1-SD decrease in SGLT1 expression to a Δ30 glucose reduction of -0.097 mmol/L. MR analysis parallels these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decrease of -0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early postload glucose response. This finding has a potential translational impact on managing early glucose response to prevent or treat type 2 diabetes. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Simon Peschard
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1011 Nuclear Receptors, Metabolic and Cardiovascular Diseases, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
| | - Violeta Raverdy
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1190 Translational Research on Diabetes, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
- Department of General and Endocrine Surgery, CHU Lille, Lille, France
| | - Pierre Bauvin
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1190 Translational Research on Diabetes, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
| | - Rebecca Goutchtat
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1190 Translational Research on Diabetes, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
| | - Veronique Touche
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1011 Nuclear Receptors, Metabolic and Cardiovascular Diseases, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
| | - Bruno Derudas
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1011 Nuclear Receptors, Metabolic and Cardiovascular Diseases, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
| | - Celine Gheeraert
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1011 Nuclear Receptors, Metabolic and Cardiovascular Diseases, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
| | - Julie Dubois-Chevalier
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1011 Nuclear Receptors, Metabolic and Cardiovascular Diseases, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
| | - Robert Caiazzo
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1190 Translational Research on Diabetes, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
- Department of General and Endocrine Surgery, CHU Lille, Lille, France
| | - Gregory Baud
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1190 Translational Research on Diabetes, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
- Department of General and Endocrine Surgery, CHU Lille, Lille, France
| | - Camille Marciniak
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1190 Translational Research on Diabetes, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
- Department of General and Endocrine Surgery, CHU Lille, Lille, France
| | - Helene Verkindt
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1190 Translational Research on Diabetes, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
- Department of General and Endocrine Surgery, CHU Lille, Lille, France
| | - Naima Oukhouya Daoud
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1190 Translational Research on Diabetes, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
- Department of General and Endocrine Surgery, CHU Lille, Lille, France
| | - Carel W. Le Roux
- Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland
| | - Philippe Lefebvre
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1011 Nuclear Receptors, Metabolic and Cardiovascular Diseases, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
| | - Bart Staels
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1011 Nuclear Receptors, Metabolic and Cardiovascular Diseases, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
| | - Sophie Lestavel
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1011 Nuclear Receptors, Metabolic and Cardiovascular Diseases, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
| | - François Pattou
- European Genomic Institute for Diabetes, University Lille, Lille, France
- U1190 Translational Research on Diabetes, Institut Pasteur de Lille, CHU Lille, INSERM, University Lille, Lille, France
- Department of General and Endocrine Surgery, CHU Lille, Lille, France
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Walmsley R, Chong L, Hii MW, Brown RM, Sumithran P. The effect of bariatric surgery on the expression of gastrointestinal taste receptors: A systematic review. Rev Endocr Metab Disord 2024; 25:421-446. [PMID: 38206483 PMCID: PMC10942945 DOI: 10.1007/s11154-023-09865-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/11/2023] [Indexed: 01/12/2024]
Abstract
Gastrointestinal nutrient sensing via taste receptors may contribute to weight loss, metabolic improvements, and a reduced preference for sweet and fatty foods following bariatric surgery. This review aimed to investigate the effect of bariatric surgery on the expression of oral and post-oral gastrointestinal taste receptors and associations between taste receptor alterations and clinical outcomes of bariatric surgery. A systematic review was conducted to capture data from both human and animal studies on changes in the expression of taste receptors in oral or post-oral gastrointestinal tissue following any type of bariatric surgery. Databases searched included Medline, Embase, Emcare, APA PsychInfo, Cochrane Library, and CINAHL. Two human and 21 animal studies were included. Bariatric surgery alters the quantity of many sweet, umami, and fatty acid taste receptors in the gastrointestinal tract. Changes to the expression of sweet and amino acid receptors occur most often in intestinal segments surgically repositioned more proximally, such as the alimentary limb after gastric bypass. Conversely, changes to fatty acid receptors were observed more frequently in the colon than in the small intestine. Significant heterogeneity in the methodology of included studies limited conclusions regarding the direction of change in taste receptor expression induced by bariatric surgeries. Few studies have investigated associations between taste receptor expression and clinical outcomes of bariatric surgery. As such, future studies should look to investigate the relationship between bariatric surgery-induced changes to gut taste receptor expression and function and the impact of surgery on taste preferences, food palatability, and eating behaviour.Registration code in PROSPERO: CRD42022313992.
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Affiliation(s)
- Rosalind Walmsley
- Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Parkville, VIC, 3052, Australia
- Department of Surgery, St Vincent's Hospital Melbourne, University of Melbourne, Victoria, Australia
| | - Lynn Chong
- Department of Surgery, St Vincent's Hospital Melbourne, University of Melbourne, Victoria, Australia
| | - Michael W Hii
- Department of Surgery, St Vincent's Hospital Melbourne, University of Melbourne, Victoria, Australia
| | - Robyn M Brown
- Department of Pharmacology and Biochemistry, University of Melbourne, Victoria, Australia
| | - Priya Sumithran
- Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Parkville, VIC, 3052, Australia.
- Department of Surgery, Central Clinical School, Monash University, Victoria, Australia.
- Department of Endocrinology and Diabetes, Alfred Health, Victoria, Australia.
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14
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Silina NV, Mazurina NV, Ershova EV, Komshilova KA. The effect of sweeteners on carbohydrate metabolism, metabolic parameters and intestinal microbiota. OBESITY AND METABOLISM 2024; 21:58-67. [DOI: 10.14341/omet13020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The prevalence of obesity and type 2 diabetes continues to grow, which determines the need to develop new methods of prevention in order to reduce the population risks of developing these diseases. The current direction is to limit the consumption of easily digestible carbohydrates and use low-calorie or non-calorie sweeteners instead. Currently, there is an increase in the use of non-calorie sweeteners in the manufacture of food. In this regard, the study of their possible effects on metabolic processes is of great importance.This review presents studies that have shown different effects of non-calorie sweeteners on carbohydrate and fat metabolism, body weight, the composition of intestinal microbiota, as well as the regulation of eating behavior. Some studies show that low-calorie sugar substitutes can be used in obese people as part of a comprehensive weight loss program, as well as in patients with type 2 diabetes mellitus with the aim of reducing postprandial hyperglycemia. Other studies demonstrate the negative effect of a number of low-calorie sweeteners on carbohydrate metabolism.The main search for materials was carried out in Pubmed databases, eLIBRARY.ru, Google Scholar. Temporary search criteria 2012–2023 The relevant additional literature was included after a manual search in the literature lists of the included articles.
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15
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Sibthorpe PEM, Fitzgerald DM, Sillence MN, de Laat MA. Associations between feeding and glucagon-like peptide-2 in healthy ponies. Equine Vet J 2024; 56:309-317. [PMID: 37705248 DOI: 10.1111/evj.14004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 08/25/2023] [Indexed: 09/15/2023]
Abstract
BACKGROUND Gastrointestinal peptides, such as glucagon-like peptide-2 (GLP-2), could play a direct role in the development of equine hyperinsulinaemia. OBJECTIVES To describe the secretory pattern of endogenous GLP-2 over 24 h in healthy ponies and determine whether oral administration of a synthetic GLP-2 peptide increases blood glucose or insulin responses to feeding. STUDY DESIGN A cohort study followed by a randomised, controlled, cross-over study. METHODS In the cohort study, blood samples were collected every 2 h for 24 h in seven healthy ponies and plasma [GLP-2] was measured. In the cross-over study, 75 μg/kg bodyweight of synthetic GLP-2, or carrier only, was orally administered to 10 ponies twice daily for 10 days. The area under the curve (AUC0-3h ) of post-prandial blood glucose and insulin were determined before and after each treatment. RESULTS Endogenous [GLP-2] ranged from <0.55 to 1.95 ± 0.29 [CI 0.27] ng/mL with similar peak concentrations in response to meals containing 88-180 g of non-structural carbohydrate, that were ~4-fold higher (P < 0.001) than the overnight nadir. After GLP-2 treatment peak plasma [GLP-2] increased from 1.1 [0.63-1.37] ng/mL to 1.54 [1.1-2.31] ng/mL (28.6%; P = 0.002), and AUC0-3h was larger (P = 0.01) than before treatment. The peptide decreased (7%; P = 0.003) peak blood glucose responses to feeding from 5.33 ± 0.45 mmol/L to 5.0 ± 0.21 mmol/L, but not AUC0-3h (P = 0.07). There was no effect on insulin secretion. MAIN LIMITATIONS The study only included healthy ponies and administration of a single dose of GLP-2. CONCLUSIONS The diurnal pattern of GLP-2 secretion in ponies was similar to other species with no apparent effect of daylight. Although GLP-2 treatment did not increase post-prandial glucose or insulin responses to eating, studies using alternative dosing strategies for GLP-2 are required.
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Affiliation(s)
- Poppy E M Sibthorpe
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Danielle M Fitzgerald
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Martin N Sillence
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Melody A de Laat
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
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16
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De Vito F, Suraci E, Marasco R, Luzza F, Andreozzi F, Sesti G, Fiorentino TV. Association between higher duodenal levels of the fructose carrier glucose transporter-5 and nonalcoholic fatty liver disease and liver fibrosis. J Intern Med 2024; 295:171-180. [PMID: 37797237 DOI: 10.1111/joim.13729] [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] [Indexed: 10/07/2023]
Abstract
BACKGROUND An increased dietary fructose intake has been shown to exert several detrimental metabolic effects and contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). An augmented intestinal abundance of the fructose carriers glucose transporter-5 (GLUT-5) and glucose transporter-2 (GLUT-2) has been found in subjects with obesity and type 2 diabetes. Herein, we investigated whether elevated intestinal levels of GLUT-5 and GLUT-2, resulting in a higher dietary fructose uptake, are associated with NAFLD and its severity. METHODS GLUT-5 and GLUT-2 protein levels were assessed on duodenal mucosa biopsies of 31 subjects divided into 2 groups based on ultrasound-defined NAFLD presence who underwent an upper gastrointestinal endoscopy. RESULTS Individuals with NAFLD exhibited increased duodenal GLUT-5 protein levels in comparison to those without NAFLD, independently of demographic and anthropometric confounders. Conversely, no difference in duodenal GLUT-2 abundance was observed amongst the two groups. Univariate correlation analyses showed that GLUT-5 protein levels were positively related with body mass index, waist circumference, fasting and 2 h post-load insulin concentrations, and insulin resistance (IR) degree estimated by homeostatic model assessment of IR (r = 0.44; p = 0.02) and liver IR (r = 0.46; p = 0.03) indexes. Furthermore, a positive relationship was observed between duodenal GLUT-5 abundance and serum uric acid concentrations (r = 0.40; p = 0.05), a product of fructose metabolism implicated in NAFLD progression. Importantly, duodenal levels of GLUT-5 were positively associated with liver fibrosis risk estimated by NAFLD fibrosis score. CONCLUSION Increased duodenal GLUT-5 levels are associated with NAFLD and liver fibrosis. Inhibition of intestinal GLUT-5-mediated fructose uptake may represent a strategy for prevention and treatment of NAFLD.
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Affiliation(s)
- Francesca De Vito
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Evelina Suraci
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Raffaella Marasco
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Francesco Luzza
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Francesco Andreozzi
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, University of Rome-Sapienza, Rome, Italy
| | - Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
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17
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Zhang Y, Chen L, Gao J, Cheng Y, Luo F, Bai X, Ding H. Nutritive/non-nutritive sweeteners and high fat diet contribute to dysregulation of sweet taste receptors and metabolic derangements in oral, intestinal and central nervous tissues. Eur J Nutr 2023; 62:3149-3159. [PMID: 37537344 DOI: 10.1007/s00394-023-03187-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 05/31/2023] [Indexed: 08/05/2023]
Abstract
OBJECTIVES Overconsumption of non-nutritive sweeteners is associated with obesity, whereas the underlying mechanisms remain controversial. This study aimed to investigate the effects of long-term consumption of nutritive or non-nutritive sweeteners with or without high fat diet on sweet taste receptor expression in nutrient-sensing tissues and energy regulation dependent on sweet-sensing. METHODS 50 Male Sprague-Dawley rats (140-160 g) were assigned to 10 groups (n = 5/group). All received fructose at 2.5% or 10%, sucralose at 0.01% or 0.015% or water with a normal chow diet or high fat diet for 12 weeks. Food and drink intake were monitored daily. Oral glucose tolerance test and intraperitoneal glucose tolerance test were performed at week 10 and 11 respectively. Serum was obtained for measurement of biochemical parameters. Tongue, duodenum, jejunum, ileum, colon and hypothalamus were rapidly removed to assess gene expression. RESULTS Long-term consumption of sweeteners impaired glucose tolerance, increased calorie intake and body weight. A significant upregulation of sweet taste receptor expression was observed in all the four intestinal segments in groups fed 0.01% sucralose or 0.015% sucralose, most strikingly in the ileum, accompanied by elevated serum glucagon-like peptide-1 levels and up-regulated expression of sodium-dependent glucose cotransporter 1 and glucose transporter 2. A significant down-regulation in the tongue and hypothalamus was observed in groups fed 10% fructose or 0.015% sucralose, with alterations in hypothalamic appetite signals. The presence of high fat diet differentially modulates sweet taste perception in nutrient-sensing tissues. CONCLUSIONS Long-term consumption of whether nutritive sweeteners or non-nutritive sweeteners combined with high fat diet contribute to dysregulation of sweet taste receptor expression in oral, intestinal and central nervous tissues.
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Affiliation(s)
- Yiyuan Zhang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Lu Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Jiefang Gao
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Yahong Cheng
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Fei Luo
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Xinying Bai
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China
| | - Hong Ding
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Wuhan, 430000, China.
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18
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Bordier V, Teysseire F, Drewe J, Madörin P, Bieri O, Schmidt-Trucksäss A, Hanssen H, Beglinger C, Meyer-Gerspach AC, Wölnerhanssen BK. Effects of a 5-week intake of erythritol and xylitol on vascular function, abdominal fat and glucose tolerance in humans with obesity: a pilot trial. BMJ Nutr Prev Health 2023; 6:264-272. [PMID: 38618550 PMCID: PMC11009538 DOI: 10.1136/bmjnph-2023-000764] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/25/2023] [Indexed: 04/16/2024] Open
Abstract
Introduction Previous studies in humans and rats suggest that erythritol might positively affect vascular function, xylitol decrease visceral fat mass and both substances improve glycaemic control. The objective of this study was to investigate the impact of a 5-week intake of erythritol and xylitol on vascular function, abdominal fat and blood lipids, glucose tolerance, uric acid, hepatic enzymes, creatinine, gastrointestinal tolerance and dietary patterns in humans with obesity. Methods Forty-two participants were randomised to consume either 36 g erythritol, 24 g xylitol, or no substance daily for 5 weeks. Before and after the intervention, arterial stiffness (pulse wave velocity, arteriolar-to-venular diameter ratio), abdominal fat (liver volume, liver fat percentage, visceral and subcutaneous adipose tissue, blood lipids), glucose tolerance (glucose and insulin concentrations), uric acid, hepatic enzymes, creatinine, gastrointestinal tolerance and dietary patterns were assessed. Data were analysed by linear mixed effect model. Results The 5-week intake of erythritol and xylitol showed no statistically significant effect on vascular function. Neither the time nor the treatment effects were significantly different for pulse wave velocity (time effect: p=0.079, Cohen's D (95% CI) -0.14 (-0.54-0.25); treatment effect: p=0.792, Cohen's D (95% CI) control versus xylitol: -0.11 (-0.61-0.35), control versus erythritol: 0.05 (0.44-0.54), erythritol versus xylitol: 0.07 (-0.41-0.54)). There was no statistically significant effect on abdominal fat, glucose tolerance, uric acid, hepatic enzymes and creatinine. Gastrointestinal tolerance was good except for a few diarrhoea-related symptoms. Participants of all groups reduced their consumption of sweetened beverages and sweets compared with preintervention. Conclusions The 5-week intake of erythritol and xylitol showed no statistically significant effects on vascular function, abdominal fat, or glucose tolerance in people with obesity. Clinical trial registration NCT02821923.
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Affiliation(s)
- Valentine Bordier
- Metabolic Research Group, St. Clara Research Ltd, Basel, Switzerland
- Department of Clinical Research, Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Fabienne Teysseire
- Metabolic Research Group, St. Clara Research Ltd, Basel, Switzerland
- Department of Clinical Research, Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Jürgen Drewe
- Department of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland
| | - Philipp Madörin
- Department of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Oliver Bieri
- Department of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | | | - Henner Hanssen
- Department for Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Christoph Beglinger
- Department of Clinical Research, Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Anne Christin Meyer-Gerspach
- Metabolic Research Group, St. Clara Research Ltd, Basel, Switzerland
- Department of Clinical Research, Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Bettina K Wölnerhanssen
- Metabolic Research Group, St. Clara Research Ltd, Basel, Switzerland
- Department of Clinical Research, Faculty of Medicine, University of Basel, Basel, Switzerland
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Dobbie LJ, Cuthbertson DJ, Hydes TJ, Alam U, Zhao SS. Mendelian randomisation reveals Sodium-glucose Cotransporter-1 inhibition's potential in reducing Non-Alcoholic Fatty Liver Disease risk. Eur J Endocrinol 2023; 188:K33-K37. [PMID: 37343141 PMCID: PMC11188739 DOI: 10.1093/ejendo/lvad068] [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: 03/23/2023] [Revised: 04/22/2023] [Accepted: 05/24/2023] [Indexed: 06/23/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has no approved pharmacological treatments. Sodium-glucose cotransporter (SGLT)-1 is a glucose transporter that mediates small intestinal glucose absorption. We evaluated the impact of genetically proxied SGLT-1 inhibition (SGLT-1i) on serum liver transaminases and NAFLD risk. We used a missense variant, rs17683430, in the SLC5A1 gene (encoding SGLT1) associated with HbA1c in a genome-wide association study (n = 344 182) to proxy SGLT-1i. Outcome genetic data comprised 1483 NAFLD cases and 17 781 controls. Genetically proxied SGLT-1i was associated with reduced NAFLD risk (OR 0.36; 95%CI 0.15, 0.87; P = .023) per 1 mmol/mol HbA1c reduction, and with reductions in liver enzymes (alanine transaminase, aspartate transaminase, gamma-glutamyl transferase). Genetically proxied HbA1c, not specifically via SGLT-1i, was not associated with NAFLD risk. Colocalisation did not demonstrate genetic confounding. Overall, genetically proxied SGLT-1i is associated with improved liver health, this may be underpinned by SGLT-1-specific mechanisms. Clinical trials should evaluate the impact of SGLT-1/2 inhibitors on the prevention and treatment of NAFLD.
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Affiliation(s)
- Laurence J Dobbie
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, United Kingdom
- Department of Diabetes & Endocrinology, Guys Hospital, Guy's and St Thomas’ NHS Foundation Trust, London, SE1 9RT, United Kingdom
| | - Daniel J Cuthbertson
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, United Kingdom
- University Hospital Aintree, Liverpool University Hospitals NHS Foundation Trust, Liverpool, L9 7JR, United Kingdom
| | - Theresa J Hydes
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, United Kingdom
- University Hospital Aintree, Liverpool University Hospitals NHS Foundation Trust, Liverpool, L9 7JR, United Kingdom
| | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, United Kingdom
- University Hospital Aintree, Liverpool University Hospitals NHS Foundation Trust, Liverpool, L9 7JR, United Kingdom
| | - Sizheng Steven Zhao
- Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal and Dermatological Science, School of Biological Sciences, Faculty of Biological Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, United Kingdom
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20
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de Laat MA, Fitzgerald DM. Equine metabolic syndrome: Role of the enteroinsular axis in the insulin response to oral carbohydrate. Vet J 2023; 294:105967. [PMID: 36858344 DOI: 10.1016/j.tvjl.2023.105967] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 01/17/2023] [Accepted: 02/26/2023] [Indexed: 03/02/2023]
Abstract
Equine insulin dysregulation (ID) comprises amplified insulin responses to oral carbohydrates or insulin resistance, or both, which leads to sustained or periodic hyperinsulinaemia. Hyperinsulinaemia is important in horses because of its clear association with laminitis risk, and the gravity of this common sequela justifies the need for a better understanding of insulin and glucose homoeostasis in this species. Post-prandial hyperinsulinaemia is the more commonly identified component of ID and is diagnosed using tests that include an assessment of the gastrointestinal tract (GIT). There are several factors present in the GIT that either directly, or indirectly, enhance insulin secretion from the endocrine pancreas, and these factors are collectively referred to as the enteroinsular axis (EIA). A role for key components of the EIA, such as the incretin peptides glucagon-like peptide-1 and 2, in the pathophysiology of ID has been investigated in horses. By comparison, the function (and even existence) of many EIA peptides of potential importance, such as glicentin and oxyntomodulin, remains unexplored. The incretins that have been examined all increase insulin responses to oral carbohydrate through one or more mechanisms. This review presents what is known about the EIA in horses, and discusses how it might contribute to ID, then compares this to current understanding derived from the extensive studies undertaken in other species. Future directions for research are discussed and knowledge gaps that should be prioritised are suggested.
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Affiliation(s)
- Melody A de Laat
- School of Biology and Environmental Science, Faculty of Science, Queensland University of Technology, Brisbane 4000, Australia.
| | - Danielle M Fitzgerald
- School of Biology and Environmental Science, Faculty of Science, Queensland University of Technology, Brisbane 4000, Australia
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21
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Anhê FF, Zlitni S, Zhang SY, Choi BSY, Chen CY, Foley KP, Barra NG, Surette MG, Biertho L, Richard D, Tchernof A, Lam TKT, Marette A, Schertzer J. Human gut microbiota after bariatric surgery alters intestinal morphology and glucose absorption in mice independently of obesity. Gut 2023; 72:460-471. [PMID: 36008102 PMCID: PMC9933168 DOI: 10.1136/gutjnl-2022-328185] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/05/2022] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Bariatric surgery is an effective treatment for type 2 diabetes (T2D) that changes gut microbial composition. We determined whether the gut microbiota in humans after restrictive or malabsorptive bariatric surgery was sufficient to lower blood glucose. DESIGN Women with obesity and T2D had biliopancreatic diversion with duodenal switch (BPD-DS) or laparoscopic sleeve gastrectomy (LSG). Faecal samples from the same patient before and after each surgery were used to colonise rodents, and determinants of blood glucose control were assessed. RESULTS Glucose tolerance was improved in germ-free mice orally colonised for 7 weeks with human microbiota after either BPD-DS or LSG, whereas food intake, fat mass, insulin resistance, secretion and clearance were unchanged. Mice colonised with microbiota post-BPD-DS had lower villus height/width and crypt depth in the distal jejunum and lower intestinal glucose absorption. Inhibition of sodium-glucose cotransporter (Sglt)1 abrogated microbiota-transmissible improvements in blood glucose control in mice. In specific pathogen-free (SPF) rats, intrajejunal colonisation for 4 weeks with microbiota post-BPD-DS was sufficient to improve blood glucose control, which was negated after intrajejunal Sglt-1 inhibition. Higher Parabacteroides and lower Blautia coincided with improvements in blood glucose control after colonisation with human bacteria post-BPD-DS and LSG. CONCLUSION Exposure of rodents to human gut microbiota after restrictive or malabsorptive bariatric surgery improves glycaemic control. The gut microbiota after bariatric surgery is a standalone factor that alters upper gut intestinal morphology and lowers Sglt1-mediated intestinal glucose absorption, which improves blood glucose control independently from changes in obesity, insulin or insulin resistance.
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Affiliation(s)
- Fernando F Anhê
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Soumaya Zlitni
- Department of Genetics and Medicine, Stanford University, Stanford, California, USA
| | - Song-Yang Zhang
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Béatrice So-Yun Choi
- Quebec Heart and Lung Institute Research Centre, Laval University, Quebec, Quebec, Canada
| | - Cassandra Y Chen
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Kevin P Foley
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Nicole G Barra
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Michael G Surette
- Department of Medicine, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Laurent Biertho
- Quebec Heart and Lung Institute Research Centre, Laval University, Quebec, Quebec, Canada
| | - Denis Richard
- Quebec Heart and Lung Institute Research Centre, Laval University, Quebec, Quebec, Canada
| | - André Tchernof
- Quebec Heart and Lung Institute Research Centre, Laval University, Quebec, Quebec, Canada.,School of Nutrition, Laval University, Quebec, Quebec, Canada
| | - Tony K T Lam
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Andre Marette
- Quebec Heart and Lung Institute Research Centre, Laval University, Quebec, Quebec, Canada
| | - Jonathan Schertzer
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
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22
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Fiorentino TV, De Vito F, Suraci E, Marasco R, Hribal ML, Luzza F, Sesti G. Obesity and overweight are linked to increased sodium-glucose cotransporter 1 and glucose transporter 5 levels in duodenum. Obesity (Silver Spring) 2023; 31:724-731. [PMID: 36746764 DOI: 10.1002/oby.23653] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/03/2022] [Accepted: 10/23/2022] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Prior evidence indicates that individuals with obesity have an accelerated intestinal glucose absorption. This cross-sectional study evaluated whether those with overweight or obesity display higher duodenal protein levels of the glucose carriers sodium-glucose cotransporter 1 (SGLT-1), glucose transporter 2 (GLUT-2), and glucose transporter 5 (GLUT-5). METHODS SGLT-1, GLUT-2, and GLUT-5 protein levels were assessed on duodenal mucosa biopsies of 52 individuals without diabetes categorized on the basis of their BMI as lean, with overweight, or with obesity. RESULTS Individuals with overweight and obesity exhibited progressively increased duodenal protein levels of SGLT-1 and GLUT-5 as compared with the lean group. Conversely, no differences in duodenal GLUT-2 abundance were found among the three groups. Univariate analysis showed that SGLT-1 and GLUT-5 protein levels were positively correlated with BMI, waist circumference, 1-hour post-load glucose, fasting and post-load insulin, and insulin secretion and resistance levels. Furthermore, a positive relationship was detected between intestinal GLUT-5 levels and serum uric acid concentrations, a product of fructose metabolism known to be involved in the pathogenesis of obesity and its complications. CONCLUSIONS Individuals with overweight and obesity display enhanced duodenal SGLT-1 and GLUT-5 abundance, which correlates with increased postprandial glucose concentrations, insulin resistance, and hyperinsulinemia.
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Affiliation(s)
- Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Francesca De Vito
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Evelina Suraci
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Raffaella Marasco
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Marta Letizia Hribal
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Francesco Luzza
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, University of Rome-Sapienza, Rome, Italy
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23
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Yang J, van Dijk TH, Koehorst M, Havinga R, de Boer JF, Kuipers F, van Zutphen T. Intestinal Farnesoid X Receptor Modulates Duodenal Surface Area but Does Not Control Glucose Absorption in Mice. Int J Mol Sci 2023; 24:ijms24044132. [PMID: 36835544 PMCID: PMC9961586 DOI: 10.3390/ijms24044132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/18/2023] [Accepted: 02/10/2023] [Indexed: 02/22/2023] Open
Abstract
Bile acids facilitate the intestinal absorption of dietary lipids and act as signalling molecules in the maintenance of metabolic homeostasis. Farnesoid X receptor (FXR) is a bile acid-responsive nuclear receptor involved in bile acid metabolism, as well as lipid and glucose homeostasis. Several studies have suggested a role of FXR in the control of genes regulating intestinal glucose handling. We applied a novel dual-label glucose kinetic approach in intestine-specific FXR-/- mice (iFXR-KO) to directly assess the role of intestinal FXR in glucose absorption. Although iFXR-KO mice showed decreased duodenal expression of hexokinase 1 (Hk1) under obesogenic conditions, the assessment of glucose fluxes in these mice did not show a role for intestinal FXR in glucose absorption. FXR activation with the specific agonist GS3972 induced Hk1, yet the glucose absorption rate remained unaffected. FXR activation increased the duodenal villus length in mice treated with GS3972, while stem cell proliferation remained unaffected. Accordingly, iFXR-KO mice on either chow, short or long-term HFD feeding displayed a shorter villus length in the duodenum compared to wild-type mice. These findings indicate that delayed glucose absorption reported in whole-body FXR-/- mice is not due to the absence of intestinal FXR. Yet, intestinal FXR does have a role in the small intestinal surface area.
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Affiliation(s)
- Jiufang Yang
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
| | - Theo H. van Dijk
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
| | - Martijn Koehorst
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
| | - Rick Havinga
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
| | - Folkert Kuipers
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
- European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
- Correspondence: (F.K.); (T.v.Z.); Tel.: +31-58-288-2132 (F.K.)
| | - Tim van Zutphen
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
- Faculty Campus Fryslân, University of Groningen, 8911CE Leeuwarden, The Netherlands
- Correspondence: (F.K.); (T.v.Z.); Tel.: +31-58-288-2132 (F.K.)
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24
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Paulussen F, Kulkarni CP, Stolz F, Lescrinier E, De Graeve S, Lambin S, Marchand A, Chaltin P, In't Veld P, Mebis J, Tavernier J, Van Dijck P, Luyten W, Thevelein JM. The β2-adrenergic receptor in the apical membrane of intestinal enterocytes senses sugars to stimulate glucose uptake from the gut. Front Cell Dev Biol 2023; 10:1041930. [PMID: 36699012 PMCID: PMC9869975 DOI: 10.3389/fcell.2022.1041930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Accepted: 12/14/2022] [Indexed: 01/12/2023] Open
Abstract
The presence of sugar in the gut causes induction of SGLT1, the sodium/glucose cotransporter in intestinal epithelial cells (enterocytes), and this is accompanied by stimulation of sugar absorption. Sugar sensing was suggested to involve a G-protein coupled receptor and cAMP - protein kinase A signalling, but the sugar receptor has remained unknown. We show strong expression and co-localization with SGLT1 of the β2-adrenergic receptor (β 2-AR) at the enterocyte apical membrane and reveal its role in stimulating glucose uptake from the gut by the sodium/glucose-linked transporter, SGLT1. Upon heterologous expression in different reporter systems, the β 2-AR responds to multiple sugars in the mM range, consistent with estimated gut sugar levels after a meal. Most adrenergic receptor antagonists inhibit sugar signaling, while some differentially inhibit epinephrine and sugar responses. However, sugars did not inhibit binding of I125-cyanopindolol, a β 2-AR antagonist, to the ligand-binding site in cell-free membrane preparations. This suggests different but interdependent binding sites. Glucose uptake into everted sacs from rat intestine was stimulated by epinephrine and sugars in a β 2-AR-dependent manner. STD-NMR confirmed direct physical binding of glucose to the β 2-AR. Oral administration of glucose with a non-bioavailable β 2-AR antagonist lowered the subsequent increase in blood glucose levels, confirming a role for enterocyte apical β 2-ARs in stimulating gut glucose uptake, and suggesting enterocyte β 2-AR as novel drug target in diabetic and obese patients. Future work will have to reveal how glucose sensing by enterocytes and neuroendocrine cells is connected, and whether β 2-ARs mediate glucose sensing also in other tissues.
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Affiliation(s)
- Frederik Paulussen
- 1Center for Microbiology, VIB, Leuven-Heverlee, Belgium,2Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium
| | - Chetan P. Kulkarni
- 1Center for Microbiology, VIB, Leuven-Heverlee, Belgium,3Functional Genomics and Proteomics Research Unit, Department of Biology, KU Leuven, Leuven, Belgium
| | - Frank Stolz
- 1Center for Microbiology, VIB, Leuven-Heverlee, Belgium,2Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium
| | - Eveline Lescrinier
- 4Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Stijn De Graeve
- 1Center for Microbiology, VIB, Leuven-Heverlee, Belgium,2Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium
| | - Suzan Lambin
- 1Center for Microbiology, VIB, Leuven-Heverlee, Belgium,2Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium
| | | | | | - Peter In't Veld
- 6Department of Pathology, Free University of Brussels, Brussels, Belgium
| | - Joseph Mebis
- 7Department of Pathology, KU Leuven, Flanders, Belgium
| | - Jan Tavernier
- 8Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium,9Center for Medical Biotechnology, VIB, Ghent, Belgium
| | - Patrick Van Dijck
- 1Center for Microbiology, VIB, Leuven-Heverlee, Belgium,2Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium
| | - Walter Luyten
- 3Functional Genomics and Proteomics Research Unit, Department of Biology, KU Leuven, Leuven, Belgium
| | - Johan M. Thevelein
- 1Center for Microbiology, VIB, Leuven-Heverlee, Belgium,2Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium,10NovelYeast bv, Bio-Incubator BIO4, Gaston Geenslaan 3, Leuven-Heverlee,, Belgium,*Correspondence: Johan M. Thevelein,
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25
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Nie L, Yan Q, Zhang S, Cao Y, Zhou X. Duodenal Mucosa: A New Target for the Treatment of Type 2 Diabetes. Endocr Pract 2023; 29:53-59. [PMID: 36309189 DOI: 10.1016/j.eprac.2022.10.177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 01/11/2023]
Abstract
OBJECTIVE After a high-fat and high-sugar diet, the duodenal mucosa of rodents proliferate and trigger the signal of insulin resistance, which may be the cause of type 2 diabetes (T2D). In response to this phenomenon, researchers have designed the duodenal mucosal resurfacing (DMR) procedure, mainly through the hydrothermal ablation procedure, to restore the normal mucosal surface, thereby correcting this abnormal metabolic signal. This article aims to understand the changes in duodenum before and after the onset or treatment of T2D, and the potential mechanisms of DMR procedure. METHODS A literature search of PubMed and Web of Science was conducted using appropriate keywords. RESULTS Both animal and clinical studies have shown that the villus thickness, intestinal cells, glucose transporters, enteric nerves, and gut microbiota and their metabolites in the duodenum undergo corresponding changes before and after the onset or treatment of T2D. These changes may be related to the pathogenesis of T2D. DMR procedure may produce beneficial glycemic and hepatic metabolic effects by regulating these changes. CONCLUSION The duodenum is an important metabolic signaling center, and limiting nutrient exposure to this critical region will have powerful metabolic benefits. The DMR procedure may regulate glycemic and hepatic parameters through various mechanisms, which needs to be further confirmed by a large number of animal and clinical studies.
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Affiliation(s)
- LiJuan Nie
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - QianHua Yan
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shu Zhang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - YuTian Cao
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - XiQiao Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
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26
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A self-powered ingestible wireless biosensing system for real-time in situ monitoring of gastrointestinal tract metabolites. Nat Commun 2022; 13:7405. [PMID: 36456568 PMCID: PMC9715945 DOI: 10.1038/s41467-022-35074-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 11/17/2022] [Indexed: 12/03/2022] Open
Abstract
Information related to the diverse and dynamic metabolite composition of the small intestine is crucial for the diagnosis and treatment of various diseases. However, our current understanding of the physiochemical dynamics of metabolic processes within the small intestine is limited due to the lack of in situ access to the intestinal environment. Here, we report a demonstration of a battery-free ingestible biosensing system for monitoring metabolites in the small intestine. As a proof of concept, we monitor the intestinal glucose dynamics on a porcine model. Battery-free operation is achieved through a self-powered glucose biofuel cell/biosensor integrated into a circuit that performs energy harvesting, biosensing, and wireless telemetry via a power-to-frequency conversion scheme using magnetic human body communication. Such long-term biochemical analysis could potentially provide critical information regarding the complex and dynamic small intestine metabolic profiles.
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27
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Abstract
Modern changes in diet and lifestyle have led to an explosion of insulin resistance and metabolic diseases around the globe which, if left unchecked, will become a principal driver of morbidity and mortality in the 21st century. The nature of the metabolic homeostatic shift within the body has therefore become a topic of considerable interest. While the gut has long been recognized as an acute nutrient sensor with signaling mechanisms to the other metabolic organs of the body, its role in regulating the body's metabolic status over longer periods of time has been underappreciated. Recent insights from bariatric surgery and intestinal nutrient stimulation experiments provide a window into the adaptive role of the intestinal mucosa in a foregut/hindgut metabolic balance model that helps to define metabolic parameters within the body-informing the metabolic regulation of insulin resistance versus sensitivity, hunger versus satiety, energy utilization versus energy storage, and protection from hypoglycemia versus protection from hyperglycemia. This intestinal metabolic balance model provides an intellectual framework with which to understand the distinct roles of proximal and distal intestinal segments in metabolic regulation. The model may also aid in the development of novel disease-modifying therapies that can correct the dysregulated metabolic signals from the intestine and stem the tide of metabolic diseases in society.
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Affiliation(s)
- Harith Rajagopalan
- Fractyl Health, Inc., Lexington,
MA, USA
- Harith Rajagopalan, M.D. PhD.,
Fractyl Health, Inc., 17 Hartwell Avenue, Lexington, MA 02421, USA.
| | | | - David C. Klonoff
- Diabetes Research Institute,
Mills-Peninsula Medical Center, San Mateo, California
| | - Alan D. Cherrington
- Department of Molecular
Physiology and Biophysics, Vanderbilt University School of Medicine,
Nashville, TN, USA
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28
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Sibthorpe PEM, Fitzgerald DM, Chen L, Sillence MN, de Laat MA. A starch-rich treat affects enteroinsular responses in ponies. J Am Vet Med Assoc 2022; 260:S94-S101. [PMID: 36191143 DOI: 10.2460/javma.22.06.0272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To determine the effect of a starch-rich treat, added to the daily diet of ponies for 10 days, on enteroinsular responses to meal consumption. ANIMALS 10 mixed-breed adult ponies owned by Queensland University of Technology were used in the study. Six ponies were metabolically healthy, and 4 were insulin dysregulated at the start of the study, according to the results of an in-feed oral glucose test. PROCEDURES A bread-based treat was offered twice daily for 10 days, adding 0.36 ± 0.04 g/kg body weight (BW) carbohydrates to the daily diet. Before and after treatment, the intestinal capacity for simple carbohydrate absorption was approximated with a modified D-xylose absorption test. Plasma glucagon-like peptide-2 (GLP-2), blood glucose, and serum insulin responses to eating were also measured before and after treatment. RESULTS The absorption of D-xylose (area under the curve [AUC]) increased 1.6-fold (P < .001) after 10 days of eating the treat. In addition, while basal (fasted) GLP-2 concentrations were not affected, GLP-2 AUC increased 1.4-fold in response to eating (P = .005). The treat did not change blood glucose or serum insulin concentrations, before, during, or after eating. CLINICAL RELEVANCE A small amount of additional carbohydrate each day in the form of a treat can cause a measurable change in the enteroinsular responses to eating.
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Affiliation(s)
- Poppy E M Sibthorpe
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, QLD, Australia
| | - Danielle M Fitzgerald
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, QLD, Australia
| | - Lan Chen
- Central Analytical Research Facility, Queensland University of Technology, Brisbane, QLD, Australia
| | - Martin N Sillence
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, QLD, Australia
| | - Melody A de Laat
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, QLD, Australia
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29
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Loos CMM, Urschel KL, Vanzant ES, Oberhaus EL, Bohannan AD, Klotz JL, McLeod KR. Effects of Bromocriptine on Glucose and Insulin Dynamics in Normal and Insulin Dysregulated Horses. Front Vet Sci 2022; 9:889888. [PMID: 35711802 PMCID: PMC9194999 DOI: 10.3389/fvets.2022.889888] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/09/2022] [Indexed: 12/04/2022] Open
Abstract
The objectives of the study were to study the effects of the synthetic ergot alkaloid (EA), bromocriptine, on glucose and lipid metabolism in insulin dysregulated (ID, n = 7) and non-ID (n = 8) mares. Horses were individually housed and fed timothy grass hay and two daily concentrate meals so that the total diet provided 120% of daily DE requirements for maintenance. All horses were given intramuscular bromocriptine injections (0.1 mg/kg BW) every 3 days for 14 days. Before and after 14 days of treatment horses underwent a combined glucose-insulin tolerance test (CGIT) to assess insulin sensitivity and a feed challenge (1 g starch/kg BW from whole oats) to evaluate postprandial glycemic and insulinemic responses. ID horses had higher basal plasma concentrations of insulin (P = 0.01) and triglycerides (P = 0.02), and lower concentrations of adiponectin (P = 0.05) compared with non-ID horses. The CGIT response curve showed that ID horses had slower glucose clearance rates (P = 0.02) resulting in a longer time in positive phase (P = 0.03) and had higher insulin concentrations at 75 min (P = 0.0002) compared with non-ID horses. Glucose (P = 0.02) and insulin (P = 0.04) responses to the feeding challenge were lower in non-ID compared to ID horses. Regardless of insulin status, bromocriptine administration increased hay intake (P = 0.03) and decreased grain (P < 0.0001) and total DE (P = 0.0002) intake. Bromocriptine treatment decreased plasma prolactin (P = 0.0002) and cholesterol (P = 0.10) and increased (P = 0.02) adiponectin concentrations in all horses. Moreover, in both groups of horses, bromocriptine decreased glucose clearance rates (P = 0.02), increased time in positive phase (P = 0.04) of the CGIT and increased insulin concentrations at 75 min (P = 0.001). The postprandial glycemic (P = 0.01) and insulinemic (P = 0.001) response following the oats meal was lower after bromocriptine treatment in all horses. In conclusion, in contrast to data in humans and rodents, bromocriptine treatment reduced insulin sensitivity in all horses, regardless of their insulin status. These results indicate that the physiological effects of EA might be different in horses compared to other species. Moreover, because bromocriptine shares a high degree of homology with natural EA, further investigation is warranted in horses grazing endophyte-infected grasses.
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Affiliation(s)
- Caroline M M Loos
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, United States
| | - Kristine L Urschel
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, United States
| | - Eric S Vanzant
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, United States
| | - Erin L Oberhaus
- School of Animal Sciences, Louisiana State University, Baton Rouge, LA, United States
| | - Adam D Bohannan
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, United States
| | - James L Klotz
- Forage-Animal Production Research Unit, Agricultural Research Service, United States Department of Agriculture, Lexington, KY, United States
| | - Kyle R McLeod
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, United States
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Zhang X, Cheng Z, Dong S, Rayner C, Wu T, Zhong M, Zhang G, Wang K, Hu S. Effects of ileal glucose infusion on enteropancreatic hormone secretion in humans: relationship to glucose absorption. Metabolism 2022; 131:155198. [PMID: 35395220 DOI: 10.1016/j.metabol.2022.155198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/13/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUNDS The distal small intestine plays an important role in regulating the secretion of entero-pancreatic hormones that are critical to the control of glucose metabolism and appetite, but the quantitative contribution of a specific segment to these effects is unknown. PURPOSES To determine the effects of 30 cm of the ileum exposed to glucose on the secretion of ghrelin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) insulin, C-peptide and glucagon, in relation to glucose absorption in non-diabetic subjects. BASIC PROCEDURES 10 non-diabetic subjects with a loop ileostomy after early-stage rectal cancer resection were studied on 2 days in a double-blind, randomized and crossover fashion, when a catheter was inserted retrogradely 30 cm from the ileostomy for infusion of a glucose solution containing 30 g glucose and 3 g 3-O-methylglucose (as a marker of active glucose absorption), or 0.9% saline, over 60 min. Ghrelin, GIP, GLP-1, insulin, C-peptide, glucagon and ileal glucose absorption (from concentrations of 3-O-methylglucose in serum and glucose in ileostomy effluent) were measured over 180 min. MAIN FINDINGS 12.0 ± 1.2 g glucose was absorbed over 180 min. Compared to saline, ileal glucose resulted in minimal increases in blood glucose and plasma insulin and C-peptide, but substantial increases in plasma GLP-1, without affecting ghrelin, GIP or glucagon. The magnitude of the GLP-1 response to glucose was strongly related to the increase in serum 3-O-methylglucose. PRINCIPAL CONCLUSIONS Stimulation of the terminal ileum by glucose, even over a short length (30 cm), induces substantial GLP-1 release, coupled primarily to active glucose absorption. CLINICAL REGISTRATION NCT05030376 (ClinicalTrials.gov).
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Affiliation(s)
- Xiang Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Zhiqiang Cheng
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Shuohui Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Christopher Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
| | - Mingwei Zhong
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China
| | - Guangyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China
| | - Kexin Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China.
| | - Sanyuan Hu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China; Shandong University, China.
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Fiorentino TV, De Vito F, Suraci E, Marasco R, Catalano F, Andreozzi F, Hribal ML, Luzza F, Sesti G. Augmented duodenal levels of sodium/glucose co-transporter 1 are associated with higher risk of nonalcoholic fatty liver disease and noninvasive index of liver fibrosis. Diabetes Res Clin Pract 2022; 185:109789. [PMID: 35192912 DOI: 10.1016/j.diabres.2022.109789] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/11/2022] [Accepted: 02/16/2022] [Indexed: 11/16/2022]
Abstract
AIMS Subjects with elevated 1 h post-load glucose concentrations (1hPG) exhibit increased risk of non-alcoholic fatty liver disease (NAFLD) and duodenal sodium/glucose co-transporter 1 (SGLT-1) levels. Herein, we evaluate whether higher SGLT-1 duodenal levels are associated with NAFLD and increased risk of advance liver fibrosis. METHODS SGLT-1 levels were assessed on duodenal mucosa in 52 individuals subdivided into two groups according to ultrasonography-defined presence of NAFLD. Intracellular triglycerides levels and activation of endoplasmic reticulum (ER) stress were evaluated in human hepatocytes exposed to high-glucose concentration (HG). RESULTS Individuals with NAFLD exhibited higher duodenal SGLT-1 abundance along with raised 1hPG, as compared to those without NAFLD. The mediation analysis showed that augmented duodenal SGLT-1 levels were a predictor of NAFLD, and the link between increased duodenal SGLT-1 content and NAFLD risk was mediated by augmented 1hPG. Amongst participants with NAFLD, those with intermediate/high probability of advance liver fibrosis, estimated by NAFLD fibrosis score, exhibited higher duodenal SGLT-1 abundance and 1hPG levels as compared to the low probability group. Hepatocytes exposed to HG showed increased triglycerides accumulation and an up-regulation of ER stress pathway. CONCLUSIONS Increased duodenal SGLT-1 abundance and the related early post-prandial hyperglycemia are associated with NAFLD and advance liver fibrosis.
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Affiliation(s)
- Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy.
| | - Francesca De Vito
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Evelina Suraci
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Raffaella Marasco
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Federica Catalano
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Francesco Andreozzi
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Marta Letizia Hribal
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Francesco Luzza
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, University of Rome-Sapienza, Rome 00189, Italy
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Xie F, Shen J, Liu T, Zhou M, Johnston LJ, Zhao J, Zhang H, Ma X. Sensation of dietary nutrients by gut taste receptors and its mechanisms. Crit Rev Food Sci Nutr 2022; 63:5594-5607. [PMID: 34978220 DOI: 10.1080/10408398.2021.2021388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Nutrients sensing is crucial for fundamental metabolism and physiological functions, and it is also an essential component for maintaining body homeostasis. Traditionally, basic taste receptors exist in oral cavity to sense sour, sweet, bitter, umami, salty and et al. Recent studies indicate that gut can sense the composition of nutrients by activating relevant taste receptors, thereby exerting specific direct or indirect effects. Gut taste receptors, also named as intestinal nutrition receptors, including at least bitter, sweet and umami receptors, have been considered to be activated by certain nutrients and participate in important intestinal physiological activities such as eating behavior, intestinal motility, nutrient absorption and metabolism. Additionally, gut taste receptors can regulate appetite and body weight, as well as maintain homeostasis via targeting hormone secretion or regulating the gut microbiota. On the other hand, malfunction of gut taste receptors may lead to digestive disorders, and then result in obesity, type 2 diabetes and gastrointestinal diseases. At present, researchers have confirmed that the brain-gut axis may play indispensable roles in these diseases via the secretion of brain-gut peptides, but the mechanism is still not clear. In this review, we summarize the current observation of knowledge in gut taste systems in order to shed light on revealing their important nutritional functions and promoting clinical implications.
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Affiliation(s)
- Fei Xie
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Jiakun Shen
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Tianyi Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Min Zhou
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Lee J Johnston
- West Central Research & Outreach Center, University of Minnesota, Morris, Minnesota, USA
| | - Jingwen Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Xi Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
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Ota T, Ishikawa T, Sakakida T, Endo Y, Matsumura S, Yoshida J, Hirai Y, Mizushima K, Oka K, Doi T, Okayama T, Inoue K, Kamada K, Uchiyama K, Takagi T, Konishi H, Naito Y, Itoh Y. Treatment with broad-spectrum antibiotics upregulates Sglt1 and induces small intestinal villous hyperplasia in mice. J Clin Biochem Nutr 2022; 70:21-27. [PMID: 35068677 PMCID: PMC8764108 DOI: 10.3164/jcbn.21-42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/02/2021] [Indexed: 11/22/2022] Open
Abstract
Although extensive evidence indicates that the gut microbiota plays a crucial role in regulating glucose homeostasis, the exact regulatory mechanism remains unclear. This study aimed to investigate the effect of broad-spectrum antibiotics on the expression of glucose transporters, histomorphology of the small intestine, and glucose metabolism in mice. C57BL/6 mice were administered drinking water with or without a broad-spectrum antibiotic combination for 4 weeks. Thereafter, an oral glucose tolerance test was performed. Body weight, small intestine histopathology, mRNA levels of glucose transporters (SGLT1 and GLUT2) and intestinal transcription factors (CDX1 and CDX2) were evaluated. SGLT1 and CDX1 were upregulated in the small intestine upon antibiotic administration compared with that in the control group. The height and surface area of the jejunal villi were significantly higher upon antibiotic administration than in the control group. Fasting glucose levels were significantly higher upon antibiotic administration than in the control group. The present results indicate that treatment with broad-spectrum antibiotics upregulates SGLT1 and CDX1 and induces hyperplasia in the small intestine, thus increasing fasting blood glucose levels. Our results further the current understanding of the effects of broad-spectrum antibiotics on the gut microbiota and glucose homeostasis that may have future clinical implications.
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Affiliation(s)
- Takayuki Ota
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Takeshi Ishikawa
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Tomoki Sakakida
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Yuki Endo
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Shinya Matsumura
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Juichirou Yoshida
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Yasuko Hirai
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Katsura Mizushima
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Kaname Oka
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Toshifumi Doi
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Tetsuya Okayama
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Ken Inoue
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Kazuhiro Kamada
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Kazuhiko Uchiyama
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Hideyuki Konishi
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Yuji Naito
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
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Bordier V, Teysseire F, Schlotterbeck G, Senner F, Beglinger C, Meyer-Gerspach AC, Wölnerhanssen BK. Effect of a Chronic Intake of the Natural Sweeteners Xylitol and Erythritol on Glucose Absorption in Humans with Obesity. Nutrients 2021; 13:nu13113950. [PMID: 34836205 PMCID: PMC8618859 DOI: 10.3390/nu13113950] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/01/2021] [Accepted: 11/02/2021] [Indexed: 02/07/2023] Open
Abstract
In patients with obesity, accelerated nutrients absorption is observed. Xylitol and erythritol are of interest as alternative sweeteners, and it has been shown in rodent models that their acute ingestion reduces intestinal glucose absorption. This study aims to investigate whether a chronic intake of xylitol and erythritol impacts glucose absorption in humans with obesity. Forty-six participants were randomized to take either 8 g of xylitol or 12 g of erythritol three times a day for five to seven weeks, or to be part of the control group (no substance). Before and after the intervention, intestinal glucose absorption was assessed during an oral glucose tolerance test with 3-Ortho-methyl-glucose (3-OMG). The effect of xylitol or erythritol intake on the area under the curve for 3-OMG concentration was not significant. Neither the time (pre or post intervention), nor the group (control, xylitol, or erythritol), nor the time-by-group interaction effects were significant (p = 0.829, p = 0.821, and p = 0.572, respectively). Therefore, our results show that a chronic intake of the natural sweeteners xylitol and erythritol does not affect intestinal glucose absorption in humans with obesity.
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Affiliation(s)
- Valentine Bordier
- St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland; (V.B.); (F.T.); (C.B.)
- Faculty of Medicine, University of Basel, 4001 Basel, Switzerland
| | - Fabienne Teysseire
- St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland; (V.B.); (F.T.); (C.B.)
- Faculty of Medicine, University of Basel, 4001 Basel, Switzerland
| | - Götz Schlotterbeck
- Institute for Chemistry and Bioanalytics, School of Life Science, FHNW University of Applied Sciences and Arts Northwestern Switzerland, 4132 Muttenz, Switzerland; (G.S.); (F.S.)
| | - Frank Senner
- Institute for Chemistry and Bioanalytics, School of Life Science, FHNW University of Applied Sciences and Arts Northwestern Switzerland, 4132 Muttenz, Switzerland; (G.S.); (F.S.)
| | - Christoph Beglinger
- St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland; (V.B.); (F.T.); (C.B.)
- Faculty of Medicine, University of Basel, 4001 Basel, Switzerland
| | - Anne Christin Meyer-Gerspach
- St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland; (V.B.); (F.T.); (C.B.)
- Faculty of Medicine, University of Basel, 4001 Basel, Switzerland
- Correspondence: (A.C.M.-G.); (B.K.W.); Tel.: +41-61-685-85-85 (A.C.M.-G. & B.K.W.)
| | - Bettina K. Wölnerhanssen
- St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland; (V.B.); (F.T.); (C.B.)
- Faculty of Medicine, University of Basel, 4001 Basel, Switzerland
- Correspondence: (A.C.M.-G.); (B.K.W.); Tel.: +41-61-685-85-85 (A.C.M.-G. & B.K.W.)
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Fiorentino TV, Suraci E, De Vito F, Cimellaro A, Hribal ML, Sciacqua A, Andreozzi F, Luzza F, Sesti G. One-hour post-load hyperglycemia combined with HbA1c identifies individuals with augmented duodenal levels of sodium/glucose co-transporter 1. Diabetes Res Clin Pract 2021; 181:109094. [PMID: 34662689 DOI: 10.1016/j.diabres.2021.109094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 10/20/2022]
Abstract
AIMS Individuals with HbA1c-defined prediabetes (HbA1c 5.7-6.4%) and 1-hour post-load plasma glucose (1hPG) ≥ 155 mg/dl have an increased risk to develop type 2 diabetes (T2DM). T2DM is associated with a higher intestinal expression of sodium/glucose co-transporter 1 (SGLT-1) and glucose transporter 2 (GLUT-2). It is currently unsettled whether HbA1c-defined dysglycemic conditions combined to 1hPG ≥ 155 mg/dl are associated with changes in SGLT-1 and GLUT-2 duodenal abundance. METHODS SGLT-1 and GLUT-2 protein levels were assessed by western blot on duodenal mucosa biopsies of 57 individuals underwent an upper gastrointestinal endoscopy. RESULTS Compared with the normal group (HbA1c < 5.7%), individuals with HbA1c-defined pre-diabetes and diabetes exhibit no significant change in duodenal SGLT-1 abundance. Conversely, duodenal GLUT-2 levels were progressively increased in subjects with prediabetes and diabetes. Stratifying participants according to HbA1c and 1hPG we found that amongst subjects with HbA1c-defined normal or prediabetes condition those having 1hPG ≥ 155 mg/dl displayed higher duodenal levels of SGLT-1 as compared to their counterparts with 1hPG < 155 mg/dl; in contrast to GLUT-2 levels, which were similar between normal and with prediabetes subjects, regardless of 1hPG value. CONCLUSION A value of 1hPG ≥ 155 mg/dl may identify a subset of individuals within HbA1c-defined glycemic categories having a higher duodenal abundance of SGLT-1.
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Affiliation(s)
- Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Evelina Suraci
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Francesca De Vito
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Antonio Cimellaro
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Marta Letizia Hribal
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Angela Sciacqua
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Francesco Andreozzi
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Francesco Luzza
- Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, University of Rome-Sapienza, Rome 00189, Italy.
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Involvement of Intestinal Goblet Cells and Changes in Sodium Glucose Transporters Expression: Possible Therapeutic Targets in Autistic BTBR T +Itpr3 tf/J Mice. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182111328. [PMID: 34769857 PMCID: PMC8583041 DOI: 10.3390/ijerph182111328] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/21/2021] [Accepted: 10/26/2021] [Indexed: 12/22/2022]
Abstract
Autism spectrum disorder is a neurodevelopmental syndrome with a complicated etiology and could be responsible for disrupted gastrointestinal tract microbiota. The aim of this work was to study intestinal samples from an autistic animal model (BTBR mouse strain) to better describe gastrointestinal alterations. We performed a morphological and biological evaluation of small intestine samples. In terms of morphology, we studied the goblet cells, cells of intestinal mucosal responsible for the production and maintenance of the protective mucous blanket. Alterations in their secretion may indicate an altered rate of mucus synthesis and this is one of the possible causes of gastrointestinal problems. In terms of biological evaluation, impaired regulation of glucose homeostasis regulated by sodium-glucose transporters has been suggested as an important component of obesity and associated comorbidities; therefore, this study analyzed the expression of sodium/glucose transporter-1 and -3 in BTBR mice to better define their role. We demonstrated that, in BTBR mice as compared to C57BL/6J (B6) strain animals: (1) The goblet cells had different protein content in their vesicles and apparently a larger number of Golgi cisternae; (2) the expression and level of sodium/glucose transporters were higher. These findings could suggest new possible targets in autism spectrum disorder to maintain mucus barrier function.
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Bhori M, Rastogi V, Tungare K, Marar T. A review on interplay between obesity, lipoprotein profile and nutrigenetics with selected candidate marker genes of type 2 diabetes mellitus. Mol Biol Rep 2021; 49:687-703. [PMID: 34669123 DOI: 10.1007/s11033-021-06837-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/12/2021] [Indexed: 12/06/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus, a rapidly growing epidemic, and its frequently related complications demand global attention. The two factors commonly attributed to the epidemic are genetic factors and environmental factors. Studies indicate that the genetic makeup at an individual level and the environmental aspects influence the occurrence of the disease. However, there is insufficiency in understanding the mechanisms through which the gene mutations and environmental components individually lead to T2DM. Also, discrepancies have often been noted in the association of gene variants and type 2 diabetes when the gene factor is examined as a sole attribute to the disease. STUDY In this review initially, we have focused on the proposed ways through which CAPN10, FABP2, GLUT2, TCF7L2, and ENPP1 variants lead to T2DM along with the inconsistencies observed in the gene-disease association. The article also emphasizes on obesity, lipoprotein profile, and nutrition as environmental factors and how they lead to T2DM. Finally, the main objective is explored, the environment-gene-disease association i.e. the influence of each environmental factor on the aforementioned specific gene-T2DM relationship to understand if the disease-causing capability of the gene variants is exacerbated by environmental influences. CONCLUSION We found that environmental factors may influence the gene-disease relationship. Reciprocally, the genetic factors may alter the environment-disease relationship. To precisely conclude that the two factors act synergistically to lead to T2DM, more attention has to be paid to the combined influence of the genetic variants and environmental factors on T2DM occurrence instead of studying the influence of the factors separately.
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Affiliation(s)
- Mustansir Bhori
- School of Biotechnology and Bioinformatics, D. Y. Patil Deemed To Be University, Navi Mumbai, 400614, India
| | - Varuni Rastogi
- School of Biotechnology and Bioinformatics, D. Y. Patil Deemed To Be University, Navi Mumbai, 400614, India
| | - Kanchanlata Tungare
- School of Biotechnology and Bioinformatics, D. Y. Patil Deemed To Be University, Navi Mumbai, 400614, India.
| | - Thankamani Marar
- School of Biotechnology and Bioinformatics, D. Y. Patil Deemed To Be University, Navi Mumbai, 400614, India
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Sun EW, Iepsen EW, Pezos N, Lumsden AL, Martin AM, Schober G, Isaacs NJ, Rayner CK, Nguyen NQ, de Fontgalland D, Rabbitt P, Hollington P, Wattchow DA, Hansen T, Holm JC, Liou AP, Jackson VM, Torekov SS, Young RL, Keating DJ. A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans. Gastroenterology 2021; 161:536-547.e2. [PMID: 33848536 DOI: 10.1053/j.gastro.2021.04.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/04/2021] [Accepted: 04/06/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. DESIGN GLP-1 and PYY levels were assessed in body mass index-matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. RESULTS Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. CONCLUSION Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders.
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Affiliation(s)
- Emily W Sun
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
| | - Eva W Iepsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Nektaria Pezos
- Nutrition, Diabetes and Metabolism, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, Australia; Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia
| | - Amanda L Lumsden
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
| | - Alyce M Martin
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
| | - Gudrun Schober
- Nutrition, Diabetes and Metabolism, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, Australia; Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia
| | - Nichole J Isaacs
- Nutrition, Diabetes and Metabolism, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, Australia; Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia
| | - Christopher K Rayner
- Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Nam Q Nguyen
- Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | | | - Philippa Rabbitt
- Department of Surgery, Flinders Medical Centre, Bedford Park, Australia
| | - Paul Hollington
- Department of Surgery, Flinders Medical Centre, Bedford Park, Australia
| | - David A Wattchow
- Department of Surgery, Flinders Medical Centre, Bedford Park, Australia
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Jens-Christian Holm
- The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Holbæk University Hospital, Holbæk, Denmark
| | - Alice P Liou
- Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts
| | - V Margaret Jackson
- Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts
| | - Signe S Torekov
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
| | - Richard L Young
- Nutrition, Diabetes and Metabolism, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, Australia; Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia.
| | - Damien J Keating
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, Australia.
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Mechanisms of Glucose Absorption in the Small Intestine in Health and Metabolic Diseases and Their Role in Appetite Regulation. Nutrients 2021; 13:nu13072474. [PMID: 34371983 PMCID: PMC8308647 DOI: 10.3390/nu13072474] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/13/2021] [Accepted: 07/16/2021] [Indexed: 12/11/2022] Open
Abstract
The worldwide prevalence of metabolic diseases such as obesity, metabolic syndrome and type 2 diabetes shows an upward trend in recent decades. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. In fact, recent progress in understanding the molecular and cellular mechanisms of glucose absorption in the gut and its reabsorption in the kidney helped to develop a new strategy of diabetes treatment. Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The key role of SGLT1 transporter in intestinal glucose absorption in both physiological conditions and in diabetes was clearly established. We conclude that although inhibition of small intestinal glucose absorption represents a valuable target for the treatment of hyperglycemia, it is not always suitable for the treatment of hyperphagia. In fact, independent regulation of glucose absorption and appetite requires a more complex approach for the treatment of metabolic diseases.
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Telese A, Sehgal V, Magee CG, Naik S, Alqahtani S, Lovat L, Haidry RJ. Bariatric and Metabolic Endoscopy: A New Paradigm. Clin Transl Gastroenterol 2021; 12:e00364. [PMID: 34142665 PMCID: PMC8216681 DOI: 10.14309/ctg.0000000000000364] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 04/14/2021] [Indexed: 12/26/2022] Open
Abstract
The prevalence of obesity, type 2 diabetes mellitus, and metabolic syndromes is increasing globally. Minimally invasive metabobariatric (MB) endoscopic therapies are adjunct treatments that can potentially bridge the gap between surgical interventions and medical therapy. A growing number of MB techniques are becoming available, allowing for more personalized and patient-targeted treatment options for specific disease states. MB techniques are less invasive than surgery and can precisely target different parts of the gastrointestinal tract that may be responsible for the pathophysiology of obesity and metabolic syndromes such as type 2 diabetes mellitus. These alternatives should be selected on an individualized patient basis to balance the expected clinical outcomes and desired anatomical targets with the level of invasiveness and degree of acceptable risk. Each MB intervention presents great flexibility allowing for a tailored intervention and different levels of patient engagement. Patient awareness and motivation are essential to avoid therapy withdrawal and failure. Differences between MB procedures in terms of weight loss and metabolic benefit will be discussed in this review, along with the insights on clinical decision-making processes to evaluate the potential of further evolution and growth of bariatric and metabolic endoscopy.
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Affiliation(s)
- Andrea Telese
- Department of Gastrointestinal Services, University College London Hospital, London, UK;
| | - Vinay Sehgal
- Department of Gastrointestinal Services, University College London Hospital, London, UK;
| | - Cormac G. Magee
- Department of Gastrointestinal Services, University College London Hospital, London, UK;
- Centre for Obesity research, University College London, London, UK;
| | - S. Naik
- Centre for Obesity research, University College London, London, UK;
| | - S.A. Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA;
- Liver Transplantation Unit, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - L.B. Lovat
- Department of Gastrointestinal Services, University College London Hospital, London, UK;
- Division of Surgery and Interventional Science, University College London, London, UK.
| | - Rehan J. Haidry
- Department of Gastrointestinal Services, University College London Hospital, London, UK;
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The Function of Gastrointestinal Hormones in Obesity-Implications for the Regulation of Energy Intake. Nutrients 2021; 13:nu13061839. [PMID: 34072172 PMCID: PMC8226753 DOI: 10.3390/nu13061839] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 05/20/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023] Open
Abstract
The global burden of obesity and the challenges of prevention prompted researchers to investigate the mechanisms that control food intake. Food ingestion triggers several physiological responses in the digestive system, including the release of gastrointestinal hormones from enteroendocrine cells that are involved in appetite signalling. Disturbed regulation of gut hormone release may affect energy homeostasis and contribute to obesity. In this review, we summarize the changes that occur in the gut hormone balance during the pre- and postprandial state in obesity and the alterations in the diurnal dynamics of their plasma levels. We further discuss how obesity may affect nutrient sensors on enteroendocrine cells that sense the luminal content and provoke alterations in their secretory profile. Gastric bypass surgery elicits one of the most favorable metabolic outcomes in obese patients. We summarize the effect of different strategies to induce weight loss on gut enteroendocrine function. Although the mechanisms underlying obesity are not fully understood, restoring the gut hormone balance in obesity by targeting nutrient sensors or by combination therapy with gut peptide mimetics represents a novel strategy to ameliorate obesity.
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Altered intestinal epithelial nutrient transport: an underappreciated factor in obesity modulated by diet and microbiota. Biochem J 2021; 478:975-995. [PMID: 33661278 DOI: 10.1042/bcj20200902] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 12/31/2022]
Abstract
Dietary nutrients absorbed in the proximal small intestine and assimilated in different tissues have a profound effect on overall energy homeostasis, determined by a balance between body's energy intake and expenditure. In obesity, altered intestinal absorption and consequently tissue assimilation of nutrients may disturb the energy balance leading to metabolic abnormalities at the cellular level. The absorption of nutrients such as sugars, amino acids and fatty acids released from food digestion require high-capacity transporter proteins expressed in the intestinal epithelial absorptive cells. Furthermore, nutrient sensing by specific transporters/receptors expressed in the epithelial enteroendocrine cells triggers release of gut hormones involved in regulating energy homeostasis via their effects on appetite and food intake. Therefore, the intestinal epithelial cells play a pivotal role in the pathophysiology of obesity and associated complications. Over the past decade, gut microbiota has emerged as a key factor contributing to obesity via its effects on digestion and absorption of nutrients in the small intestine, and energy harvest from dietary fiber, undigested component of food, in the large intestine. Various mechanisms of microbiota effects on obesity have been implicated. However, the impact of obesity-associated microbiota on the intestinal nutrient transporters needs extensive investigation. This review marshals the limited studies addressing the altered structure and function of the gut epithelium in obesity with special emphasis on nutrient transporters and role of diet and microbiota. The review also discusses the thoughts and controversies and research gaps in this field.
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Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance. Int J Mol Sci 2021; 22:ijms22020623. [PMID: 33435513 PMCID: PMC7827500 DOI: 10.3390/ijms22020623] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/29/2020] [Accepted: 01/02/2021] [Indexed: 12/12/2022] Open
Abstract
Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the organism. These hormones are involved in tissue repair, immune stability, and metabolic processes, such as the regulation of carbohydrate, lipid, and protein metabolism. Globally, GCs are presented as ‘flight and fight’ hormones and, in that purpose, they are catabolic hormones required to mobilize storage to provide energy for the organism. If acute GC secretion allows fast metabolic adaptations to respond to danger, stress, or metabolic imbalance, long-term GC exposure arising from treatment or Cushing’s syndrome, progressively leads to insulin resistance and, in fine, cardiometabolic disorders. In this review, we briefly summarize the pharmacological actions of GC and metabolic dysregulations observed in patients exposed to an excess of GCs. Next, we describe in detail the molecular mechanisms underlying GC-induced insulin resistance in adipose tissue, liver, muscle, and to a lesser extent in gut, bone, and brain, mainly identified by numerous studies performed in animal models. Finally, we present the paradoxical effects of GCs on beta cell mass and insulin secretion by the pancreas with a specific focus on the direct and indirect (through insulin-sensitive organs) effects of GCs. Overall, a better knowledge of the specific action of GCs on several organs and their molecular targets may help foster the understanding of GCs’ side effects and design new drugs that possess therapeutic benefits without metabolic adverse effects.
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Soták M, Casselbrant A, Rath E, Zietek T, Strömstedt M, Adingupu DD, Karlsson D, Fritsch Fredin M, Ergang P, Pácha J, Batorsky A, Alpers CE, Börgeson E, Hansen PBL, Ericsson A, Björnson Granqvist A, Wallenius V, Fändriks L, Unwin RJ. Intestinal sodium/glucose cotransporter 3 expression is epithelial and downregulated in obesity. Life Sci 2020; 267:118974. [PMID: 33385407 DOI: 10.1016/j.lfs.2020.118974] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/11/2020] [Accepted: 12/20/2020] [Indexed: 12/12/2022]
Abstract
AIM We aimed to determine whether the sodium/glucose cotransporter family member SGLT3, a proposed glucose sensor, is expressed in the intestine and/or kidney, and if its expression is altered in mouse models of obesity and in humans before and after weight-loss surgery. MAIN METHODS We used in-situ hybridization and quantitative PCR to determine whether the Sglt3 isoforms 3a and 3b were expressed in the intestine and kidney of C57, leptin-deficient ob/ob, and diabetic BTBR ob/ob mice. Western blotting and immunohistochemistry were also used to assess SGLT3 protein levels in jejunal biopsies from obese patients before and after weight-loss Roux-en-Y gastric bypass surgery (RYGB), and in lean healthy controls. KEY FINDINGS Sglt3a/3b mRNA was detected in the small intestine (duodenum, jejunum and ileum), but not in the large intestine or kidneys of mice. Both isoforms were detected in epithelial cells (confirmed using intestinal organoids). Expression of Sglt3a/3b mRNA in duodenum and jejunum was significantly lower in ob/ob and BTBR ob/ob mice than in normal-weight littermates. Jejunal SGLT3 protein levels in aged obese patients before RYGB were lower than in lean individuals, but substantially upregulated 6 months post-RYGB. SIGNIFICANCE Our study shows that Sglt3a/3b is expressed primarily in epithelial cells of the small intestine in mice. Furthermore, we observed an association between intestinal mRNA Sglt3a/3b expression and obesity in mice, and between jejunal SGLT3 protein levels and obesity in humans. Further studies are required to determine the possible role of SGLT3 in obesity.
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Affiliation(s)
- Matúš Soták
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden.
| | - Anna Casselbrant
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Eva Rath
- Chair of Nutrition and Immunology, Technische Universität München, Freising, Germany
| | - Tamara Zietek
- Department of Nutritional Physiology, Technische Universität München, Freising, Germany
| | - Maria Strömstedt
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Damilola D Adingupu
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Daniel Karlsson
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Maria Fritsch Fredin
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Peter Ergang
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Jiří Pácha
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Anna Batorsky
- Department of Pathology, University of Washington School of Medicine, Seattle, USA
| | - Charles E Alpers
- Department of Pathology, University of Washington School of Medicine, Seattle, USA
| | - Emma Börgeson
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden; Department of Clinical Physiology, Sahlgrenska University Hospital, Sweden
| | - Pernille B L Hansen
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden
| | - Anette Ericsson
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Anna Björnson Granqvist
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Ville Wallenius
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lars Fändriks
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Robert J Unwin
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Department of Renal Medicine, Division of Medicine, University College London, UK
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Hasan NM, Johnson KF, Yin J, Baetz NW, Fayad L, Sherman V, Blutt SE, Estes MK, Kumbhari V, Zachos NC, Kovbasnjuk O. Intestinal stem cell-derived enteroids from morbidly obese patients preserve obesity-related phenotypes: Elevated glucose absorption and gluconeogenesis. Mol Metab 2020; 44:101129. [PMID: 33246140 PMCID: PMC7770968 DOI: 10.1016/j.molmet.2020.101129] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/28/2020] [Accepted: 11/21/2020] [Indexed: 12/11/2022] Open
Abstract
Objective The mechanisms behind the efficacy of bariatric surgery (BS) for treating obesity and type 2 diabetes, particularly with respect to the influence of the small bowel, remain poorly understood. In vitro and animal models are suboptimal with respect to their ability to replicate the human intestinal epithelium under conditions induced by obesity. Human enteroids have the potential to accelerate the development of less invasive anti-obesity therapeutics if they can recapitulate the pathophysiology of obesity. Our aim was to determine whether adult stem cell-derived enteroids preserve obesity-characteristic patient-specific abnormalities in carbohydrate absorption and metabolism. Methods We established 24 enteroid lines representing 19 lean, overweight, or morbidly obese patients, including post-BS cases. Dietary glucose absorption and gluconeogenesis in enteroids were measured. The expression of carbohydrate transporters and gluconeogenic enzymes was assessed and a pharmacological approach was used to dissect the specific contribution of each transporter or enzyme to carbohydrate absorption and metabolism, respectively. Results Four phenotypes representing the relationship between patients’ BMI and intestinal dietary sugar absorption were found, suggesting that human enteroids retain obese patient phenotype heterogeneity. Intestinal glucose absorption and gluconeogenesis were significantly elevated in enteroids from a cohort of obese patients. Elevated glucose absorption was associated with increased expression of SGLT1 and GLUT2, whereas elevated gluconeogenesis was related to increased expression of GLUT5, PEPCK1, and G6Pase. Conclusions Obesity phenotypes preserved in human enteroids provide a mechanistic link to aberrant dietary carbohydrate absorption and metabolism. Enteroids can be used as a preclinical platform to understand the pathophysiology of obesity, study the heterogeneity of obesity mechanisms, and identify novel therapeutics.
Human stem cell-derived enteroids preserve the heterogeneity of obesity-related phenotypes. Four phenotypes representing the relationship between patients' BMI and intestinal dietary glucose absorption were found. Glucose absorption and gluconeogenesis were elevated in enteroids from a cohort of obese patients. Elevated glucose absorption was associated with increased expression of SGLT1 and GLUT2 in enteroids. Elevated gluconeogenesis was associated with increased expression of GLUT5, PEPCK1, and G6Pase in enteroids.
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Affiliation(s)
- Nesrin M Hasan
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA; Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Kelli F Johnson
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA
| | - Jianyi Yin
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Nicholas W Baetz
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA
| | - Lea Fayad
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA
| | - Vadim Sherman
- Department of Surgery, Minimally Invasive Bariatric and General Division, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Sarah E Blutt
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Mary K Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Vivek Kumbhari
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA
| | - Nicholas C Zachos
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
| | - Olga Kovbasnjuk
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
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Jadhav K, Cohen TS. Can You Trust Your Gut? Implicating a Disrupted Intestinal Microbiome in the Progression of NAFLD/NASH. Front Endocrinol (Lausanne) 2020; 11:592157. [PMID: 33193105 PMCID: PMC7641624 DOI: 10.3389/fendo.2020.592157] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disorders, ranging from fatty liver to a more insulin resistant, inflammatory and fibrotic state collectively termed non-alcoholic steatohepatitis (NASH). In the United States, 30%-40% of the adult population has fatty liver and 3%-12% has NASH, making it a major public health concern. Consumption of diets high in fat, obesity and Type II diabetes (T2D) are well-established risk factors; however, there is a growing body of literature suggesting a role for the gut microbiome in the development and progression of NAFLD. The gut microbiota is separated from the body by a monolayer of intestinal epithelial cells (IECs) that line the small intestine and colon. The IEC layer is exposed to luminal contents, participates in selective uptake of nutrients and acts as a barrier to passive paracellular permeability of luminal contents through the expression of tight junctions (TJs) between adjacent IECs. A dysbiotic gut microbiome also leads to decreased gut barrier function by disrupting TJs and the gut vascular barrier (GVB), thus exposing the liver to microbial endotoxins. These endotoxins activate hepatic Toll-like receptors (TLRs), further promoting the progression of fatty liver to a more inflammatory and fibrotic NASH phenotype. This review will summarize major findings pertaining to aforementioned gut-liver interactions and its role in the pathophysiology of NAFLD.
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Affiliation(s)
| | - Taylor S. Cohen
- Microbiome Discovery, Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
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Santoro S, Aquino CGG, Mota FC, Artoni RF. DOES EVOLUTIONARY BIOLOGY HELP THE UNDERSTANDING OF METABOLIC SURGERY? A FOCUSED REVIEW. ACTA ACUST UNITED AC 2020; 33:e1503. [PMID: 32667533 PMCID: PMC7357560 DOI: 10.1590/0102-672020190001e1503] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023]
Abstract
Introduction: The wide net of physiological issues involved in metabolic surgery is
extremely complex. Nonetheless, compared anatomy and phisiology can provide
good clues of how digestive tracts are shaped for more or less caloric food,
for more or less fiber, for abundance and for scarcity.
Objective: To review data from Compared Anatomy and Physiology, and in the Evolutionary
Sciences that could help in the better comprehension of the metabolic
surgery.
Method: A focused review of the literature selecting information from these three
fields of knowledge in databases: Cochrane Library, Medline and SciELO,
articles and book chapters in English and Portuguese, between 1955 and 2019,
using the headings “GIP, GLP-1, PYY, type 2 diabetes, vertebrates digestive
system, hominid evolution, obesity, bariatric surgery “.
Results: The digestive tract of superior animals shows highly specialized organs to
digest and absorb specific diets. In spite of the wide variations of
digestive systems, some general rules are observed. The proximal part of the
digestive tract, facing the scarcity of sugars, is basically dedicated to
generate sugar from different substrates (gluconeogenesis). Basic proximal
gut tasks are to proportionally input free sugars, insulin, other fuels and
to generate anabolic elements to the blood, some of them obesogenic. To
limit the ingestion by satiety, by gastric emptying diminution and to limit
the excessive elevation of major fuels (sugar and fat) in the blood are
mostly the metabolict asks of the distal gut. A rapid and profound change in
human diet composition added large amounts of high glycemic index foods.
They seem to have caused an enhancement in the endocrine and metabolic
activities of the proximal gut and a reduction in these activities of the
distal gut. The most efficient models of metabolic surgery indeed make
adjustments in this proximal/distal balance in the gut metabolic activities.
Conclusion: Metabolic surgery works basically by making adjustments to the proximal and
distal gut metabolic activities that resemble the action of natural
selection in the development the digestive systems of superior animals.
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Affiliation(s)
- Sergio Santoro
- Department of Surgery, Albert Einstein Hospital, São Paulo, SP, Brazil
| | - Caio G G Aquino
- Department of Surgery, Albert Einstein Hospital, São Paulo, SP, Brazil
| | - Filippe Camarotto Mota
- Department of Surgery, Albert Einstein Hospital, São Paulo, SP, Brazil.,Department of Surgery, School of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Roberto Ferreira Artoni
- Evolutionary Genetics Laboratory, Department of Structural, Molecular and Genetic Biology, Ponta Grossa State University, PR, Brazil
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Gil-Iturbe E, Félix-Soriano E, Sáinz N, Idoate-Bayón A, Castilla-Madrigal R, Moreno-Aliaga MJ, Lostao MP. Effect of aging and obesity on GLUT12 expression in small intestine, adipose tissue, muscle, and kidney and its regulation by docosahexaenoic acid and exercise in mice. Appl Physiol Nutr Metab 2020; 45:957-967. [PMID: 32176854 DOI: 10.1139/apnm-2019-0721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2023]
Abstract
Obesity is characterized by excessive fat accumulation and inflammation. Aging has also been characterized as an inflammatory condition, frequently accompanied by accumulation of visceral fat. Beneficial effects of exercise and n-3 long-chain polyunsaturated fatty acids in metabolic disorders have been described. Glucose transporter 12 (GLUT12) is one of the less investigated members of the GLUT family. Glucose, insulin, and tumor necrosis factor alpha (TNF-α) induce GLUT12 translocation to the membrane in muscle, adipose tissue, and intestine. We aimed to investigate GLUT12 expression in obesity and aging, and under diet supplementation with docosahexaenoic acid (DHA) alone or in combination with physical exercise in mice. Aging increased GLUT12 expression in intestine, kidney, and adipose tissue, whereas obesity reduced it. No changes on the transporter occurred in skeletal muscle. In obese 18-month-old mice, DHA further decreased GLUT12 in the 4 organs. Aerobic exercise alone did not modify GLUT12, but the changes triggered by exercise were able to prevent the DHA-diminishing effect, and almost restored GLUT12 basal levels. In conclusion, the downregulation of metabolism in aging would be a stimulus to upregulate GLUT12 expression. Contrary, obesity, an excessive energy condition, would induce GLUT12 downregulation. The combination of exercise and DHA would contribute to restore basal function of GLUT12. Novelty In small intestine, kidney and adipose tissue aging increases GLUT12 protein expression whereas obesity reduces it. Dietary DHA decreases GLUT12 in small intestine, kidney, adipose tissue and skeletal muscle. Exercise alone does not modify GLUT12 expression, nevertheless exercise prevents the DHA-diminishing effect on GLUT12.
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Affiliation(s)
- Eva Gil-Iturbe
- Department of Nutrition, Food Science and Physiology, University of Navarra, 31008 Pamplona, Navarra, Spain
- Centre for Nutrition Research, University of Navarra, 31008 Pamplona, Navarra, Spain
| | - Elisa Félix-Soriano
- Department of Nutrition, Food Science and Physiology, University of Navarra, 31008 Pamplona, Navarra, Spain
- Centre for Nutrition Research, University of Navarra, 31008 Pamplona, Navarra, Spain
| | - Neira Sáinz
- Department of Nutrition, Food Science and Physiology, University of Navarra, 31008 Pamplona, Navarra, Spain
- Centre for Nutrition Research, University of Navarra, 31008 Pamplona, Navarra, Spain
| | - Adrián Idoate-Bayón
- Department of Nutrition, Food Science and Physiology, University of Navarra, 31008 Pamplona, Navarra, Spain
| | | | - María J Moreno-Aliaga
- Department of Nutrition, Food Science and Physiology, University of Navarra, 31008 Pamplona, Navarra, Spain
- Centre for Nutrition Research, University of Navarra, 31008 Pamplona, Navarra, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Navarra, Spain
- Institute of Health Carlos III (ISCIII), Biomedical Research Networking Center in Physiopathology of Obesity and Nutrition (CIBERobn), 28029 Madrid, Spain
| | - María Pilar Lostao
- Department of Nutrition, Food Science and Physiology, University of Navarra, 31008 Pamplona, Navarra, Spain
- Centre for Nutrition Research, University of Navarra, 31008 Pamplona, Navarra, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Navarra, Spain
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49
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Martinussen C, Veedfald S, Dirksen C, Bojsen-Møller KN, Svane MS, Wewer Albrechtsen NJ, van Hall G, Kristiansen VB, Fenger M, Holst JJ, Madsbad S. The effect of acute dual SGLT1/SGLT2 inhibition on incretin release and glucose metabolism after gastric bypass surgery. Am J Physiol Endocrinol Metab 2020; 318:E956-E964. [PMID: 32182123 DOI: 10.1152/ajpendo.00023.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Enhanced meal-related enteroendocrine secretion, particularly of glucagon-like peptide-1 (GLP-1), contributes to weight-loss and improved glycemia after Roux-en-Y gastric bypass (RYGB). Dietary glucose drives GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion postoperatively. Understanding how glucose triggers incretin secretion following RYGB could lead to new treatments of diabetes and obesity. In vitro, incretin release depends on glucose absorption via sodium-glucose cotransporter 1 (SGLT1). We investigated the importance of SGLT1/SGLT2 for enteropancreatic hormone concentrations and glucose metabolism after RYGB in a randomized, controlled, crossover study. Ten RYGB-operated patients ingested 50 g of oral glucose with and without acute pretreatment with 600 mg of the SGLT1/SGLT2-inhibitor canagliflozin. Paracetamol and 3-O-methyl-d-glucopyranose (3-OMG) were added to the glucose drink to evaluate rates of intestinal entry and absorption of glucose, respectively. Blood samples were collected for 4 h. The primary outcome was 4-h plasma GLP-1 (incremental area-under the curve, iAUC). Secondary outcomes included glucose, GIP, insulin, and glucagon. Canagliflozin delayed glucose absorption (time-to-peak 3-OMG: 50 vs. 132 min, P < 0.01) but did not reduce iAUC GLP-1 (6,067 vs. 7,273·min·pmol-1·L-1, P = 0.23), although peak GLP-1 concentrations were lowered (-28%, P = 0.03). Canagliflozin reduced GIP (iAUC -28%, P = 0.01; peak concentrations -57%, P < 0.01), insulin, and glucose excursions, whereas plasma glucagon (AUC 3,216 vs. 4,160 min·pmol·L-1, P = 0.02) and amino acids were increased. In conclusion, acute SGLT1/SGLT2-inhibition during glucose ingestion did not reduce 4-h plasma GLP-1 responses in RYGB-patients but attenuated the early rise in GLP-1, GIP, and insulin, whereas late glucagon concentrations were increased. The results suggest that SGLT1-mediated glucose absorption contributes to incretin hormone secretion after RYGB.
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Affiliation(s)
- Christoffer Martinussen
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Danish Diabetes Academy, Odense, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Simon Veedfald
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Dirksen
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Kirstine N Bojsen-Møller
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Maria S Svane
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Gerrit van Hall
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Metabolomics Core Facility, Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Viggo B Kristiansen
- Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark
| | - Mogens Fenger
- Department of Clinical Biochemistry, Hvidovre Hospital, Hvidovre, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
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50
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Tatarian T, Rona KA, Shin DH, Chen DG, Ducoin CG, Moore RL, Brunaldi VO, Galvão-Neto M, Ardila-Gatas J, Docimo S, Hourneax de Moura DT, Jirapinyo P, Thompson CC, Billy HT, Roslin MS, Borden B, Zarabi S, Sweigert PJ, Chand B, Pryor AD. Evolving procedural options for the treatment of obesity. Curr Probl Surg 2020; 57:100742. [DOI: 10.1016/j.cpsurg.2020.100742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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