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Esteves-Monteiro M, Ferreira-Duarte M, Vitorino-Oliveira C, Costa-Pires J, Oliveira S, Matafome P, Morato M, Dias-Pereira P, Costa VM, Duarte-Araújo M. Oxidative Stress and Histomorphometric Remodeling: Two Key Intestinal Features of Type 2 Diabetes in Goto-Kakizaki Rats. Int J Mol Sci 2024; 25:12115. [PMID: 39596183 PMCID: PMC11594829 DOI: 10.3390/ijms252212115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
Gastrointestinal complications of diabetes are often overlooked, despite affecting up to 75% of patients. This study innovatively explores local glutathione levels and morphometric changes in the gut of Goto-Kakizaki (GK) rats, a type 2 diabetes animal model. Segments of the intestine, cecum, and colon were collected for histopathological analysis and glutathione quantification. A significant increase in the total thickness of the intestinal wall of GK rats was observed, particularly in the duodenum (1089.02 ± 39.19 vs. 864.19 ± 37.17 µm), ileum (726.29 ± 24.75 vs. 498.76 ± 16.86 µm), cecum (642.24 ± 34.15 vs. 500.97 ± 28.81 µm), and distal colon (1211.81 ± 51.32 vs. 831.71 ± 53.2 µm). Additionally, diabetic rats exhibited thickening of the muscular layers in all segments, except for the duodenum, which was also the only portion where the number of smooth muscle cells did not decrease. Moreover, myenteric neuronal density was lower in GK rats, suggesting neurological loss. Total glutathione levels were lower in all intestinal segments of diabetic rats (except duodenum), and the reduced/oxidized glutathione ratio (GSH/GSSG) was significantly decreased in GK rats, indicating increased oxidative stress. These findings strongly indicate that GK rats undergo significant intestinal remodeling, notable shifts in neuronal populations, and heightened oxidative stress-factors that likely contribute to the functional gastrointestinal alterations seen in diabetic patients.
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Affiliation(s)
- Marisa Esteves-Monteiro
- Associated Laboratory for Green Chemistry (LAQV) Network of Chemistry and Technology (REQUIMTE), University of Porto, 4050-313 Porto, Portugal (M.M.)
- Department of Immuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto (FFUP), 4050-313 Porto, Portugal
| | - Mariana Ferreira-Duarte
- Associated Laboratory for Green Chemistry (LAQV) Network of Chemistry and Technology (REQUIMTE), University of Porto, 4050-313 Porto, Portugal (M.M.)
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto (FFUP), 4050-313 Porto, Portugal
| | - Cláudia Vitorino-Oliveira
- Institute for Health and Bioeconomy (i4HB), Laboratory of Toxicology, Department of Biological Sciences, FFUP, 4050-313 Porto, Portugal (V.M.C.)
- Research Unit on Applied Molecular Biosciences (UCIBIO), FFUP, Laboratory of Toxicology, Department of Biological Sciences, FFUP, 4050-313 Porto, Portugal
| | - José Costa-Pires
- Department of Immuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
| | - Sara Oliveira
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine, University of Coimbra (UC), 3000-548 Coimbra, Portugal; (S.O.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), UC, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
| | - Paulo Matafome
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine, University of Coimbra (UC), 3000-548 Coimbra, Portugal; (S.O.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), UC, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
- Coimbra Health School (ESTeSC), Polytechnic University of Coimbra, 3046-854 Coimbra, Portugal
| | - Manuela Morato
- Associated Laboratory for Green Chemistry (LAQV) Network of Chemistry and Technology (REQUIMTE), University of Porto, 4050-313 Porto, Portugal (M.M.)
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto (FFUP), 4050-313 Porto, Portugal
| | - Patrícia Dias-Pereira
- Department of Pathology and Molecular Immunology, ICBAS-UP, 4050-313 Porto, Portugal;
| | - Vera Marisa Costa
- Institute for Health and Bioeconomy (i4HB), Laboratory of Toxicology, Department of Biological Sciences, FFUP, 4050-313 Porto, Portugal (V.M.C.)
- Research Unit on Applied Molecular Biosciences (UCIBIO), FFUP, Laboratory of Toxicology, Department of Biological Sciences, FFUP, 4050-313 Porto, Portugal
| | - Margarida Duarte-Araújo
- Associated Laboratory for Green Chemistry (LAQV) Network of Chemistry and Technology (REQUIMTE), University of Porto, 4050-313 Porto, Portugal (M.M.)
- Department of Immuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
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Sharma S, Buist ML. Comparing finite viscoelastic constitutive relations and variational principles in modeling gastrointestinal soft tissue deformation. J Mech Behav Biomed Mater 2024; 155:106560. [PMID: 38744120 DOI: 10.1016/j.jmbbm.2024.106560] [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: 12/18/2023] [Revised: 04/20/2024] [Accepted: 04/23/2024] [Indexed: 05/16/2024]
Abstract
The mechanical attributes of soft tissues within the gastrointestinal (GI) tract are crucial for the effective operation of the GI system, and alterations in these properties may play a role in motility-related disorders. Various constitutive modeling approaches have been suggested to comprehend the response of soft tissues to diverse loading conditions. Among these, hyperelastic constitutive models based on finite elasticity have gained popularity. However, these models fall short in capturing rate- and time-dependent tissue properties. In contrast, finite viscoelastic models offer a solution to overcome these limitations. Nevertheless, the development of a suitable finite viscoelastic model, coupled with a variational formulation for efficient finite element (FE) implementation, remains an ongoing challenge. This study aims to address this gap by developing diverse finite viscoelastic constitutive relations and applying them to characterize soft tissue. Furthermore, the research explores the creation of compressible, nearly incompressible, and incompressible versions of viscoelastic constitutive relations, along with their variational formulation, to facilitate efficient FE implementation. The proposed model demonstrates remarkable accuracy in replicating experimental results, achieving an R2 value exceeding 0.99.
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Affiliation(s)
- Swati Sharma
- Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, Singapore 117583, Singapore
| | - Martin Lindsay Buist
- Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, Singapore 117583, Singapore.
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3
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Bao L, Zhao J, Gregersen H. Association between jejunal remodeling in fasting rats and hypersensitivity of intestinal afferent nerves to mechanical stimulation. Biomech Model Mechanobiol 2024; 23:73-86. [PMID: 37548873 DOI: 10.1007/s10237-023-01758-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 07/24/2023] [Indexed: 08/08/2023]
Abstract
Remodeling of Intestinal properties and hypersensitivity of intestinal afferents to mechanical stimulation were previously demonstrated in a fasting rat model. Other studies investigated the association between mechanical and histological remodeling during fasting. This study aimed to further explore the relationship between the jejunal remodeling and intestinal afferent hypersensitivity by combining afferent nerve recordings with histological and mechanical data. Eight male Sprague Dawley rats had no access to food for 7 days (Fasting group). Seven male rats served as controls (Control group). Jejunal segments were studied in vitro in an organ bath for analysis of afferent signaling and for analysis of mechanical and histomorphological parameters. Correlation analyses were done to analyze association between nerve activity (spike rate increase ratio, SRIR) at distension levels of 20, 40 and 80 cmH2O and mechanical stress and histomorphological changes of the jejunal segments. Compared with the Control group, the main findings in jejunal segments in the Fasting group were (1) Most histomorphometry parameters were reduced (P < 0.05-P < 0.001), (2) SRIR values were higher (P < 0.001), (3) The relative numbers of intermuscular and submucosal neurons were increased (P < 0.05-P < 0.01), and (4) SRIR was negatively correlated with intestinal wall thickness, circumferential muscle layer thickness and positively correlated with the inner residual strain, the number of neurons, and the mechanical stress. In conclusion, the fasting-induced histomorphological remodeling (reduced wall thickness and increased relative number of neurons) and biomechanical remodeling (residual strain changes and high stress level) of the intestine in fasting rats were associated with hypersensitivity of intestinal afferents. Afferent hypersensitivity appears to be dependent on stress rather than on strain.
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Affiliation(s)
- Lingxia Bao
- Chongqing University of Posts and Telecommunications, Chongqing, 400065, China
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering at Chongqing University, Chongqing, 400044, China
| | - Jingbo Zhao
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering at Chongqing University, Chongqing, 400044, China.
- Anbiping (Chongqing) Pathological Diagnosis Center, No. 8 Xiyuan North Road, Shapingba District, Chongqing, 401334, China.
| | - Hans Gregersen
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering at Chongqing University, Chongqing, 400044, China
- GIOME, California Medical Innovations Institute, San Diego, CA, USA
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Durcan C, Hossain M, Chagnon G, Perić D, Girard E. Mechanical experimentation of the gastrointestinal tract: a systematic review. Biomech Model Mechanobiol 2024; 23:23-59. [PMID: 37935880 PMCID: PMC10901955 DOI: 10.1007/s10237-023-01773-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 09/10/2023] [Indexed: 11/09/2023]
Abstract
The gastrointestinal (GI) organs of the human body are responsible for transporting and extracting nutrients from food and drink, as well as excreting solid waste. Biomechanical experimentation of the GI organs provides insight into the mechanisms involved in their normal physiological functions, as well as understanding of how diseases can cause disruption to these. Additionally, experimental findings form the basis of all finite element (FE) modelling of these organs, which have a wide array of applications within medicine and engineering. This systematic review summarises the experimental studies that are currently in the literature (n = 247) and outlines the areas in which experimentation is lacking, highlighting what is still required in order to more fully understand the mechanical behaviour of the GI organs. These include (i) more human data, allowing for more accurate modelling for applications within medicine, (ii) an increase in time-dependent studies, and (iii) more sophisticated in vivo testing methods which allow for both the layer- and direction-dependent characterisation of the GI organs. The findings of this review can also be used to identify experimental data for the readers' own constitutive or FE modelling as the experimental studies have been grouped in terms of organ (oesophagus, stomach, small intestine, large intestine or rectum), test condition (ex vivo or in vivo), number of directions studied (isotropic or anisotropic), species family (human, porcine, feline etc.), tissue condition (intact wall or layer-dependent) and the type of test performed (biaxial tension, inflation-extension, distension (pressure-diameter), etc.). Furthermore, the studies that investigated the time-dependent (viscoelastic) behaviour of the tissues have been presented.
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Affiliation(s)
- Ciara Durcan
- Zienkiewicz Centre for Modelling, Data and AI, Faculty of Science and Engineering, Swansea University, Swansea, SA1 8EN, UK
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000, Grenoble, France
| | - Mokarram Hossain
- Zienkiewicz Centre for Modelling, Data and AI, Faculty of Science and Engineering, Swansea University, Swansea, SA1 8EN, UK.
| | - Grégory Chagnon
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000, Grenoble, France
| | - Djordje Perić
- Zienkiewicz Centre for Modelling, Data and AI, Faculty of Science and Engineering, Swansea University, Swansea, SA1 8EN, UK
| | - Edouard Girard
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000, Grenoble, France
- Laboratoire d'Anatomie des Alpes Françaises, Université Grenoble Alpes, Grenoble, France
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Yang X, Zhao J, Li H, Pan L, Guo J, Li J, Zhang Y, Chen P, Li P. Effect of Tangshen formula on the remodeling of small intestine and colon in Zucker diabetic fatty rats. Heliyon 2023; 9:e21007. [PMID: 37886764 PMCID: PMC10597860 DOI: 10.1016/j.heliyon.2023.e21007] [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: 08/03/2023] [Revised: 09/28/2023] [Accepted: 10/12/2023] [Indexed: 10/28/2023] Open
Abstract
Background and aim Previous study have demonstrated that Tangshen Formula (TSF) could attenuate colonic histomorphological remodeling in the diabetic rat model induced by high fat diet plus low dosage streptozotocin (STZ). However, it is not clear whether TSF has same effect on small intestine and the effect on biomechanical properties of bowel. The aim of this study is to investigate the effect of TSF on histomorphological and biomechanical remodeling of small intestine and colon by using Zucker Diabetic Fatty (ZDF) Rat model. Materials and methods ZDF rats (obese fa/fa) with blood glucose higher than 11.7 mmol/L were divided into ZDF group (diabetic control group) and ZDF + TSF group (TSF treatment group), the later were intragastrically administered TSF. The ZDF rats (lean fa/+) were served as normal control (ZL) group. The rats in the ZL and ZDF groups were administered with saline. The experimental period covered from 8 weeks to 24 weeks. At the end of experiment, the ileal and colonic segments were studied in vitro. The histomorphometry and biomechanical parameters were measured. Results Compared with ZL group histomorphologically, the wet weight per unit length, wall thickness, wall area and fractions of total and type I and type III collagen in different layers for both ileum and colon increased in ZDF group. Those increasing parameters were partially inhibited in ZDF + TSF group. Compared with ZL group biomechanically, ZDF and ZDF + TSF groups had smaller opening angle and residual strain in ileum, and bigger opening angle and residual strain in colon. Whereas the wall became softer in circumferential direction and stiffer in longitudinal direction for both ileum and colon. However, no difference of biomechanical parameters was found between ZDF and ZDF + TSF groups. Conclusion The histomorphological and biomechanical remodeling of ileum and colon were happened in ZDF rats （obese fa/fa）. TSF could partly attenuate ileal and colonic histomorphological remodeling rather than biomechanical remodeling.
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Affiliation(s)
- Xin Yang
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Jingbo Zhao
- Anbiping (Chongqing) Pathological Diagnosis Center, Chongqing, China
| | - Hong Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Lin Pan
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Jing Guo
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Jing Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Yuting Zhang
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Pengmin Chen
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
| | - Ping Li
- Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing (100029), China
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Wei L, Ji L, Miao Y, Han X, Li Y, Wang Z, Fu J, Guo L, Su Y, Zhang Y. Constipation in DM are associated with both poor glycemic control and diabetic complications: Current status and future directions. Biomed Pharmacother 2023; 165:115202. [PMID: 37506579 DOI: 10.1016/j.biopha.2023.115202] [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: 05/05/2023] [Revised: 07/15/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Constipation is a major complications of diabetes mellitus. With the accelerating prevalence of diabetes worldwide and an aging population, there is considerable research interest regarding the altered function and structure of the gastrointestinal tract in diabetic patients. Despite current advances in hyperglycemic treatment strategies, the specific pathogenesis of diabetic constipation remains unknown. Patients with constipation, may be reluctant to eat regularly, which may worsen glycemic control and thus worsen symptoms associated with underlying diabetic bowel disease. This paper presents a review of the complex relationship between diabetes and constipation, exploring the morphological alterations and biomechanical remodeling associated with intestinal motility dysfunction, as well as alterations in intestinal neurons, cellular signaling pathways, and oxidative stress. Further studies focusing on new targets that may play a role in the pathogenesis of diabetic constipation may, provide new ideas for the development of novel therapies to treat or even prevent diabetic constipation.
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Affiliation(s)
- Luge Wei
- Tianjin University of Traditional Chinese Medicine, China.
| | - Lanqi Ji
- Tianjin University of Traditional Chinese Medicine, China
| | - Yulu Miao
- Tianjin University of Traditional Chinese Medicine, China
| | - Xu Han
- Tianjin University of Traditional Chinese Medicine, China
| | - Ying Li
- Tianjin University of Traditional Chinese Medicine, China
| | - Zhe Wang
- Tianjin University of Traditional Chinese Medicine, China
| | - Jiafeng Fu
- Tianjin University of Traditional Chinese Medicine, China
| | - Liuli Guo
- Tianjin University of Traditional Chinese Medicine, China
| | - Yuanyuan Su
- Tianjin University of Traditional Chinese Medicine, China
| | - Yanjun Zhang
- Tianjin University of Traditional Chinese Medicine, China; First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, China
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Taylor VJ. Lactation from the inside out: Maternal homeorhetic gastrointestinal adaptations regulating energy and nutrient flow into milk production. Mol Cell Endocrinol 2023; 559:111797. [PMID: 36243202 DOI: 10.1016/j.mce.2022.111797] [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: 05/28/2022] [Revised: 08/30/2022] [Accepted: 10/06/2022] [Indexed: 11/06/2022]
Abstract
Lactation invokes homeorhetic processes to ramp up and supply milk synthesis components to fulfil nutritional, immunological and microbiological requirements of developing offspring, overseen by complex neuroendocrine networks. The maternal gut meets these intense metabolic demands, supported by hyperphagia and rapid adjustments to process larger food quantities. Enteroplasticity describes an inherent ability of the gastrointestinal tract to harness metabolic and structural adaptations that increase nutrient absorption. Most shifts in response to increased demands are transitory and by secreting milk, the continuous energetic drain out of the maternal body avoids development of pathological metabolic diseases. Lactation has various positive benefits for long-term maternal health but many females do not lactate for long post pregnancy and younger women are increasingly pre-disposed to excessive body mass and/or metabolic complications prior to reproducing. Inadvertently invoking intestinal adaptations to harvest and store excess nutrients has negative health implications with increased risks for both mother and offspring.
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Affiliation(s)
- Vicky J Taylor
- School of Life, Health and Chemical Sciences (LHCS), Faculty of Science, Technology, Engineering and Mathematics (STEM), The Open University, United Kingdom.
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8
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Esteves-Monteiro M, Menezes-Pinto D, Ferreira-Duarte M, Dias-Pereira P, Morato M, Duarte-Araújo M. Histomorphometry Changes and Decreased Reactivity to Angiotensin II in the Ileum and Colon of Streptozotocin-Induced Diabetic Rats. Int J Mol Sci 2022; 23:13233. [PMID: 36362021 PMCID: PMC9656372 DOI: 10.3390/ijms232113233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/19/2022] [Accepted: 10/27/2022] [Indexed: 10/15/2023] Open
Abstract
Diabetes mellitus (DM) is a chronic progressive metabolic disorder associated with several gastrointestinal complications, affecting up to 75% of patients. Knowing that Angiotensin II (AngII) also regulates intestinal contraction, we decided to evaluate changes in ileum and colon histomorphometry and AngII reactivity in a rat model of DM. Streptozotocin (STZ, 55 mg/kg) was administered to induce DM to 24 adult male Wistar rats. Diabetic rats displayed all the characteristic signs of type 1 DM (T1DM) and fecal excretion increased about 4-fold over 14 days, while the excretion of controls remained unaltered. Compared to controls, diabetic ileum and colon presented an increase in both macroscopic (length, perimeter and weight) and microscopic (muscular wall thickness) parameters. Functionally, AngII-induced smooth muscle contraction was lower in diabetic rats, except in the distal colon. These differences in the contractile response to AngII may result from an imbalance between AngII type 1 (antagonized by candesartan, 10 nM) and type 2 receptors activation (antagonized by PD123319, 100 nM). Taken together, these results indicate that an early and refined STZ-induced T1DM rat model already shows structural remodelling of the gut wall and decreased contractile response to AngII, findings that may help to explain diabetic dysmotility.
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Affiliation(s)
- Marisa Esteves-Monteiro
- LAQV-REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Department of Immuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto (FFUP), 4050-313 Porto, Portugal
| | - Daniela Menezes-Pinto
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto (FFUP), 4050-313 Porto, Portugal
| | - Mariana Ferreira-Duarte
- LAQV-REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto (FFUP), 4050-313 Porto, Portugal
| | - Patrícia Dias-Pereira
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
| | - Manuela Morato
- LAQV-REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto (FFUP), 4050-313 Porto, Portugal
| | - Margarida Duarte-Araújo
- LAQV-REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Department of Immuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
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Patel B, Gizzi A, Hashemi J, Awakeem Y, Gregersen H, Kassab G. Biomechanical constitutive modeling of the gastrointestinal tissues: a systematic review. MATERIALS & DESIGN 2022; 217:110576. [PMID: 35935127 PMCID: PMC9351365 DOI: 10.1016/j.matdes.2022.110576] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
The gastrointestinal (GI) tract is a continuous channel through the body that consists of the esophagus, the stomach, the small intestine, the large intestine, and the rectum. Its primary functions are to move the intake of food for digestion before storing and ultimately expulsion of feces. The mechanical behavior of GI tissues thus plays a crucial role for GI function in health and disease. The mechanical properties are characterized by a biomechanical constitutive model, which is a mathematical representation of the relation between load and deformation in a tissue. Hence, validated biomechanical constitutive models are essential to characterize and simulate the mechanical behavior of the GI tract. Here, a systematic review of these constitutive models is provided. This review is limited to studies where a model of the strain energy function is proposed to characterize the stress-strain relation of a GI tissue. Several needs are identified for more advanced modeling including: 1) Microstructural models that provide actual structure-function relations; 2) Validation of coupled electro-mechanical models accounting for active muscle contractions; 3) Human data to develop and validate models. The findings from this review provide guidelines for using existing constitutive models as well as perspective and directions for future studies.
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Affiliation(s)
- Bhavesh Patel
- California Medical Innovations Institute, 11107 Roselle St, San Diego, CA 92121, USA
| | - Alessio Gizzi
- Department of Engineering, Campus Bio-Medico University of Rome, Via A. del Portillo 21, 00128 Rome, IT
| | - Javad Hashemi
- California Medical Innovations Institute, 11107 Roselle St, San Diego, CA 92121, USA
| | - Yousif Awakeem
- California Medical Innovations Institute, 11107 Roselle St, San Diego, CA 92121, USA
| | - Hans Gregersen
- California Medical Innovations Institute, 11107 Roselle St, San Diego, CA 92121, USA
| | - Ghassan Kassab
- California Medical Innovations Institute, 11107 Roselle St, San Diego, CA 92121, USA
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Piccolo BD, Graham JL, Kang P, Randolph CE, Shankar K, Yeruva L, Fox R, Robeson MS, Moody B, LeRoith T, Stanhope KL, Adams SH, Havel PJ. Progression of diabetes is associated with changes in the ileal transcriptome and ileal-colon morphology in the UC Davis Type 2 Diabetes Mellitus rat. Physiol Rep 2021; 9:e15102. [PMID: 34806320 PMCID: PMC8606862 DOI: 10.14814/phy2.15102] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/15/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Deterioration in glucose homeostasis has been associated with intestinal dysbiosis, but it is not known how metabolic dysregulation alters the gastrointestinal environment. We investigated how the progression of diabetes alters ileal and colonic epithelial mucosal structure, microbial abundance, and transcript expression in the University of California Davis Type 2 Diabetes Mellitus (UCD-T2DM) rat model. Male UCD-T2DM rats (age ~170 days) were included if <1-month (n = 6, D1M) or 3-month (n = 6, D3M) post-onset of diabetes. Younger nondiabetic UCD-T2DM rats were included as a nondiabetic comparison (n = 6, ND, age ~70 days). Ileum villi height/crypt depths and colon crypt depths were assessed by histology. Microbial abundance of colon content was measured with 16S rRNA sequencing. Ileum and colon transcriptional abundances were analyzed using RNA sequencing. Ileum villi height and crypt depth were greater in D3M rats compared to ND. Colon crypt depth was greatest in D3M rats compared to both ND and D1M rats. Colon abundances of Akkermansia and Muribaculaceae were lower in D3M rats relative to D1M, while Oscillospirales, Phascolarctobacterium, and an unidentified genus of Lachnospiraceae were higher. Only two transcripts were altered by diabetes advancement within the colon; however, 2039 ileal transcripts were altered. Only colonic abundances of Sptlc3, Enpp7, Slc7a15, and Kctd14 had more than twofold changes between D1M and D3M rats. The advancement of diabetes in the UCD-T2DM rat results in a trophic effect on the mucosal epithelia and was associated with regulation of gastrointestinal tract RNA expression, which appears more pronounced in the ileum relative to the colon.
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Affiliation(s)
- Brian D. Piccolo
- USDA‐ARS Arkansas Children's Nutrition CenterLittle RockArkansasUSA
- Department of PediatricsUniversity of Arkansas for Medical SciencesLittle RockArkansasUSA
| | - James L. Graham
- Department of Molecular BiosciencesSchool of Veterinary MedicineUniversity of California DavisDavisCaliforniaUSA
- Department of NutritionUniversity of California DavisDavisCaliforniaUSA
| | - Ping Kang
- USDA‐ARS Arkansas Children's Nutrition CenterLittle RockArkansasUSA
| | - Christopher E. Randolph
- Center for Translational Pediatric ResearchArkansas Children's Research InstituteLittle RockArkansasUSA
| | - Kartik Shankar
- Department of PediatricsSection of NutritionUniversity of Colorado School of MedicineAnschutz Medical CampusAuroraColoradoUSA
| | - Laxmi Yeruva
- USDA‐ARS Arkansas Children's Nutrition CenterLittle RockArkansasUSA
- Department of PediatricsUniversity of Arkansas for Medical SciencesLittle RockArkansasUSA
- Arkansas Children's Research InstituteLittle RockArkansasUSA
| | - Renee Fox
- USDA‐ARS Arkansas Children's Nutrition CenterLittle RockArkansasUSA
| | - Michael S. Robeson
- Department of Biomedical InformaticsUniversity of Arkansas for Medical SciencesLittle RockArkansasUSA
| | - Becky Moody
- USDA‐ARS Arkansas Children's Nutrition CenterLittle RockArkansasUSA
| | - Tanya LeRoith
- Department of Biomedical Science and PathobiologyVirginia Polytechnic Institute and State UniversityBlacksburgVirginiaUSA
| | - Kimber L. Stanhope
- Department of Molecular BiosciencesSchool of Veterinary MedicineUniversity of California DavisDavisCaliforniaUSA
- Department of NutritionUniversity of California DavisDavisCaliforniaUSA
| | - Sean H. Adams
- Department of SurgeryUniversity of California Davis School of MedicineSacramentoCaliforniaUSA
- Center for Alimentary and Metabolic ScienceUniversity of California Davis School of MedicineSacramentoCaliforniaUSA
| | - Peter J. Havel
- Department of Molecular BiosciencesSchool of Veterinary MedicineUniversity of California DavisDavisCaliforniaUSA
- Department of NutritionUniversity of California DavisDavisCaliforniaUSA
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11
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Klinge MW, Sutter N, Mark EB, Haase AM, Borghammer P, Schlageter V, Lund S, Fleischer J, Knudsen K, Drewes AM, Krogh K. Gastric Emptying Time and Volume of the Small Intestine as Objective Markers in Patients With Symptoms of Diabetic Enteropathy. J Neurogastroenterol Motil 2021; 27:390-399. [PMID: 34210904 PMCID: PMC8266501 DOI: 10.5056/jnm19195] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 03/13/2020] [Accepted: 12/19/2020] [Indexed: 12/15/2022] Open
Abstract
Background/Aims Patients with diabetes mellitus (DM) often suffer from gastrointestinal (GI) symptoms, but these correlate poorly to established objective GI motility measures. Our aim is to perform a detailed evaluation of potential measures of gastric and small intestinal motility in patients with DM type 1 and severe GI symptoms. Methods Twenty patients with DM and 20 healthy controls (HCs) were included. GI motility was examined with a 3-dimensional-Transit capsule, while organ volumes were determined by CT scans. Results Patients with DM and HCs did not differ with regard to median gastric contraction frequency (DM 3.0 contractions/minute [interquartile range {IQR}, 2.9-3.0]; HCs 2.9 [IQR, 2.8-3.1]; P = 0.725), amplitude of gastric contractions (DM 9 mm [IQR, 8-11]; HCs 11 mm (IQR, 9-12); P = 0.151) or fasting volume of the stomach wall (DM 149 cm3 [IQR, 112-187]; HCs 132 cm3 [IQR, 107-154]; P = 0.121). Median gastric emptying time was prolonged in patients (DM 3.3 hours [IQR, 2.6-4.6]; HCs 2.4 hours [IQR, 1.8-2.7]; P = 0.002). No difference was found in small intestinal transit time (DM 5 hours [IQR, 3.7-5.6]; HCs 4.8 hours [IQR, 3.9-6.0]; P = 0.883). However, patients with DM had significantly larger volume of the small intestinal wall (DM 623 cm3 [IQR, 487-766]; HCs 478 cm3 [IQR, 393-589]; P = 0.003). Among patients, 13 (68%) had small intestinal wall volume and 9 (50%) had gastric emptying time above the upper 95% percentile of HCs. Conclusion In our study, gastric emptying time and volume of the small intestinal wall appeared to be the best objective measures in patients with DM type 1 and symptoms and gastroenteropathy.
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Affiliation(s)
- Mette W Klinge
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
| | - Nanna Sutter
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
| | - Esben B Mark
- Mech-Sense, Department of Hepatology and Gastroenterology, and Department of Clinical Medicine, Aalborg University Hospital, Denmark
| | - Anne-Mette Haase
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
| | - Per Borghammer
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Denmark.,Department of Clinical Medicine, Aarhus University, Denmark
| | | | - Sten Lund
- Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Denmark.,Steno Diabetes Center Aarhus, Denmark
| | - Jesper Fleischer
- Steno Diabetes Center Aarhus, Denmark.,Steno Diabetes Center Copenhagen, Denmark
| | - Karoline Knudsen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Denmark
| | - Asbjørn M Drewes
- Mech-Sense, Department of Hepatology and Gastroenterology, and Department of Clinical Medicine, Aalborg University Hospital, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark.,Steno Diabetes Center Aarhus, Denmark
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12
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Castro VMDD, Medeiros KCDP, Lemos LICD, Pedrosa LDFC, Ladd FVL, Carvalho TGD, Araújo Júnior RFD, Abreu BJ, Farias NBDS. S-methyl cysteine sulfoxide ameliorates duodenal morphological alterations in streptozotocin-induced diabetic rats. Tissue Cell 2021; 69:101483. [PMID: 33444959 DOI: 10.1016/j.tice.2020.101483] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/08/2020] [Accepted: 12/22/2020] [Indexed: 12/14/2022]
Abstract
Diabetes mellitus (DM) is a metabolic disease associated with several intestinal disorders. S-methyl cysteine sulfoxide (SMCS) is an amino acid present in Allium cepa L with hypoglycemic effects. However, the effects of SMCS on diabetic intestinal changes are unknown. Thus, we aimed to investigate the effects of SMCS on duodenal morphology and immunomodulatory markers in diabetic rats. Twenty-six rats were divided into three groups: control (C), diabetic (D) and diabetic +200 mg/kg SMCS (DSM). DM was induced by intraperitoneal injection of streptozotocin (50 mg/kg). After 30 days, duodenum samples were processed to assess histopathological and stereological alterations in volume, villus length, and immunohistochemical expression of NF-kB, IL-10, BCL-2, and caspase-3. SMCS reduced hyperglycemia and mitigated the increase in total reference volume of the duodenum, the absolute volume of the mucosa, and the length of the intestinal crypts in the DMS group when compared to D. IL-10 immunostaining was reduced in D when compared to C, while NF-kB was increased in D in comparison to the other groups. SMCS supplementation could decrease the NF-kB immunostaining observed in D. Positive staining for BCL-2 and caspase-3 were not statistically different between groups. In summary, SMCS decreased hyperglycemia and mitigated the morphological changes of the duodenum in diabetic animals, and these beneficial effects can be partially explained by NF-kB modulation.
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Affiliation(s)
| | | | | | | | | | | | | | - Bento João Abreu
- Department of Morphology, Federal University of Rio Grande do Norte, Natal, Brazil.
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13
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Kornum DS, Terkelsen AJ, Bertoli D, Klinge MW, Høyer KL, Kufaishi HHA, Borghammer P, Drewes AM, Brock C, Krogh K. Assessment of Gastrointestinal Autonomic Dysfunction: Present and Future Perspectives. J Clin Med 2021; 10:jcm10071392. [PMID: 33807256 PMCID: PMC8037288 DOI: 10.3390/jcm10071392] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 11/16/2022] Open
Abstract
The autonomic nervous system delicately regulates the function of several target organs, including the gastrointestinal tract. Thus, nerve lesions or other nerve pathologies may cause autonomic dysfunction (AD). Some of the most common causes of AD are diabetes mellitus and α-synucleinopathies such as Parkinson’s disease. Widespread dysmotility throughout the gastrointestinal tract is a common finding in AD, but no commercially available method exists for direct verification of enteric dysfunction. Thus, assessing segmental enteric physiological function is recommended to aid diagnostics and guide treatment. Several established assessment methods exist, but disadvantages such as lack of standardization, exposure to radiation, advanced data interpretation, or high cost, limit their utility. Emerging methods, including high-resolution colonic manometry, 3D-transit, advanced imaging methods, analysis of gut biopsies, and microbiota, may all assist in the evaluation of gastroenteropathy related to AD. This review provides an overview of established and emerging assessment methods of physiological function within the gut and assessment methods of autonomic neuropathy outside the gut, especially in regards to clinical performance, strengths, and limitations for each method.
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Affiliation(s)
- Ditte S. Kornum
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
- Steno Diabetes Centre Aarhus, Aarhus University Hospital, DK8200 Aarhus, Denmark
- Correspondence:
| | - Astrid J. Terkelsen
- Department of Neurology, Aarhus University Hospital, DK8200 Aarhus, Denmark;
| | - Davide Bertoli
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, DK9100 Aalborg, Denmark; (D.B.); (A.M.D.); (C.B.)
| | - Mette W. Klinge
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
| | - Katrine L. Høyer
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
- Steno Diabetes Centre Aarhus, Aarhus University Hospital, DK8200 Aarhus, Denmark
| | - Huda H. A. Kufaishi
- Steno Diabetes Centre Copenhagen, Gentofte Hospital, DK2820 Gentofte, Denmark;
| | - Per Borghammer
- Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, DK8200 Aarhus, Denmark;
| | - Asbjørn M. Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, DK9100 Aalborg, Denmark; (D.B.); (A.M.D.); (C.B.)
- Steno Diabetes Centre North Jutland, Aalborg University Hospital, DK9100 Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, DK9100 Aalborg, Denmark; (D.B.); (A.M.D.); (C.B.)
- Steno Diabetes Centre North Jutland, Aalborg University Hospital, DK9100 Aalborg, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
- Steno Diabetes Centre Aarhus, Aarhus University Hospital, DK8200 Aarhus, Denmark
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14
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Pereira JNB, Murata GM, Sato FT, Marosti AR, Carvalho CRDO, Curi R. Small intestine remodeling in male Goto-Kakizaki rats. Physiol Rep 2021; 9:e14755. [PMID: 33580916 PMCID: PMC7881800 DOI: 10.14814/phy2.14755] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Obesity is associated with the development of insulin resistance (IR) and type-2 diabetes mellitus (T2DM); however, not all patients with T2DM are obese. The Goto-Kakizaki (GK) rat is an experimental model of spontaneous and non-obese T2DM. There is evidence that the intestine contributes to IR development in GK animals. This information prompted us to investigate small intestine remodeling in this animal model. METHODS Four-month-old male Wistar (control) and GK rats were utilized for the present study. After removing the small intestine, the duodenum, proximal jejunum, and distal ileum were separated. We then measured villi and muscular and mucosa layer histomorphometry, goblet cells abundance, total myenteric and submucosal neuron populations, and inflammatory marker expression in the small intestinal segments and intestinal transit of both groups of animals. KEY RESULTS We found that the GK rats exhibited decreased intestinal area (p < 0.0001), decreased crypt depth in the duodenum (p = 0.01) and ileum (p < 0.0001), increased crypt depth in the jejunum (p < 0.0001), longer villi in the jejunum and ileum (p < 0.0001), thicker villi in the duodenum (p < 0.01) and ileum (p < 0.0001), thicker muscular layers in the duodenum, jejunum, and ileum (p < 0.0001), increased IL-1β concentrations in the duodenum and jejunum (p < 0.05), and increased concentrations of NF-κB p65 in the duodenum (p < 0.01), jejunum and ileum (p < 0.05). We observed high IL-1β reactivity in the muscle layer, myenteric neurons, and glial cells of the experimental group. GK rats also exhibited a significant reduction in submucosal neuron density in the jejunum and ileum, ganglionic hypertrophy in all intestinal segments studied (p < 0.0001), and a slower intestinal transit (about 25%) compared to controls. CONCLUSIONS The development of IR and T2DM in GK rats is associated with small intestine remodeling that includes marked alterations in small intestine morphology, local inflammation, and reduced intestinal transit.
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Affiliation(s)
| | | | - Fabio Takeo Sato
- Department of GeneticsEvolution, Microbiology and ImmunologyInstitute of BiologyState University of CampinasCampinasBrazil
| | | | | | - Rui Curi
- Interdisciplinary Post‐Graduate Program in Health SciencesCruzeiro do Sul UniversitySão PauloBrazil
- Department of Physiology and BiophysicsInstitute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
- Butantan InstituteSão PauloBrazil
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15
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Panda SK, Buist ML. A viscoelastic framework for inflation testing of gastrointestinal tissue. J Mech Behav Biomed Mater 2020; 103:103569. [DOI: 10.1016/j.jmbbm.2019.103569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 11/26/2019] [Accepted: 11/29/2019] [Indexed: 12/01/2022]
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16
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Klinge MW, Borghammer P, Lund S, Fedorova T, Knudsen K, Haase AM, Christiansen JJ, Krogh K. Enteric cholinergic neuropathy in patients with diabetes: Non-invasive assessment with positron emission tomography. Neurogastroenterol Motil 2020; 32:e13731. [PMID: 31595630 DOI: 10.1111/nmo.13731] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/09/2019] [Accepted: 09/12/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND 11 C-Donepezil positron emission tomography (PET) allows non-invasive assessment of cholinergic innervation of visceral organs. We aimed to compare cholinergic innervation in the gut in patients with diabetes mellitus (DM) and in healthy controls (HC). METHODS 11 C-Donepezil PET and computed tomography (CT) were performed in 19 patients with type 1 DM and gastrointestinal symptoms and in 19 age- and sex-matched HC in a cross-sectional design. KEY RESULTS All patients had severe gastrointestinal symptoms when assessed by standard questionnaires. DM patients had significantly increased volume of the small intestinal wall (DM: median 557 cm3 [interquartile range [IQR] 446-697] vs HC median: 448 cm3 [IQR; 341-518; P < .01]), and the 11 C Donepezil PET uptake was reduced in patients (DM: median 7.08 standardized uptake value [SUV] [IQR; 5.94-8.43] vs HC: median 9.18 SUV [IQR; 8.57-10.11; P < .01]). A similar pattern was found in colon (DM: median volume 1064 cm3 [IQR; 882-1312] vs HC: median 939 cm3 [IQR; 785-1081; P = .13] and DM: median 1.22 SUV (IQR; 1.08-1.36) vs HC: median 1.42 SUV (IQR; 1.32-1.53; P = .03). Furthermore, patients had significantly reduced pancreatic volume (DM: median 53 cm3 [IQR; 41-69] vs HC: median 98 cm3 [IQR;82-110; P < .01]) and reduced PET uptake of the pancreas (DM: median 13.14 SUV [IQR;9.58-15.82] vs HC: median 21.46 SUV [IQR;18.97-24.06; P < .01]) as well as the adrenal gland (DM: median 7.62 SUV [IQR;7.61;15.82] vs HC: median 15.51 SUV [IQR;12.22;19.49; P = .03]). CONCLUSION AND INFERENCES Assessed with 11 C-Donepezil PET/CT, patients with DM and severe bowel symptoms have reduced cholinergic innervation of the gut indicative of parasympathetic denervation.
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Affiliation(s)
- Mette W Klinge
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Per Borghammer
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Sten Lund
- Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark.,Steno Diabetes Center, Aarhus, Denmark
| | - Tatyana Fedorova
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Karoline Knudsen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Anne-Mette Haase
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Jens Juel Christiansen
- Department of Internal Medicine and Endocrinology, Herning Regional Hospital, Herning, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.,Steno Diabetes Center, Aarhus, Denmark
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17
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Zhao J, Liao D, Gregersen H. Mechanical analysis of intestinal contractility in a neonatal maternal deprivation irritable bowel syndrome rat model. J Biomech 2019; 93:42-51. [PMID: 31213281 DOI: 10.1016/j.jbiomech.2019.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 06/05/2019] [Accepted: 06/05/2019] [Indexed: 02/07/2023]
Abstract
The aims of the present study are to investigate biomechanical properties and provide mechanical analysis of contractility in ileum and colon in a neonatal maternal deprivation (NMD) irritable bowel syndrome (IBS) rat model. Mechanical testing was done on segments from ileum and colon in 25 IBS rats and 13 Control rats. Morphometric data were obtained from digitized images of the segments at no-load and zero-stress states. Pressure and diameter changes were measured during flow and ramp distensions under active and passive experimental conditions. Circumferential stresses (force per area) and strains (deformation) were computed with referenced to the zero-stress state. The contraction frequency was analyzed. Contraction thresholds and maximum contraction amplitude were calculated in terms of mechanical stress and strain. Compared with controls, the IBS rats had lower body weight (P < 0.01), smaller colonic opening angle (P < 0.05), higher colonic contraction frequency (P < 0.05 and P < 0.01) and lower contraction thresholds of pressure, stress and strain in both ileum and colon (P < 0.05 and P < 0.01). The maximum contraction pressure, stress and strain did not differ between IBS and Control groups (P > 0.05). In conclusion, the pressure, stress, and strain to evoke contractility in ileum and colon were lower whereas the frequency of induced colon contractions was higher in NMD IBS rats compared to normal rats. Furthermore, zero-stress state remodeling occur in colon in NMD IBS rats. Further studies on the association between intestinal biomechanical properties, hypersensitivity and afferent signaling in the IBS animal models are warranted.
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Affiliation(s)
- Jingbo Zhao
- GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
| | - Donghua Liao
- GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | - Hans Gregersen
- GIOME, Department of Surgery, Prince of Wales Hospital and Chinese University of Hong Kong, Hong Kong Special Administrative Region
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18
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Bao L, Zhao J, Liao D, Wang G, Gregersen H. Refeeding reverses fasting-induced remodeling of afferent nerve activity in rat small intestine. Biomech Model Mechanobiol 2019; 18:1915-1926. [DOI: 10.1007/s10237-019-01185-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 06/05/2019] [Indexed: 02/08/2023]
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19
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Liu Y, Zhao J, Liao D, Wang G, Gregersen H. Stress-strain analysis of duodenal contractility in response to flow and ramp distension in rabbits fed low-fiber diet. Neurogastroenterol Motil 2019; 31:e13476. [PMID: 30246440 DOI: 10.1111/nmo.13476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 08/24/2018] [Accepted: 08/28/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Previously we demonstrated that low-fiber diet in rabbits affects the passive mechanomorphological properties in the small intestine, resulting in reduced intestinal wall thickness and collagen content, as well as intestinal wall softening. The aim of the present study was to evaluate the contractility in rabbits on long-term low-fiber diet and specifically to compare the contraction threshold, the frequency, and the amplitude of flow-induced and distension-induced contractions in the duodenum between rabbits on normal diet and on long-term low-fiber diet. METHODS Ten rabbits were fed a low-fiber diet for 5 months (Intervention group), and five rabbits were fed normal diet (Control group). The duodenal segments were used for determination of mechanical parameters for analyses of contractility. The duodenal experiments were carried out in organ baths containing physiological Krebs solution. Pressure and diameter changes induced by contractions in response to flow and ramp distension were measured. The frequencies and amplitude of contractions were analyzed. Distension-induced contraction thresholds and maximum contraction amplitude of flow-induced contractions were calculated in terms of mechanical stress and strain. Multiple linear regression analyses were applied to study dependencies between contractility parameters and wall thickness, wall area, and muscle layer thickness. KEY RESULTS During distension, the pressure, stress, and strain thresholds for induction of phasic contraction were biggest in the Intervention Group (P < 0.05). In addition, the contraction frequencies during flow-induced contraction were highest in the Intervention Group (P < 0.05), whereas the maximum contraction amplitudes in terms of pressure, diameter, stress, and strain were lowest in the Intervention Group (P < 0.05). The contraction thresholds and contraction frequencies were negatively associated with the wall thickness, wall area, and muscle layer thickness, whereas maximum contraction amplitudes were positively associated with the wall thickness, wall area, and muscle layer thickness. CONCLUSIONS AND INFERENCES Duodenal contractility in rabbits fed with long-term low-fiber diet exhibited low contraction amplitudes and high contraction thresholds and frequencies. The changes were associated with the low-fiber diet-induced histomorphological remodeling. Studies on detailed structural and functional diet-induced changes in smooth muscle and intestinal nerves are needed for better understanding the remodeling mechanisms.
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Affiliation(s)
- Yue Liu
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China.,GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.,Zhuhai Da Hengqin Technology Development Co. Ltd., Zhuhai, China
| | - Jingbo Zhao
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China.,GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.,Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | - Donghua Liao
- GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Guixue Wang
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China
| | - Hans Gregersen
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China.,GIOME, Department of Surgery, Chinese University of Hong Kong, Hong Kong SAR, China
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20
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Zhao J, Yang J, Liao D, Gregersen H. Interdependency between mechanical parameters and afferent nerve discharge in remodeled diabetic Goto-Kakizaki rat intestine. Clin Exp Gastroenterol 2017; 10:303-314. [PMID: 29238211 PMCID: PMC5716675 DOI: 10.2147/ceg.s145016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Background Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. Objective We aimed to characterize the stimulus–response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Design Seven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress–strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Results Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity (P<0.05). The stress relaxed less in the diabetic intestinal segment (P<0.05). Linear association between SRIR and the thickness of circumferential muscle layer was found at high stress levels as well as for SRIR and the glucose level. Conclusion Altered viscoelastic properties and elevated mechanosensitivity were found in the GK rat intestine. The altered nerve signaling is related to muscle layer remodeling and glucose levels and may contribute to gastrointestinal symptoms experienced by diabetic patients.
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Affiliation(s)
- Jingbo Zhao
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jian Yang
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Donghua Liao
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Hans Gregersen
- Giome Center, Department of Surgery, Chinese University of Hong Kong and Prince of Wales Hospital, Shatin, Hong Kong
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21
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Liu Y, Zhao J, Liao D, Wang G, Gregersen H. Intestinal Mechanomorphological Remodeling Induced by Long-Term Low-Fiber Diet in Rabbits. Ann Biomed Eng 2017; 45:2867-2878. [DOI: 10.1007/s10439-017-1922-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 09/11/2017] [Indexed: 12/23/2022]
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22
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Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes 2017; 8:249-269. [PMID: 28694926 PMCID: PMC5483424 DOI: 10.4239/wjd.v8.i6.249] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/05/2017] [Accepted: 05/05/2017] [Indexed: 02/05/2023] Open
Abstract
The disorders of gastrointestinal (GI) tract including intestine and colon are common in the patients with diabetes mellitus (DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DM-induced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.
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Liu Y, Zhao J, Liao D, Bao L, Gregersen H. Low-residue diet fed to rabbits induces histomorphological and biomechanical remodeling of small intestine. Neurogastroenterol Motil 2017; 29. [PMID: 27790839 DOI: 10.1111/nmo.12983] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 09/27/2016] [Indexed: 12/29/2022]
Abstract
BACKGROUND The composition of ingested food is important for the gut microbiome and intestinal homeostasis. We have previously demonstrated that the structure and mechanical properties in the small intestine remodel significantly during fasting. However, it is not clear to what extent the intestinal mechanical properties changes when the composition of food is changed. This study aimed to investigate the passive biomechanical properties and intestinal tissue remodeling in rabbits fed a low-residue diet. METHODS New Zealand rabbits (control group n=6, intervention group n=7) were studied. Segments from duodenum, jejunum and ileum were excised. The intestinal diameter and length were obtained from digitized images of the segments at preselected luminal pressure levels and at no-load and zero-stress states. Circumferential and longitudinal stresses (force per area) and strains (deformation) were computed from the length, diameter and pressure data referenced to the zero-stress state geometry. Histomorphometric data were also obtained. KEY RESULTS The wet weight-per-unit length, wall thickness and wall area decreased in the intervention group (P<.05, P<.01). Histological measurement confirmed that the wall thickness decreased in all three segments, which was primarily due to mucosal thinning (P<.05). The opening angle tended to increase in all segments in the intervention group. Significant difference between the two groups was found for the jejunum (P<.05). Feeding the low-residue diet shifted the circumferential stress-strain curves in the intervention group to the right, indicating intestinal wall softening. CONCLUSIONS & INFERENCES Low-residue diet in rabbits for 1 month induces location-dependent histomorphometric and biomechanical remodeling of the intestine.
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Affiliation(s)
- Y Liu
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.,GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - J Zhao
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.,GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - D Liao
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.,GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - L Bao
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China
| | - H Gregersen
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China
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24
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Ravages of Diabetes on Gastrointestinal Sensory-Motor Function: Implications for Pathophysiology and Treatment. Curr Gastroenterol Rep 2016; 18:6. [PMID: 26768896 DOI: 10.1007/s11894-015-0481-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Symptoms related to functional and sensory abnormalities are frequently encountered in patients with diabetes mellitus. Most symptoms are associated with impaired gastric and intestinal function. In this review, we discuss basic concepts of sensory-motor dysfunction and how they relate to clinical findings and gastrointestinal abnormalities that are commonly seen in diabetes. In addition, we review techniques that are available for investigating the autonomic nervous system, neuroimaging and neurophysiology of sensory-motor function. Such technological advances, while not readily available in the clinical setting, may facilitate stratification and individualization of therapy in diabetic patients in the future. Unraveling the structural, mechanical, and sensory remodeling in diabetes disease is based on a multidisciplinary approach that can bridge the knowledge from a variety of scientific disciplines. The final goal is to increase the understanding of the damage to GI structures and to sensory processing of symptoms, in order to assist clinicians with developing an optimal mechanics based treatment.
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25
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D'Addio F, Fiorina P. Type 1 Diabetes and Dysfunctional Intestinal Homeostasis. Trends Endocrinol Metab 2016; 27:493-503. [PMID: 27185326 DOI: 10.1016/j.tem.2016.04.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 04/09/2016] [Accepted: 04/13/2016] [Indexed: 12/11/2022]
Abstract
Despite the relatively high frequency of gastrointestinal (GI) disorders in individuals with type 1 diabetes (T1D), termed diabetic enteropathy (DE), the pathogenic mechanisms of these disorders remain to be elucidated. While previous studies have assumed that DE is a manifestation of diabetic autonomic neuropathy, other contributing factors such as enteric hormones, inflammation, and microbiota were later recognized. More recently, the emerging role of intestinal stem cells (ISCs) in several GI diseases has led to a new understanding of DE. Given the absence of diagnostic methods and the lack of broadly efficacious therapeutic remedies in DE, targeting factors and pathways that control ISC homeostasis and are dysfunctional in DE may represent a new path for the detection and cure of DE.
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Affiliation(s)
- Francesca D'Addio
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Paolo Fiorina
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
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26
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Ouyang H, Yang HS, Yu T, Shan TD, Li JY, Huang CZ, Zhong W, Xia ZS, Chen QK. MEK/ERK pathway activation by insulin receptor isoform alteration is associated with the abnormal proliferation and differentiation of intestinal epithelial cells in diabetic mice. Mol Cell Biochem 2016; 413:165-78. [PMID: 26724951 DOI: 10.1007/s11010-015-2650-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 12/23/2015] [Indexed: 12/15/2022]
Abstract
In previous studies, we have reported the abnormal proliferation and differentiation of intestinal epithelial cells (IECs) in diabetes mellitus (DM) mice. The insulin receptor (IR) and its downstream mitogen-activated protein kinase kinase (MAPKK also known as MEK)/extracellular-regulated protein kinase (ERK) pathway is a classic pathway associated with cell proliferation and differentiation. The purpose of the present study is to investigate the role of the MEK/ERK pathway in abnormal proliferation and differentiation of IECs in DM mice. DM mouse models were induced by intraperitoneal injection of streptozotocin. The expression levels of the IR and its isoforms in IECs of DM mice and in IEC-6 cells were investigated. To ensure that the downstream pathways were monitored, QPCR and Western blotting were performed to detect the expression levels of MEK1/2, ERK1/2, PI3K, and Akt. Moreover, siRNA for IR-A and U0126, a specific inhibitor of MEK, were used to further investigate the relationship between the IR/MEK/ERK pathway and abnormal proliferation and differentiation of IECs in DM mice. In DM mice, excessive proliferation, disturbed differentiation, and a high ratio of IR-A/IR-B were detected in IECs. The expression levels of MEK1, MEK2, and ERK1/2 and their phosphorylated proteins in DM mice were significantly higher than those in the control group (P < 0.05), which could be offset by using siRNA for IR-A. The abnormal proliferation and differentiation of IECs in DM mice were normalized after the in vivo administration of U0126. The abnormal proliferation and differentiation of IECs in DM mice are associated with high IR-A/IR-B ratio and increased IR/MEK/ERK pathway activity.
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Affiliation(s)
- Hui Ouyang
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Hong-Sheng Yang
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Tao Yu
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China.
| | - Ti-Dong Shan
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Jie-Yao Li
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Can-Ze Huang
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Wa Zhong
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Zhong-Sheng Xia
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Qi-Kui Chen
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, 510120, Guangdong, People's Republic of China.
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27
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Siegman MJ, Eto M, Butler TM. Remodeling of the rat distal colon in diabetes: function and ultrastructure. Am J Physiol Cell Physiol 2016; 310:C151-60. [PMID: 26561639 PMCID: PMC4719031 DOI: 10.1152/ajpcell.00253.2015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 11/10/2015] [Indexed: 01/08/2023]
Abstract
This study seeks to define and explain remodeling of the distal colon in the streptozotocin (STZ)-treated rat model of diabetes through analysis of resting and active length dependence of force production, chemical composition, and ultrastructure. Compared with untreated controls, the passive stiffness on extension of the diabetic muscle is high, and active force produced at short muscle lengths is amplified but is limited by an internal resistance to shortening. The latter are accounted for by a significant increase in collagen type 1, with no changes in types 3 and 4. In the diabetic colon, ultrastructural studies show unique, conspicuous pockets of collagen among muscle cells, in addition to a thickened basement membrane and an extracellular space filled with collagen fibers and various fibrils. Measurements of DNA and total protein content revealed that the diabetic colon underwent hypertrophy, along with a proportional increase in actin and myosin contents, with no change in the actin-to-myosin ratio. Active force production per cross-sectional area was not different in the diabetic and normal muscles, consistent with the proportionality of changes in contractile proteins. The stiffness and the limit to shortening of the diabetic colon were significantly reduced by treatment with the glycation breaker alagebrium chloride (ALT-711), with no change in collagen contents. Functionally, this study shows that, in diabetes, the production of collagen type 1 and glycation increase stiffness, which limits distensibility on filling and limits shortening and expulsion of contents, both of which can be alleviated by treatment with ALT-711.
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Affiliation(s)
- Marion J Siegman
- Department of Molecular Physiology and Biophysics, Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Masumi Eto
- Department of Molecular Physiology and Biophysics, Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Thomas M Butler
- Department of Molecular Physiology and Biophysics, Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania
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28
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da Rosa CVD, Azevedo SCSF, Bazotte RB, Peralta RM, Buttow NC, Pedrosa MMD, de Godoi VAF, Natali MRM. Supplementation with L-Glutamine and L-Alanyl-L-Glutamine Changes Biochemical Parameters and Jejunum Morphophysiology in Type 1 Diabetic Wistar Rats. PLoS One 2015; 10:e0143005. [PMID: 26659064 PMCID: PMC4681705 DOI: 10.1371/journal.pone.0143005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 10/29/2015] [Indexed: 01/01/2023] Open
Abstract
We evaluated the effects of the supplementation with L-glutamine and glutamine dipeptide (GDP) on biochemical and morphophysiological parameters in streptozotocin-diabetic rats. For this purpose, thirty animals were distributed into six groups treated orally (gavage) during thirty days: non diabetic rats (Control) + saline, diabetic + saline; Control + L-glutamine (248 mg/kg), Diabetic + L-glutamine (248 mg/kg), Control + GDP (400 mg/kg), Diabetic + GDP (400 mg/kg). Diabetes was induced by an intravenous injection of streptozotocin (60 mg/kg) and confirmed by fasting glucose ≥ 200 mg/dL. Physiological parameters, i.e., body mass, food intake, blood glucose, water intake, urine and faeces were evaluated during supplementation. After the period of supplementation, the animals were euthanized. The blood was collected for biochemical assays (fructosamine, transaminases, lipid profile, total protein, urea, ammonia). Moreover, the jejunum was excised and stored for morphophysiological assays (intestinal enzyme activity, intestinal wall morphology, crypt proliferative index, number of serotoninergic cells from the mucosa, and vipergic neurons from the submucosal tunica). The physiological parameters, protein metabolism and intestinal enzyme activity did not change with the supplementation with L-glutamine or GDP. In diabetic animals, transaminases and fructosamine improved with L-glutamine and GDP supplementations, while the lipid profile improved with L-glutamine. Furthermore, both forms of supplementation promoted changes in jejunal tunicas and wall morphometry of control and diabetic groups, but only L-glutamine promoted maintenance of serotoninergic cells and vipergic neurons populations. On the other hand, control animals showed changes that may indicate negative effects of L-glutamine. Thus, the supplementation with L-glutamine was more efficient for maintaining intestinal morphophysiology and the supplementation with GDP was more efficient to the organism as a whole. Thus, we can conclude that local differences in absorption and metabolism could explain the differences between the supplementation with L-glutamine or GDP.
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Affiliation(s)
| | | | - Roberto B. Bazotte
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná, Brazil
| | - Rosane M. Peralta
- Department of Biochemistry, State University of Maringá, Maringá, Paraná, Brazil
| | - Nilza C. Buttow
- Department of Morphological Sciences, State University of Maringá, Maringá, Paraná, Brazil
| | | | - Vilma A. F. de Godoi
- Department of Physiological Sciences, State University of Maringá, Maringá, Paraná, Brazil
| | - Maria Raquel M. Natali
- Department of Morphological Sciences, State University of Maringá, Maringá, Paraná, Brazil
- * E-mail: (MR)
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29
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Morphometric and biomechanical remodeling of the small intestine during aging in rats. J Biomech 2015; 48:4271-8. [DOI: 10.1016/j.jbiomech.2015.10.034] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 10/22/2015] [Accepted: 10/23/2015] [Indexed: 01/27/2023]
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30
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D'Addio F, La Rosa S, Maestroni A, Jung P, Orsenigo E, Nasr MB, Tezza S, Bassi R, Finzi G, Marando A, Vergani A, Frego R, Albarello L, Andolfo A, Manuguerra R, Viale E, Staudacher C, Corradi D, Batlle E, Breault D, Secchi A, Folli F, Fiorina P. Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy. Cell Stem Cell 2015; 17:486-498. [PMID: 26431183 PMCID: PMC4826279 DOI: 10.1016/j.stem.2015.07.010] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 06/02/2015] [Accepted: 07/19/2015] [Indexed: 01/10/2023]
Abstract
The role of circulating factors in regulating colonic stem cells (CoSCs) and colonic epithelial homeostasis is unclear. Individuals with long-standing type 1 diabetes (T1D) frequently have intestinal symptoms, termed diabetic enteropathy (DE), though its etiology is unknown. Here, we report that T1D patients with DE exhibit abnormalities in their intestinal mucosa and CoSCs, which fail to generate in vitro mini-guts. Proteomic profiling of T1D+DE patient serum revealed altered levels of insulin-like growth factor 1 (IGF-I) and its binding protein 3 (IGFBP3). IGFBP3 prevented in vitro growth of patient-derived organoids via binding its receptor TMEM219, in an IGF-I-independent manner, and disrupted in vivo CoSC function in a preclinical DE model. Restoration of normoglycemia in patients with long-standing T1D via kidney-pancreas transplantation or in diabetic mice by treatment with an ecto-TMEM219 recombinant protein normalized circulating IGF-I/IGFBP3 levels and reestablished CoSC homeostasis. These findings demonstrate that peripheral IGF-I/IGFBP3 controls CoSCs and their dysfunction in DE.
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Affiliation(s)
- Francesca D'Addio
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA
- Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Stefano La Rosa
- Department of Pathology, Ospedale di Circolo, Varese 21100, Italy
| | - Anna Maestroni
- Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Peter Jung
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain
| | - Elena Orsenigo
- Surgery, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Moufida Ben Nasr
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA
- Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Sara Tezza
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA
- Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Roberto Bassi
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA
- Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Giovanna Finzi
- Department of Pathology, Ospedale di Circolo, Varese 21100, Italy
| | | | - Andrea Vergani
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA
- Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Roberto Frego
- Gastroenterology, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Luca Albarello
- Pathology Unit, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Annapaola Andolfo
- ProMiFa, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Roberta Manuguerra
- Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma 43121, Italy
| | - Edi Viale
- Gastroenterology, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Carlo Staudacher
- Surgery, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Domenico Corradi
- Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma 43121, Italy
| | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08028, Spain
| | - David Breault
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA
| | - Antonio Secchi
- Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy
- Vita Salute San Raffaele University, Milano 20132, Italy
| | - Franco Folli
- Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio 78229, Texas, USA
- Department of Internal Medicine, Obesity and Comorbidities Research Center (O.C.R.C.), State University of Campinas, São Paulo 13100, Brazil
| | - Paolo Fiorina
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA
- Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy
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31
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Zhong XY, Yu T, Zhong W, Li JY, Xia ZS, Yuan YH, Yu Z, Chen QK. Lgr5 positive stem cells sorted from small intestines of diabetic mice differentiate into higher proportion of absorptive cells and Paneth cells in vitro. Dev Growth Differ 2015; 57:453-465. [PMID: 26122164 DOI: 10.1111/dgd.12226] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 04/22/2015] [Accepted: 05/06/2015] [Indexed: 12/13/2022]
Abstract
Intestinal epithelial stem cells (IESCs) can differentiate into all types of intestinal epithelial cells (IECs) and Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) is a marker for IESC. Previous studies reported enhanced proliferation of IECs in diabetic mice. In this study, the in vitro differentiation of Lgr5 positive IESCs sorted from diabetic mice was further investigated. The diabetic mouse model was induced by streptozotocin (STZ), and crypt IECs were isolated from small intestines. Subsequently, Lgr5 positive IESCs were detected by flow cytometry (FCM) and sorted by magnetic activated cell sorting (MACS). Differentiation of the sorted IESCs was investigated by detecting the IEC markers in the diabetic mice using immunostaining, quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR), and Western blot analysis, which was compared with normal mice. We found that the proportion of Lgr5 positive cells in the crypt IECs of diabetic mice was higher than that of control mice (P < 0.05). Lgr5 positive IESCs could be significantly enriched in Lgr5 positive cell fraction sorted by MACS. Furthermore, the absorptive cell marker sucrase-isomaltase (SI) and the Paneth cell marker lysozyme 1 (Lyz1) were more highly expressed in the differentiated cells derived from Lgr5 positive IESCs of diabetic mice in vitro (P < 0.05). We demonstrate that the number of Lgr5 positive IESCs is significantly increased in the small intestines of STZ-induced diabetic mice. Lgr5 positive IESCs sorted from the diabetic mice can differentiate into a higher proportion of absorptive cells and Paneth cells in vitro. We characterized the expression of Lgr5 in the small intestine of diabetic mice, and sorted Lgr5 positive intestinal epithelial stem cells (IESCs) for investigating their differentiation in vitro. We proved that the quantity of Lgr5 positive IESCs was significantly increased in the small intestines of diabetic mice. IESCs sorted from the diabetic mice can differentiate into a higher proportion of absorptive cells and Paneth cells in vitro.
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Affiliation(s)
- Xian-Yang Zhong
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, 510120, China
| | - Tao Yu
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, 510120, China
| | - Wa Zhong
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, 510120, China
| | - Jie-Yao Li
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, 510120, China
| | - Zhong-Sheng Xia
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, 510120, China
| | - Yu-Hong Yuan
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, 510120, China
| | - Zhong Yu
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, 510120, China
| | - Qi-Kui Chen
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, 510120, China
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32
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Chen PM, Gregersen H, Zhao JB. Advanced glycation end-product expression is upregulated in the gastrointestinal tract of type 2 diabetic rats. World J Diabetes 2015; 6:662-672. [PMID: 25987965 PMCID: PMC4434088 DOI: 10.4239/wjd.v6.i4.662] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Revised: 03/04/2015] [Accepted: 03/18/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate changes in advanced glycation end products (AGEs) and their receptor (RAGE) expression in the gastrointestinal (GI) tract in type 2 diabetic rats.
METHODS: Eight inherited type 2 diabetic rats Goto-Kakizak (GK) and ten age-matched normal rats were used in the study. From 18 wk of age, the body weight and blood glucose were measured every week and 2 wk respectively. When the rats reached 32 wk, two-centimeter segments of esophagus, duodenum, jejunum, ileum, and colon were excised and the wet weight was measured. The segments were fixed in 10% formalin, embedded in paraffin and five micron sections were cut. The layer thickness was measured in Hematoxylin and Eosin-stained slides. AGE [N epsilon-(carboxymethyl) lysine and N epsilon-(carboxyethyl)lysine] and RAGE were detected by immunohistochemistry staining and image analysis was done using Sigmascan Pro 4.0 image analysis software.
RESULTS: The blood glucose concentration (mmol/L) at 18 wk age was highest in the GK group (8.88 ± 1.87 vs 6.90 ± 0.43, P < 0.001), a difference that continued to exist until the end of the experiment. The wet weight per unit length (mg/cm) increased in esophagus, jejunum and colon from the normal to the GK group (60.64 ± 9.96 vs 68.56 ± 11.69, P < 0.05 for esophagus; 87.01 ± 9.35 vs 105.29 ± 15.45, P < 0.01 for jejunum; 91.37 ± 7.25 vs 97.28 ± 10.90, P < 0.05 for colon). Histologically, the layer thickness of the GI tract was higher for esophagus, jejunum and colon in the GK group [full thickness (μm): 575.37 ± 69.22 vs 753.20 ± 150.41, P < 0.01 for esophagus; 813.51 ± 44.44 vs 884.81 ± 45.31, P < 0.05 for jejunum; 467.12 ± 65.92 vs 572.26 ± 93.60, P < 0.05 for colon]. In esophagus, the AGE and RAGE mainly distributed in striated muscle cells and squamous epithelial cells. The AGE distribution was much stronger in the GK group compared to the normal group both in the striated muscle layer and mucosa layer (immuno-positive area/ total measuring area %: 4.52 ± 0.89 vs 10.96 ± 1.34, P < 0.01 for muscle; 8.90 ± 2.62 vs 22.45 ± 1.26, P < 0.01 for mucosa). No visible difference was found for RAGE distribution between the two groups. In the intestine AGE and RAGE distributed in epithelial cells of villi and crypt. RAGE was also found in neurons in the myenteric and submucosal plexus. The intensity of AGE staining in mucosa of all segments and RAGE staining in neurons in all segments were strongest in the diabetes group. Significant difference for AGE was found in the epithelial cells of villi and crypt in duodenum (immuno-positive area/total measuring area %: 13.37 ± 3.51 vs 37.48 ± 8.43, P < 0.05 for villi; 0.38 ± 0.12 vs 1.87 ± 0.53, P < 0.05 for crypt) and for RAGE in neurons of all segments (e.g., for jejunum: no staining neurons% 0 vs 0, mild 36.0 ± 5.2 vs 28.7 ± 3.5, moderate 53.2 ± 4.8 vs 55.8 ± 5.4, strong 10.7 ± 1.1 vs 15.4 ± 2.0, P < 0.05). In the colon, RAGE was primarily found in neurons in the myenteric and submucosal plexus. It was stronger in the diabetes group than in the normal group (no staining neurons% 6.2 ± 0.2 vs 0.3 ± 0.04, mild 14.9 ± 2.1 vs 17.6 ± 1.5, moderate 53.1 ± 4.6 vs 44.7 ± 4.4, strong 25.6 ± 18 vs 43.6 ± 4.0, P < 0.05). In the rectum, RAGE was primarily found in the mucosa epithelial cells.
CONCLUSION: The AGE and RAGE expression was up-regulated in the GI tract of GK diabetic rats and may contribute to GI dysfunction in type 2 diabetic patients.
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Zhao J, Chen P, Gregersen H. Stress-strain analysis of contractility in the ileum in response to flow and ramp distension in streptozotocin-induced diabetic rats--association with advanced glycation end product formation. J Biomech 2015; 48:1075-83. [PMID: 25682538 DOI: 10.1016/j.jbiomech.2015.01.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 12/23/2014] [Accepted: 01/24/2015] [Indexed: 12/28/2022]
Abstract
This study compared the ileal contractility and analyzed the association between contractility with advanced glycation end product (AGE) formation in normal and streptozotocin (STZ)-induced diabetic rats. Nine STZ-induced diabetic rats (Diabetes group) and 9 normal rats (Normal group) were used. The motility experiments were carried out on ileums in organ baths containing physiological Krebs solution. Ileal pressure and diameter changes were obtained from basic, flow-induced and ramp distension-induced contractions. The frequency and amplitude of contractions were analyzed from pressure-diameter curves. Distension-induced contraction thresholds and maximum contraction amplitude of basic and flow-induced contractions were calculated in terms of stress and strain. AGE and its receptor (RAGE) in the layers were detected by immunohistochemistry staining. The maximum stress of flow-induced contractions was lowest in the Diabetes Group (P<0.05). During ramp distension, the pressure and stress thresholds and Young's modulus to induce phasic contraction were lowest in the Diabetes Group (P<0.05 and P<0.01). AGE and RAGE expressions in the different ileum layers were highest in the Diabetes group. The contraction pressure and stress thresholds were significantly associated with AGE expression in the muscle layer and RAGE expression in mucosa epithelium and neurons. The diabetic intestine was hypersensitive to distension for contraction induction. However, the contraction force produced by smooth muscle was lowest in diabetic rats. Increased AGE/RAGE expression was associated with the contractility changes in diabetic rats.
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Affiliation(s)
- Jingbo Zhao
- Institute of Clinical medicine, Aarhus University, Brendstrupgaardsvej 100, Aarhus N 8200, Denmark; GIOME Center, College of Bioengineering, Chongqing University, Chongqing 400045, China
| | - Pengmin Chen
- Department of Molecular Biology, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China
| | - Hans Gregersen
- GIOME Center, College of Bioengineering, Chongqing University, Chongqing 400045, China.
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Asht LDS, Rêgo TDS, Pessoa LR, Leite J, Ferreira AM, dos Santos ADS, Feijó MBDS, dos Anjos JS, Correia-Santos AM, da Costa CAS, Boaventura GT. The effects of Yam (Dioscorea bulbifera) intake on small intestine morphology in streptozotocin-induced diabetic rats. Int J Food Sci Technol 2014. [DOI: 10.1111/ijfs.12598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Louise da S. Asht
- Experimental Nutrition Laboratory; College of Nutrition; Federal Fluminense University; Rua Mário Santos Braga, 30 Niterói RJ 24020-140 Brazil
| | - Thaís de S. Rêgo
- Experimental Nutrition Laboratory; College of Nutrition; Federal Fluminense University; Rua Mário Santos Braga, 30 Niterói RJ 24020-140 Brazil
| | - Letícia R. Pessoa
- Experimental Nutrition Laboratory; College of Nutrition; Federal Fluminense University; Rua Mário Santos Braga, 30 Niterói RJ 24020-140 Brazil
| | - Juliana Leite
- Department of Pathology and Veterinary Clinics; Veterinary Faculty; Federal Fluminense University; Rua Vital Brazil, 64, Vital Brazil Niterói RJ 24230-340 Brazil
| | - Ana M. Ferreira
- Department of Pathology and Veterinary Clinics; Veterinary Faculty; Federal Fluminense University; Rua Vital Brazil, 64, Vital Brazil Niterói RJ 24230-340 Brazil
| | - Aline de S. dos Santos
- Physiological Sciences Department; Institute of Biology Roberto Alcantara Gomes; State University of Rio de Janeiro; Av. 28 de Setembro, 87 Vila Isabel Rio de Janeiro RJ 20551-030 Brazil
| | - Márcia B. da S. Feijó
- Bromatology Laboratory; College of Pharmacy; Federal Fluminense University; Rua Dr. Mário Viana, 523 Niterói RJ 24241- 001 Brazil
| | - Juliana S. dos Anjos
- Experimental Nutrition Laboratory; College of Nutrition; Federal Fluminense University; Rua Mário Santos Braga, 30 Niterói RJ 24020-140 Brazil
| | - André M. Correia-Santos
- Experimental Nutrition Laboratory; College of Nutrition; Federal Fluminense University; Rua Mário Santos Braga, 30 Niterói RJ 24020-140 Brazil
| | - Carlos A. S. da Costa
- Experimental Nutrition Laboratory; College of Nutrition; Federal Fluminense University; Rua Mário Santos Braga, 30 Niterói RJ 24020-140 Brazil
| | - Gilson T. Boaventura
- Experimental Nutrition Laboratory; College of Nutrition; Federal Fluminense University; Rua Mário Santos Braga, 30 Niterói RJ 24020-140 Brazil
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Tronchini EA, Trevizan AR, Tashima CM, De Freitas P, Bazotte RB, Pereira MAS, Zanoni JN. Effect of l-glutamine on myenteric neuron and of the mucous of the ileum of diabetic rats. AN ACAD BRAS CIENC 2013; 85:1165-76. [PMID: 24068096 DOI: 10.1590/s0001-37652013005000052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 03/15/2013] [Indexed: 11/21/2022] Open
Abstract
The objective of this work was to investigate the effect of the L-glutamine supplementation to prevent - diabetes induced changes in myenteric neurons and also to verify the effect on the mucosa of the ileum of Wistar rats. The animals were divided in five groups (n = 5): untreated normoglycaemic (UN), normoglycaemic treated with L-glutamine (NG), untreated diabetics (UD), diabetics treated with L-glutamine, starting on the 4th (DG4) or 45th day following diabetes induction (DG45). The amino acid was added to the diet at 1%. The density and size of neurons, the metaphasic index in the crypt, the height of the villus, the depth of the crypt and the number of globet cells were determined. There was no difference in the neuronal density and in the cellular body area of the myosin-stained myenteric neurons of groups DG4 and DG45 when compared to group D. The metaphase index and the number of goblet cells showed no significant differences when all groups were compared (P > 0.05). The villi height of groups DG4 and DG45 were 45.5% (P < 0.05) and 32.4% (P > 0.05) higher than those in group UD, respectively. The analyzed crypts showed similar depth for all studied groups.
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Affiliation(s)
- Eleandro A Tronchini
- Departamento de Ciências Morfológicas, Universidade Estadual de Maringá, 87020-900 Maringá, PR, Brasil
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Zhao J, Chen P, Gregersen H. Stress-strain analysis of jejunal contractility in response to flow and ramp distension in type 2 diabetic GK rats: effect of carbachol stimulation. J Biomech 2013; 46:2469-76. [PMID: 23932327 DOI: 10.1016/j.jbiomech.2013.07.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 07/09/2013] [Accepted: 07/09/2013] [Indexed: 12/16/2022]
Abstract
Investigation of intestinal motility in a genetic model of GK rats abandons the possible neurotoxic effect of streptozotocin in streptozotocin-induced diabetic model. Seven GK male rats (GK group) and nine normal Wistar rats (Normal group) were used in the study. The motility experiments were carried out in an organ bath containing physiological Krebs solution. Before and after 10(-5)M carbachol application, the pressure and diameter changes of jejunum were obtained in relation to (1) basic contraction, (2) flow-induced contraction with different outlet resistance pressures and (3) contractions induced by ramp distension. The frequency and amplitude of contractions were analyzed from pressure-diameter curves. Distension-induced contraction thresholds and maximum contraction amplitude of basic and flow-induced contractions were calculated in terms of stress and strain. (1) The contraction amplitude increased to the peak value in less than 10s after adding carbachol. More than two peaks were observed in the GK group. (2) Carbachol decreased the pressure and stress threshold and Young's modulus in the GK group (P<0.01). (3) Carbachol increased the maximum pressure and stress of flow-induced contractions at most outlet pressure levels in both two groups (P<0.001). Furthermore, the flow-induced contractions were significantly bigger at low outlet pressure levels in GK group (P<0.05 and P<0.01). (4) The contraction frequency, the strain threshold and the maximum contraction strain did not differ between the two groups (P>0.05) and between before and after carbachol application (P>0.05). In GK diabetic rats, the jejunal contractility was hypersensitive to flow and distension stimulation after carbachol application.
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Affiliation(s)
- Jingbo Zhao
- Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, DK 9000 Aalborg, Denmark; Clinical Institute, Aarhus University, 8200 Aarhus N, Denmark; The College of Bioengineering, Chongqing University, Chongqing, China.
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Zhao J, Chen P, Gregersen H. Morpho-mechanical intestinal remodeling in type 2 diabetic GK rats--is it related to advanced glycation end product formation? J Biomech 2013; 46:1128-34. [PMID: 23403079 DOI: 10.1016/j.jbiomech.2013.01.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Revised: 01/07/2013] [Accepted: 01/13/2013] [Indexed: 12/14/2022]
Abstract
Little is known about the mechanisms for the biomechanical remodeling in diabetes. The histomorphology, passive biomechanical properties and expression of advanced glycation end product (N epsilon-(carboxymethyl) lysine, AGE) and its receptor (RAGE) were studied in jejunal segments from 8 GK diabetic rats (GK group) and 10 age-matched normal rats (Normal group). The mechanical test was done by using a ramp distension of fluid into the jejunal segments in vitro. Circumferential stress and strain were computed from the length, diameter and pressure data and from the zero-stress state geometry. AGE and RAGE were detected by immunohistochemistry staining. Linear regression analysis was done to study association between the glucose level and AGE/RAGE expression with the histomorphometric and biomechanical parameters. The blood glucose level, the jejunal weight per length, wall thickness, wall area and layer thickness significantly increased in the GK group compared with the Normal group (P<0.05, P<0.01 and P<0.001). The opening angle and absolute values of residual strain decreased whereas the circumferential stiffness of the jejunal wall increased in the GK group (P<0.05 and P<0.01). Furthermore, stronger AGE expression in the villi and crypt and RAGE expression in the villi were found in the GK group (P<0.05 and P<0.01). Most histomorphometric and biomechanical changes were associated with blood glucose level and AGE/RAGE expression. In conclusion, histomorphometric and biomechanical remodeling occurred in type 2 diabetic GK rats. The increasing blood glucose level and the increased AGE/RAGE expression were associated with the remodeling, indicating a causal relationship.
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Affiliation(s)
- Jingbo Zhao
- Mech-Sense, Department of Gastroenterology and Surgery, Aalborg University Hospital, Soendre Skovvej 15, DK 9000 Aalborg, Denmark.
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Frøkjaer JB, Brock C, Brun J, Simren M, Dimcevski G, Funch-Jensen P, Drewes AM, Gregersen H. Esophageal distension parameters as potential biomarkers of impaired gastrointestinal function in diabetes patients. Neurogastroenterol Motil 2012; 24:1016-e544. [PMID: 22738347 DOI: 10.1111/j.1365-2982.2012.01966.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastrointestinal (GI) symptoms, such as nausea, vomiting, bloating, postprandial fullness, and abdominal pain, are frequent in patients with diabetes mellitus (DM). The pathogenesis is complex and multi-factorial. To determine easy accessible and valid biomarkers for disordered GI function in DM patients, we aimed to study esophageal mechanical parameters and their relation to symptoms typically arising from the digestive tract. METHODS Seventeen patients with longstanding DM and GI symptoms and 13 healthy controls were studied using ultrasound monitored esophageal distension. The sensory response was recorded and their symptoms registered. Biomechanical parameters, such as compliance and stiffness were computed from luminal diameters during distension based on the ultrasound images and from pressure data. Biomechanical and sensory parameters were correlated with the clinical data. KEY RESULTS Diabetes patients had reduced esophageal sensitivity compared with controls (P = 0.046). The esophageal compliance was reduced (P = 0.004) and the esophageal stiffness was increased (P = 0.004) in the diabetes patients. Among patients, both postprandial fullness/early satiety and bloating correlated negatively to the esophageal compliance parameters (all P < 0.05). CONCLUSIONS & INFERENCES Patients with long-standing DM and GI symptoms had reduced esophageal sensitivity together with reduced compliance and increased stiffness, which were correlated to the patients' GI symptoms. Biomechanical parameters obtained during distension may serve as biomarker for similar pathophysiologic effects of diabetes in the stomach and small bowel. They may contribute to our understanding of the pathophysiology underlying GI dysfunction and symptoms in patients with longstanding DM.
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Affiliation(s)
- J B Frøkjaer
- Mech-Sense, Department of Radiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
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Liu GF, Zhao JB, Zhen Z, Sha H, Chen PM, Li M, Zhang JC, Yuan MZ, Gao W, Gregersen H, Tong XL. Effect of Tangweian Jianji on upper gastrointestinal remodeling in streptozotocin-induced diabetic rats. World J Gastroenterol 2012; 18:4875-84. [PMID: 23002359 PMCID: PMC3447269 DOI: 10.3748/wjg.v18.i35.4875] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Revised: 04/23/2012] [Accepted: 04/27/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of Tangweian Jianji (TWAJJ) on the biomechanical and morphometrical remodeling of the upper gastrointestinal tract in diabetic rats.
METHODS: Diabetes was induced in 27 rats by injecting streptozotocin (40 mg/kg body weight), the animals were then divided into three groups (n = 9 in each group), i.e., diabetic control (DM); high dose (10 g/kg, T1) and low dose (5 g/kg, T2). Another 10 rats acted as normal controls (Control). TWAJJ was administered by gavage once daily. Blood glucose and serum insulin levels were measured. Circumferential length, wall thickness and opening angle were measured from esophageal, duodenal, jejunal and ileal ring segments. The residual strain was calculated from the morphometric data. Step-wise distension was carried out on esophageal and jejunal segments. The obtained data on the length, diameter and pressure changes were then used to calculate the circumferential and longitudinal stresses and strains. Real-time reverse transcription polymerase chain reaction was used to detect the receptor of advanced glycation end-products (RAGE) mRNA level in jejunal tissues.
RESULTS: At the end of the experiment, the blood glucose level was significantly higher and the serum insulin level was significantly lower in DM, T1 and T2 groups than in the control group (Glucose: 30.23 ± 0.41 mmol/L, 27.48 ± 0.27 mmol/L and 27.84 ± 0.29 mmol/L vs 5.05 ± 0.04 mmol/L, P = 1.65 × 10-16, P = 5.89 × 10-19 and P = 1.63 × 10-18, respectively; Insulin: 1.47 ± 0.32 μg/L, 2.66 ± 0.44 μg/L, 2.03 ± 0.29 μg/L and 4.17 ± 0.54 μg/L, P = 0.0001, P = 0.029 and P = 0.025, respectively). However, these levels did not differ among the DM, T1 and T2 groups. The wet weight per unit length, wall thickness and opening angle of esophageal and intestinal segments in the DM group were significantly higher than those in the control group (from P = 0.009 to P = 0.004). These parameters in the T1 group were significantly lower than those in the DM group (wet weight, duodenum: 0.147 ± 0.003 g/cm vs 0.158 ± 0.001 g/cm, P = 0.047; jejunum, 0.127 ± 0.003 g/cm vs 0.151 ± 0.002 g/cm, P = 0.017; ileum, 0.127 ± 0.004 g/cm vs 0.139 ± 0.003 g/cm, P = 0.046; wall thickness, esophagus: 0.84 ± 0.03 mm vs 0.94 ± 0.02 mm, P = 0.014; duodenum: 1.27 ± 0.06 mm vs 1.39 ± 0.05 mm, P = 0.031; jejunum: 1.19 ± 0.07 mm vs 1.34 ± 0.04 mm, P = 0.047; ileum: 1.09 ± 0.04 mm vs 1.15 ± 0.03 mm, P = 0.049; opening angle, esophagus: 112.2 ± 13.2˚ vs 134.7 ± 14.7˚, P = 0.027; duodenum: 105.9 ± 12.3˚ vs 123.1 ± 13.1˚, P = 0.046; jejunum: 90.1 ± 15.4˚ vs 115.5 ± 13.3˚, P = 0.044; ileum: 112.9 ± 13.4˚ vs 136.1 ± 17.1˚, P = 0.035). In the esophageal and jejunal segments, the inner residual stain was significantly smaller and the outer residual strain was larger in the DM group than in the control group (P = 0.022 and P = 0.035). T1 treatment significantly restored this biomechanical alteration (P = 0.011 and P = 0.019), but T2 treatment did not. Furthermore, the circumferential and longitudinal stiffness of the esophageal and jejunal wall increased in the DM group compared with those in the control group. T1, but not T2 treatment, significantly decreased the circumferential wall stiffness in the jejunal segment (P = 0.012) and longitudinal wall stiffness in the esophageal segment (P = 0.023). The mRNA level of RAGE was significantly decreased in the T1 group compared to that in the DM group (P = 0.0069).
CONCLUSION: TWAJJ (high dose) treatment partly restored the morphometric and biomechanical remodeling of the upper gastrointestinal tract in diabetic rats.
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Zanoni JN, Tronchini EA, Moure SA, Souza IDDS. Effects of L-glutamine supplementation on the myenteric neurons from the duodenum and cecum of diabetic rats. ARQUIVOS DE GASTROENTEROLOGIA 2011; 48:66-71. [PMID: 21537546 DOI: 10.1590/s0004-28032011000100014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2009] [Accepted: 08/19/2010] [Indexed: 12/16/2022]
Abstract
CONTEXT Peripheral neuropathy is one of the chronic complications of diabetes mellitus and is directly related to gastrointestinal consequences of the disease. Myenteric neurons are affected in some pathological conditions such as diabetic neuropathy. The imbalance between cellular antioxidants and free radicals, leading to an increase in oxidative stress, is considered one of the main factors responsible for neuronal damages in diabetes. Drugs that reduce the oxidative stress may play a significant role in the treatment of neurological complications of diabetes mellitus. OBJECTIVE To evaluate the effect of L-glutamine supplementation on the myenteric neurons from the cecum and duodenum of Wistar rats with streptozotocin-induced diabetes mellitus. METHODS The animals were divided in four groups (n = 5): non-treated normoglycemics, normoglycemics treated with L-glutamine, non-treated diabetics and diabetics treated with L-glutamine from the 4th day of diabetes induction on. The amino acid L-glutamine was added to their diet at 1%. Giemsa's technique was employed to stain the myenteric neurons. We determined the cell body area of 500 neurons in each group studied. The quantitative analysis was performed by sampling in an area of 16.6 mm² in the cecum and 3.6 mm² in the duodenum of each animal. RESULTS After the supplementation with L-glutamine in the duodenum, we observed a preservation of neuronal density in groups normoglycemic and diabetic (P<0.05). We also observed a preservation of the cell bodies area in diabetic animals (group treated with L-glutamine) (P<0.05). In the cecum, that preservation was not evident. CONCLUSION Supplementation with L-glutamine (1%) promoted a neuroprotective effect on the myenteric neurons from the duodenum of rats, both in terms of natural aging and of diabetes mellitus.
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Sukhotnik I, Shamir R, Bashenko Y, Mogilner JG, Chemodanov E, Shaoul R, Coran AG, Shehadeh N. Effect of oral insulin on diabetes-induced intestinal mucosal growth in rats. Dig Dis Sci 2011; 56:2566-74. [PMID: 21374061 DOI: 10.1007/s10620-011-1654-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Accepted: 02/17/2011] [Indexed: 12/09/2022]
Abstract
BACKGROUND To evaluate the intestinal response to the induction of diabetes and to oral insulin (OI) administration in a rat. METHODS Male Sprague-Dawley rats were divided into four experimental groups: control rats, CONTR-INS rats that were treated with OI given in drinking water for 7 days, diabetic rats that were injected with one dose of streptozotocin, and diabetic rats treated with OI. Intestinal structural changes, enterocyte proliferation and enterocyte apoptosis, bax and bcl-2 mRNA and protein levels, insulin receptor expression and ERK protein levels were determined at sacrifice. A one-way ANOVA for comparison, followed by Tukey's test for pair-wise comparison, were used for statistical analysis. RESULTS Induction of diabetes resulted in a significant increase in bowel and mucosal weight (P < 0.05), mucosal protein (P < 0.05), villus height and crypt depth in jejunum and ileum (P < 0.05), and mucosal DNA in ileum (P < 0.05) (vs. control animals). Diabetes also enhances ERK-induced cell proliferation (P < 0.05) and concomitant bax/bcl-2 induced cell apoptosis (P < 0.05). Treatment of diabetic rats with OI resulted in a significant decrease in jejunal protein content (P < 0.05), jejunal and ileal villus height (P < 0.05), and jejunal crypt depth (P < 0.05), as well as an inhibition of ERK-related cell proliferation in ileum (P < 0.05). Expression of insulin receptor was down-regulated following OI administration in both control and diabetic animals. CONCLUSIONS Experimental STZ-induced diabetes causes intestinal mucosal growth and enhances enterocyte turnover in a rat model. OI administration diminishes diabetes-accelerated cell turnover and diabetes-induced mucosal hyperplasia.
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Affiliation(s)
- Igor Sukhotnik
- Laboratory of Intestinal Adaptation and Recovery, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
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Zhao J, Liao D, Yang J, Gregersen H. Stress and strain analysis of contractions during ramp distension in partially obstructed guinea pig jejunal segments. J Biomech 2011; 44:2077-82. [PMID: 21632056 PMCID: PMC3150803 DOI: 10.1016/j.jbiomech.2011.05.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Revised: 04/15/2011] [Accepted: 05/11/2011] [Indexed: 12/21/2022]
Abstract
Previous studies have demonstrated morphological and biomechanical remodeling in the intestine proximal to an obstruction. The present study aimed to obtain stress and strain thresholds to initiate contraction and the maximal contraction stress and strain in partially obstructed guinea pig jejunal segments. Partial obstruction and sham operations were surgically created in mid-jejunum of male guinea pigs. The animals survived 2, 4, 7 and 14 days. Animals not being operated on served as normal controls. The segments were used for no-load state, zero-stress state and distension analyses. The segment was inflated to 10 cmH(2)O pressure in an organ bath containing 37°C Krebs solution and the outer diameter change was monitored. The stress and strain at the contraction threshold and at maximum contraction were computed from the diameter, pressure and the zero-stress state data. Young's modulus was determined at the contraction threshold. The muscle layer thickness in obstructed intestinal segments increased up to 300%. Compared with sham-obstructed and normal groups, the contraction stress threshold, the maximum contraction stress and the Young's modulus at the contraction threshold increased whereas the strain threshold and maximum contraction strain decreased after 7 days obstruction (P<0.05 and 0.01). In conclusion, in the partially obstructed intestinal segments, a larger distension force was needed to evoke contraction likely due to tissue remodeling. Higher contraction stresses were produced and the contraction deformation (strain) became smaller.
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Affiliation(s)
- Jingbo Zhao
- Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
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De Britto Mari R, Scoz JR, De Melo Germano R, Pereira JNB, De Toledo EL, De Faria HG, Stabille SR. Quantification and morphometry of myenteric neurones in the jejunum of Holtzman rats (Rattus norvegicus). Anat Histol Embryol 2011; 40:256-62. [PMID: 21569076 DOI: 10.1111/j.1439-0264.2011.01068.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
UNLABELLED With 2 figures and 3 tables SUMMARY The morphological pattern of the myenteric plexus (MP) is species-specific, and little is known about this pattern in Holtzman rats. The aim of the current experiment was the morphological and quantitative study of myenteric neurones in the Holtzman rat jejunum. Hematoxylin-Eosin and NADH-diaphorase (NADH-dp) staining were used to assess muscular layer thickness, neurone cell body area (CBA) and nuclei area (NA). Muscular layer thickness was found to be 114.77 ± 14.89 μm. Neuronal densities across the subregions of the jejunum were similar: mesenteric, 11.78 ± 2.89/mm(2) ; intermediate, 12.06 ± 2.69/mm(2) ; and antimesenteric, 10.67 ± 1.89/mm(2) . As expected, there was positive correlation between the CBA and NA of 79.19, 79.26 and 78.5% in the mesenteric, intermediate and antimesenteric subregions of the jejunum, respectively. Medium-sized neurones predominated in the ganglionic arrangement of the MP. These results indicate that the NADH-dp myenteric neurones in the jejunum of Holtzman rats are similar in many aspects to those found in the ileum of Holtzman rats and to those found in the small intestine of Wistar rats, including their location, ganglionic disposition and predominance of medium-sized CBA. However, neuronal density in the jejunum is lower than in the ileum. Based on these results showing morphological similarities to the MP of the Wistar rat, the Holtzman strain can be used to investigate the effects of adverse conditions on the morphology of the MP.
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Affiliation(s)
- R De Britto Mari
- Institute of Biological, Medical and Health Sciences, Paranaense University (UNIPAR), Paranavaí, PR, Brazil.
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Biomechanical remodelling of obstructed guinea pig jejunum. J Biomech 2010; 43:1322-9. [PMID: 20189575 DOI: 10.1016/j.jbiomech.2010.01.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2009] [Revised: 12/18/2009] [Accepted: 01/21/2010] [Indexed: 01/19/2023]
Abstract
Data on morphological and biomechanical remodelling are needed to understand the mechanisms behind intestinal obstruction. The effect of partial obstruction on mechanical properties with reference to the zero-stress state and on the histomorphological properties of the guinea pig small intestine was determined in this study. Partial obstruction and sham operation were surgically created in mid-jejunum of guinea pigs. The animals survived 2, 4, 7, and 14 days. The age-matched guinea pigs that were not operated served as normal controls. The segment proximal to the obstruction site was used for histological analysis, no-load state and zero-stress state data, and distension test. The segment for distension was immersed in an organ bath and inflated to 10cm H(2)O. The outer diameter change during the inflation was monitored using a microscope with CCD camera. Circumferential stresses and strains were computed from the diameter, pressure and the zero-stress state data. The opening angle and absolute value of residual strain decreased (P<0.01 and P<0.001) whereas the wall thickness, wall cross-sectional area, and the wall stiffness increased after 7 days obstruction (P<0.05, P<0.01). Histologically, the muscle and submucosa layers, especially the circumferential muscle layer increased in thickness after obstruction. The opening angle and residual strain mainly depended on the thickness of the muscle layer whereas the wall stiffness mainly depended on the thickness of the submucosa layer. In conclusion, the histomorphological and biomechanical properties of small intestine (referenced for the first time to the zero-stress state) remodel proximal to the obstruction site in a time-dependent manner.
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Shah SK, Fogle LN, Aroom KR, Gill BS, Moore-Olufemi SD, Jimenez F, Uray KS, Walker PA, Stewart RH, Laine GA, Cox CS. Hydrostatic intestinal edema induced signaling pathways: potential role of mechanical forces. Surgery 2010; 147:772-9. [PMID: 20097396 DOI: 10.1016/j.surg.2009.11.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Accepted: 11/24/2009] [Indexed: 01/22/2023]
Abstract
BACKGROUND Hydrostatic intestinal edema initiates a signal transduction cascade that results in smooth muscle contractile dysfunction. Given the rapid and concurrent alterations in the mechanical properties of edematous intestine observed with the development of edema, we hypothesize that mechanical forces may serve as a stimulus for the activation of certain signaling cascades. We sought to examine whether isolated similar magnitude mechanical forces induced the same signal transduction cascades associated with edema. METHODS The distal intestine from adult male Sprague Dawley rats was stretched longitudinally for 2 h to 123% its original length, which correlates with the interstitial stress found with edema. We compared wet-to-dry ratios, myeloperoxidase activity, nuclear signal transduction and activator of transcription (STAT)-3 and nuclear factor (NF)-kappa B DNA binding, STAT-3 phosphorylation, myosin light chain phosphorylation, baseline and maximally stimulated intestinal contractile strength, and inducible nitric oxide synthase (iNOS) and sodium hydrogen exchanger 1-3 messenger RNA (mRNA) in stretched and adjacent control segments of intestine. RESULTS Mechanical stretch did not induce intestinal edema or an increase in myeloperoxidase activity. Nuclear STAT-3 DNA binding, STAT-3 phosphorylation, and nuclear NF-kappa B DNA binding were significantly increased in stretched seromuscular samples. Increased expression of sodium hydrogen exchanger 1 was found but not an increase in iNOS expression. Myosin light chain phosphorylation was significantly decreased in stretched intestine as was baseline and maximally stimulated intestinal contractile strength. CONCLUSION Intestinal stretch, in the absence of edema/inflammatory/ischemic changes, leads to the activation of signaling pathways known to be altered in intestinal edema. Edema may initiate a mechanotransductive cascade that is responsible for the subsequent activation of various signaling cascades known to induce contractile dysfunction.
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Affiliation(s)
- Shinil K Shah
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, TX, USA
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Roldi LP, Pereira RVF, Tronchini EA, Rizo GV, Scoaris CR, Zanoni JN, Natali MRM. Vitamin E (alpha-tocopherol) supplementation in diabetic rats: effects on the proximal colon. BMC Gastroenterol 2009; 9:88. [PMID: 19930636 PMCID: PMC2788574 DOI: 10.1186/1471-230x-9-88] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Accepted: 11/23/2009] [Indexed: 12/17/2022] Open
Abstract
Background Neuropathy is one of the complications caused by diabetes mellitus which is directly related to the gastrointestinal manifestations of the disease. Antioxidant substances, such as vitamin E, may play an important role in the reduction of the neurological damage caused by diabetes mellitus. The aim of the present study was to determine whether vitamin E (α-tocopherol) at different concentrations induces any effects on the morphology of the intestinal wall and intrinsic innervation in the proximal colon of diabetic rats. Methods Thirty rats (90-day-old) were assigned to the following groups: N (normoglycemic), NE1 (normoglycemic supplemented with vitamin E 0.1%), NE2 (normoglycemic supplemented with vitamin E 2%), D (diabetic), DE1 (diabetic supplemented with vitamin E 0.1%), and DE2 (diabetic supplemented with vitamin E 2%). Animals received vitamin E supplementation for 120 days and were sacrificed when they were 210 days old. The proximal colon of each animal was subjected to histology to study the intestinal wall and goblet cells and processed for whole-mount preparations to morphoquantitatively determine the total myenteric population. Results Supplementation with vitamin E significantly reduced glycemia and glycated hemoglobin values and preserved the number of myenteric neurons in group DE2, without affecting intestinal area or thickness of the intestinal wall or muscular tunic. Conclusion Vitamin E (2%) influenced the glycemic parameters and had a neuroprotective effect on the total myenteric population, but the morphometric characteristics of the intestinal wall were unaffected.
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Affiliation(s)
- Luciana P Roldi
- Department of Morphophysiological Sciences, Laboratory of Enteric Neurons, State University of Maringá, Brazil.
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Biomechanical and histomorphometric colon remodelling in STZ-induced diabetic rats. Dig Dis Sci 2009; 54:1636-42. [PMID: 18989775 DOI: 10.1007/s10620-008-0540-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Accepted: 09/11/2008] [Indexed: 12/13/2022]
Abstract
The histomorphologic and passive biomechanical properties were studied in the mid-colon of 16 non-diabetic and 20 streptozotocin (STZ)-induced diabetic rats (50 mg/kg STZ, ip). The diabetic rats were divided into groups living 4 and 8 weeks after the induction of diabetes (n = 10 for each group). The mechanical test was a ramp distension of fluid into the colon in vitro. The colon diameter and length were obtained from digitized images of the segments at pre-selected pressures and at the no-load and zero-stress states. Circumferential and longitudinal stresses and strains were computed from the length, diameter, and pressure data and from the zero-stress state geometry. The blood glucose level increased 3-4-fold in the diabetic rats compared with the controls (P < 0.001). Diabetes generated pronounced increases in the colon weight per length, wall thickness, and wall cross-sectional area (P < 0.001). Histologically, the thickness of all layers was increased during diabetes (P < 0.05), especially the mucosa layer. The opening angle, and absolute values of residual strain increased in the diabetic group (P < 0.05 and P < 0.01, respectively). Furthermore, diabetes increased the circumferential and longitudinal stiffness of the colon wall (P < 0.001). The observed changes in residual strain, opening angle, and stress-strain relation may be contributing factors to colonic dysfunction and abdominal pain in diabetic patients.
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Yang J, Zhao J, Nakaguchi T, Gregersen H. Biomechanical changes in oxazolone-induced colitis in BALB/C mice. J Biomech 2009; 42:811-7. [PMID: 19264309 DOI: 10.1016/j.jbiomech.2009.01.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2008] [Revised: 01/28/2009] [Accepted: 01/28/2009] [Indexed: 01/08/2023]
Abstract
Ulcerative colitis (UC) is associated with intestinal and extra intestinal clinical manifestations. The profound organic changes in UC indicate that the colonic mechanical and mechanosensory functions are affected. The aim was to study acute morphological and biomechanical properties of the distal colon in oxazolone-induced UC in BALB/C mice. Six normal male BALB/C mice and 10 oxazolone-induced UC mice were studied. UC was induced by epicutaneous and intrarectal administration of oxazolone. The mechanical test was done as a distension experiment where the colon was distended up to 20 cmH2O. The pressure, outer diameter and length were recorded simultaneously. Circumferential and longitudinal stresses and strains were computed. The intestinal specimens were processed for histology. The mucosa was infiltrated with acute and chronic inflammatory cells. Mucosal bleeding, irregular ulcers crypt abscess, and destruction of the epithelial border were observed. Although, the mucosa in ulcers was much thinner than in the normal controls, the mucosa and submucosa around the ulcer were thicker than in the normal controls (P<0.05). Oxazolone-induced colitis increased the circumferences and wall cross-sectional area (P<0.01), the opening angle and residual strain at the serosa increased (P<0.01). Furthermore, the circumferential and longitudinal stiffness increased in the UC wall and was most pronounced in longitudinal direction. The opening angle and residual strain was linearly correlated to the wall thickness, area and inflammation degree. In conclusion, morphological and biomechanical changes of the colon occurred during the development of UC. The increased stiffness may contribute to the abnormal function in patients with UC.
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Affiliation(s)
- Jian Yang
- Mech-Sense, Aalborg Hospital Science and Innovation Centre (AHSIC), Aalborg Hospital, Sdr. Skovvej 15, DK 9000 Aalborg, Denmark
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Chen P, Zhao J, Nielsen VH, Clausen T, Gregersen H. Intestinal remodelling in mink fed with reduced protein content. J Biomech 2009; 42:443-8. [PMID: 19159886 DOI: 10.1016/j.jbiomech.2008.11.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2008] [Revised: 11/28/2008] [Accepted: 11/29/2008] [Indexed: 12/26/2022]
Abstract
Low protein intake occurs in humans in relation to diseases, starvation and post-operatively. Low-protein diets may affect the gastrointestinal structure and mechanical function. The aim was to study the passive biomechanical properties and tissue remodelling of the intestine in minks on reduced protein diets. Twenty-seven male minks were divided into three groups receiving different protein level in the diet for 6 weeks: High protein level (group H, 55% energy from protein), moderate protein level (group M, 30% energy from protein) and low protein level (group L, 15% energy from protein) (n=9 for each group). Ten centimetre long segments from duodenum, jejunum and ileum were excised at the end of the study period. The mechanical test was performed as a ramp distension experiment. The intestinal diameter and length, wall thickness, wall area and opening angle were obtained from digitized images of the intestinal segments at pre-selected pressures, no-load and zero-stress states, respectively. Circumferential and longitudinal stresses (force per area) and strains (deformation) were computed. The layer thickness was measured from intestinal histological images. No difference in body weight was found between groups at the start of the experiment. However, at the end of the experiment the body weight was smallest in group L (P=0.0003 and 0.0004 compared with groups H and M). Similarly, the wet weight per unit length, wall thickness and area were smallest in group L (P<0.05, P<0.01). The lowest wall thickness was found in the jejunum and ileum in group L (P<0.05), mainly due to decreased mucosa and submucosa thickness. The smallest opening angle and absolute values of residual strain were found in the jejunal segment in group L (P<0.05). No difference was observed for duodenal and ileal segments among the three groups. Feeding the low-protein diet shifted the stress-strain curves to the right for the circumferential direction, indicating the wall become softer in the circumferential direction. However, no significant difference was observed in the longitudinal direction for any of the intestinal segments. In conclusion, this study demonstrated that low-protein diet in minks induce histomorphometric and biomechanical remodelling of the intestine.
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Affiliation(s)
- Pengmin Chen
- Mech-Sense, Aalborg Hospital Science and Innovation Centre (AHSIC), Sdr. Skovvej 15, DK-9000 Aalborg, Denmark
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Abstract
The gastrointestinal (GI) tract is the system of organs within multi-cellular animals that takes in food, digests it to extract energy and nutrients, and expels the remaining waste. The various patterns of GI tract function are generated by the integrated behaviour of multiple tissues and cell types. A thorough study of the GI tract requires understanding of the interactions between cells, tissues and gastrointestinal organs in health and disease. This depends on knowledge, not only of numerous cellular ionic current mechanisms and signal transduction pathways, but also of large scale GI tissue structures and the special distribution of the nervous network. A unique way of coping with this explosion in complexity is mathematical and computational modelling; providing a computational framework for the multilevel modelling and simulation of the human gastrointestinal anatomy and physiology. The aim of this review is to describe the current status of biomechanical modelling work of the GI tract in humans and animals, which can be further used to integrate the physiological, anatomical and medical knowledge of the GI system. Such modelling will aid research and ensure that medical professionals benefit, through the provision of relevant and precise information about the patient’s condition and GI remodelling in animal disease models. It will also improve the accuracy and efficiency of medical procedures, which could result in reduced cost for diagnosis and treatment.
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