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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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Khanal P, D. Axel AM, Safayi S, Elbrønd VS, Nielsen MO. Prenatal over- and undernutrition differentially program small intestinal growth, angiogenesis, absorptive capacity, and endocrine function in sheep. Physiol Rep 2020; 8:e14498. [PMID: 32597039 PMCID: PMC7322502 DOI: 10.14814/phy2.14498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/27/2020] [Accepted: 06/02/2020] [Indexed: 12/20/2022] Open
Abstract
The aim was to test the hypothesis that prenatal under- and overnutrition in late gestation can program small intestinal (SI) growth, angiogenesis, and endocrine function to predispose for a hyperabsorptive state, thereby increasing the susceptibility to the adverse effects of an early postnatal obesogenic diet. Twin-pregnant ewes were exposed to adequate (NORM), LOW (50% of NORM), or HIGH (150% energy and 110% protein of NORM) diets through the last trimester (term ~147 days). From 3 days to 6 months of age, their lambs were fed either a moderate (CONV) or a high-carbohydrate high-fat (HCHF) diet. At 6 months of age, responses in plasma metabolites and insulin to refeeding after fasting were determined and then different segments of the SI were sampled at autopsy. Prenatal overnutrition impacts were most abundant in the duodenum where HIGH had increased villus amplification factor and lowered villi thickness with increased IRS-1 and reduced GH-R expressions. In jejunum, HIGH lambs had an increased expression of Lactate gene and amplified when exposed to HCHF postnatally. Specifically, in LOW, sensitivity to HCHF was affected in ileum. Thus, the mismatching LOW-HCHF nutrition increased expressions of angiogenic genes (VEGF, VEGF-R1, ANGPT1, RTK) and increased mucosa layer (tunica mucosa) thickness but reduced muscle layer (Tunica muscularis) thickness. The SI is a target of prenatal nutritional programming, where late gestation overnutrition increased and shifted digestive capacity for carbohydrates toward the jejunum, whereas late gestation undernutrition predisposed for ileal angiogenesis and carbohydrate and fat hyperabsorptive capacity upon subsequent exposure to postnatal obesogenic diet.
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Affiliation(s)
- Prabhat Khanal
- Faculty of Biosciences and AquacultureAnimal Science, Production and Welfare DivisionNord UniversitySteinkjerNorway
| | - Anne Marie D. Axel
- Department of Veterinary and Animal SciencesFaculty of Health and Medical SciencesUniversity of CopenhagenFrederiksbergDenmark
| | | | - Vibeke S. Elbrønd
- Department of Veterinary and Animal SciencesFaculty of Health and Medical SciencesUniversity of CopenhagenFrederiksbergDenmark
| | - Mette O. Nielsen
- Department of Animal ScienceFaculty of Technical SciencesAarhus UniversityTjeleDenmark
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Brun A, Fernández Marinone G, Price ER, Nell LA, Simões BMV, Castellar A, Gontero-Fourcade M, Cruz-Neto AP, Karasov WH, Caviedes-Vidal E. Morphological bases for intestinal paracellular absorption in bats and rodents. J Morphol 2019; 280:1359-1369. [PMID: 31301093 DOI: 10.1002/jmor.21037] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/19/2019] [Accepted: 06/26/2019] [Indexed: 12/31/2022]
Abstract
Flying mammals present unique intestinal adaptations, such as lower intestinal surface area than nonflying mammals, and they compensate for this with higher paracellular absorption of glucose. There is no consensus about the mechanistic bases for this physiological phenomenon. The surface area of the small intestine is a key determinant of the absorptive capacity by both the transcellular and the paracellular pathways; thus, information about intestinal surface area and micro-anatomical structure can help explain differences among species in absorptive capacity. In order to elucidate a possible mechanism for the high paracellular nutrient absorption in bats, we performed a comparative analysis of intestinal villi architecture and enterocyte size and number in microchiropterans and rodents. We collected data from intestines of six bat species and five rodent species using hematoxylin and eosin staining and histological measurements. For the analysis we added measurements from published studies employing similar methodology, making in total a comparison of nine species each of rodents and bats. Bats presented shorter intestines than rodents. After correction for body size differences, bats had ~41% less nominal surface area (NSA) than rodents. Villous enhancement of surface area (SEF) was ~64% greater in bats than in rodents, mainly because of longer villi and a greater density of villi in bat intestines. Both taxa exhibited similar enterocyte diameter. Bats exceeded rodents by ~103% in enterocyte density per cm2 NSA, but they do not significantly differ in total number of enterocytes per whole animal. In addition, there is a correlation between SEF and clearance per cm2 NSA of L-arabinose, a nonactively transported paracellular probe. We infer that an increased enterocyte density per cm2 NSA corresponds to increased density of tight junctions per cm2 NSA, which provides a partial mechanistic explanation for understanding the high paracellular absorption observed in bats compared to nonflying mammals.
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Affiliation(s)
- Antonio Brun
- Instituto Multidisciplinario de Investigaciones Biológicas de San Luis, Consejo Nacional de Investigaciones Científicas y Técnicas, San Luis, Argentina.,Department of Forest and Wildlife Ecology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Guido Fernández Marinone
- Departamento de Bioquímica y Ciencias Biológicas, Facultad de Química, Bioquímica y Farmacia. Universidad Nacional de San Luis, San Luis, Argentina
| | - Edwin R Price
- Department of Biological Sciences, University of North Texas, Denton, Texas
| | - Lucas A Nell
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Beatriz M V Simões
- Departamento de Zoologia, Instituto de Biociências, Universidade Estadual Paulista "Julio de Mesquita Filho" Rio Claro, São Paulo, Brazil
| | - Alexandre Castellar
- Departamento de Zoologia, Instituto de Biociências, Universidade Estadual Paulista "Julio de Mesquita Filho" Rio Claro, São Paulo, Brazil
| | - Manuel Gontero-Fourcade
- Instituto Multidisciplinario de Investigaciones Biológicas de San Luis, Consejo Nacional de Investigaciones Científicas y Técnicas, San Luis, Argentina.,Departamento de Bioquímica y Ciencias Biológicas, Facultad de Química, Bioquímica y Farmacia. Universidad Nacional de San Luis, San Luis, Argentina
| | - Ariovaldo P Cruz-Neto
- Departamento de Zoologia, Instituto de Biociências, Universidade Estadual Paulista "Julio de Mesquita Filho" Rio Claro, São Paulo, Brazil
| | - William H Karasov
- Department of Forest and Wildlife Ecology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Enrique Caviedes-Vidal
- Instituto Multidisciplinario de Investigaciones Biológicas de San Luis, Consejo Nacional de Investigaciones Científicas y Técnicas, San Luis, Argentina.,Departamento de Bioquímica y Ciencias Biológicas, Facultad de Química, Bioquímica y Farmacia. Universidad Nacional de San Luis, San Luis, Argentina
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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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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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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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Li JY, Yu T, Xia ZS, Chen GC, Yuan YH, Zhong W, Zhao LN, Chen QK. Enhanced proliferation in colorectal epithelium of patients with type 2 diabetes correlates with β-catenin accumulation. J Diabetes Complications 2014; 28:689-97. [PMID: 24930713 DOI: 10.1016/j.jdiacomp.2014.05.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 05/06/2014] [Accepted: 05/07/2014] [Indexed: 12/23/2022]
Abstract
AIMS β-Catenin accumulation promotes proliferation. However, the correlation between proliferation of colorectal epithelium and β-catenin in type 2 diabetes mellitus (DM) patients remains unclear. METHODS Colorectal epithelium samples from distal ends of colorectal adenocarcinomas without histological aberrances were divided into two groups: DM patients with type 2 DM for more than 1year (n=27) and non-DM patients without hyperglycemia (n=20). Samples from patients without colorectal epithelial disease or hyperglycemia served as a control group (n=6). Proliferative index was calculated as the percentage of proliferating cell nuclear antigen positive cells. Wnt/β-catenin signaling was assessed immunohistochemically and phosphorylation of β-catenin was assessed by immunofluorescence. RESULTS Compared with the non-DM or control group, the proliferative index and expression of lactate dehydrogenase A and Wnt/β-catenin signaling were significantly higher in the DM group (all p<0.01). The proliferative index correlated positively with β-catenin expression (Spearman correlation coefficient=0.55; p<0.01). Reduced phosphorylation at serine 33/37 and increased phosphorylation at serine 675 of β-catenin were detected in the DM group (all p<0.01). CONCLUSIONS Enhanced proliferation, accompanied by increased aerobic glycolysis, was detected in colorectal epithelium of patients with diabetes. β-Catenin accumulation with altered phosphorylation correlated with the proliferative changes.
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Affiliation(s)
- Jie-Yao Li
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong 510120, 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, Guangdong 510120, 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, Guangdong 510120, People's Republic of China
| | - Guang-Cheng Chen
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong 510120, People's Republic of China
| | - Yu-Hong Yuan
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong 510120, 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, Guangdong 510120, People's Republic of China
| | - Li-Na Zhao
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong 510120, 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, Guangdong 510120, People's Republic of China.
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Min XH, Yu T, Qing Q, Yuan YH, Zhong W, Chen GC, Zhao LN, Deng N, Zhang LF, Chen QK. Abnormal differentiation of intestinal epithelium and intestinal barrier dysfunction in diabetic mice associated with depressed Notch/NICD transduction in Notch/Hes1 signal pathway. Cell Biol Int 2014; 38:1194-204. [PMID: 24890925 DOI: 10.1002/cbin.10323] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Accepted: 04/25/2014] [Indexed: 01/02/2023]
Abstract
Proliferative change and intestinal barrier dysfunction in intestinal mucosa of diabetes have been described, but the differentiation characteristics of intestinal epithelial cells (IECs) and the mechanisms in the IECs development remain unclear. To explore the intestinal epithelial constitution patterns and barrier function, the diabetic mouse model was induced by streptozotocin. Tight junctions between IECs were significantly damaged and the serum level of D-lactate was raised in diabetic mice (P < 0.05). The expression of Zo1 and Ocln in the small intestine of diabetic mice were lower, while the markers for absorptive cell (SI) and Paneth cell (Lyz1) were significantly higher than in control mice (P < 0.05). The expression of Msi1, Notch1, and Dll1 in small intestine gradually increased throughout the course of hyperglycemia in diabetic mice (P < 0.05). However, the expression of NICD, RBP-jκ, Math1, and Hes1 had a reverse trend compared with Msi1 and Notch1. Intestinal absorptive cells and Paneth cells had a high proliferation rate in diabetic mice. However, the intestinal barrier dysfunction associated with the decreased expressions of Zo1 and Ocln was detected throughout hyperglycemia. In conclusion, downregulation of Notch/Hes1 signal pathway caused by depressed Notch/NICD transduction is associated with the abnormal differentiation of IECs and intestinal barrier dysfunction in diabetic mice.
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Affiliation(s)
- Xiao-Hui Min
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, 510120, People's Republic of China
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Anti-Diabetic Activity of a Leaf Extract Prepared fromSalacia reticulatain Mice. Biosci Biotechnol Biochem 2014; 73:1096-104. [DOI: 10.1271/bbb.80854] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Hansen CF, Vassiliadis E, Vrang N, Sangild PT, Cummings BP, Havel P, Jelsing J. The effect of ileal interposition surgery on enteroendocrine cell numbers in the UC Davis type 2 diabetes mellitus rat. ACTA ACUST UNITED AC 2014; 189:31-9. [PMID: 24512816 DOI: 10.1016/j.regpep.2014.01.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 01/09/2014] [Accepted: 01/31/2014] [Indexed: 02/07/2023]
Abstract
AIM To investigate the short-term effect of ileal interposition (IT) surgery on gut morphology and enteroendocrine cell numbers in the pre-diabetic UC Davis type 2 diabetes mellitus (UCD-T2DM) rat. STUDY DESIGN Two-month old male UCD-T2DM rats underwent either sham (n=5) or IT (n=5) surgery. Intestines were collected 1.5months after surgery. The jejunum, ileum and colon regions were processed for histochemical and immunohistochemical labeling and stereological analyses of changes in gut morphometry and number of enteroendocrine cells. RESULTS Stereological analysis showed that intestinal volume, luminal surface area and the number of all chromogranin A-positive enteroendocrine cells were markedly increased in the IT rats compared with sham-operated animals. Subanalyses of the glucagon-like peptide 2, cholecystokinin, serotonin cells and the neurotensin immunoreactive sub-pool of enteroendocrine cells in the IT region revealed an increase in numbers across phenotypes. However, the density of the different cell types varied. CONCLUSION IT surgery in the UCD-T2DM rat leads to rapid alterations in gut morphometry and an increase in the number of enteroendocrine cells. This effect may potentially explain why IT surgery delays the onset of type 2 diabetes in the UCD-T2DM rat.
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Affiliation(s)
- Carl Frederik Hansen
- Gubra, Hørsholm, Denmark; Department of Human Nutrition, University of Copenhagen, Frederiksberg, Denmark
| | | | | | - Per T Sangild
- Department of Human Nutrition, University of Copenhagen, Frederiksberg, Denmark
| | - Bethany P Cummings
- Department of Biomedical Sciences, School of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Peter Havel
- Department of Molecular Biosciences, University of California, Davis, CA, USA
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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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12
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Sharma R, Kaur J, Chauhan SS, Mahmood A. Gestational diabetes affects postnatal development of transport and enzyme functions in rat intestine. Mol Cell Biochem 2012; 361:71-77. [PMID: 21964563 DOI: 10.1007/s11010-011-1090-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Accepted: 09/16/2011] [Indexed: 10/17/2022]
Abstract
The effect of alloxan-induced gestational diabetes on the postnatal development of brush border disaccharidases and D-glucose transport in rat intestine was studied. Pups born to diabetic mothers showed 92-22% increase in blood sugar levels compared with the controls. Western blot and RT-PCR analyses revealed that the activities of brush border sucrase, lactase and Sodium Glucose Co-transporter 1 (SGLT1) correlates with protein and mRNA levels in intestine of pups born to diabetic rat mothers after 5-45 days of birth. Intestinal histology in pups born to diabetic mothers at day 10 and 45 after birth showed distorted cellular organization of mucosa with a decrease in the number of secretary goblet cells and regression of tubular mass. These findings suggest that the genetic switch in utero regulates the postnatal expression of enzyme and transport functions in intestine of pups born to diabetic rat mothers. This may influence the growth and development of offsprings later in life.
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Affiliation(s)
- Ruchi Sharma
- Department of Biotechnology, Government College for Girls, Chandigarh, India
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13
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Chen P, Zhao J, Gregersen H. Up-regulated expression of advanced glycation end-products and their receptor in the small intestine and colon of diabetic rats. Dig Dis Sci 2012; 57:48-57. [PMID: 22057282 DOI: 10.1007/s10620-011-1951-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Accepted: 10/12/2011] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Gastrointestinal disorders and symptoms are common in diabetic patients. Advanced glycation end-products (AGEs) and their receptor (RAGE) have been proposed as an important pathological mechanism underlying diabetic complications, such as diabetic cardiopathy, retinopathy, nephropathy, etc. The aims were to study the distribution of AGE and RAGE in the normal and diabetic small intestine and colon in rats and the possible relationship between AGEs/RAGE and diabetes-induced intestinal structural remodeling. METHODS Diabetic and age-matched normal rats survived for 56 days. The body weight and blood glucose were measured regularly until day 56. Jejunal, ileal, and colonic segments were excised. The wet weight per unit length and the layer thickness were measured. AGE and RAGE were detected by immunohistochemical staining. RESULTS The wet weight per unit length in the three segments and the layer thickness in jejunum and ileum increased in the diabetic rats. The staining density of AGE in diabetic rats was higher in the villi of jejunum and ileum, and in the crypt and circumferential muscle layer of ileum compared to normal rats. The staining intensity of RAGE increased in ganglia, crypt, and brush border of diabetic jejunum and ileum as well as in ganglia of diabetic colon. Positive association was found between the accumulation of AGE and RAGE and the thickness of the different layers. CONCLUSIONS The expression of AGE and RAGE is up-regulated in the small intestine and colon of diabetic rats. The increased AGE and RAGE levels may contribute to diabetic GI dysfunction.
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Affiliation(s)
- Pengmin Chen
- Mech-Sense, Aalborg Hospital, Sdr Skovvej 15, 9000 Aalborg, Denmark
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Rajani Kanth V, Uma Maheswara Reddy P, Raju TN. Attenuation of streptozotocin-induced oxidative stress in hepatic and intestinal tissues of Wistar rat by methanolic-garlic extract. Acta Diabetol 2008; 45:243-51. [PMID: 18696004 DOI: 10.1007/s00592-008-0051-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2007] [Accepted: 06/16/2008] [Indexed: 10/21/2022]
Abstract
Diabetes is a major socio-economical burden with serious health consequences. The reactive oxygen species generated in this pathology alters the internal milieu of the cellular systems paving way to metabolic disorders. In the present investigation garlic's dose-dependent protective action against streptozotocin (STZ)-induced oxidative stress in hepatic and intestinal tissues has been studied. Methanolic garlic extract scavenged the DPPH radical with an IC(50) of 424 +/- 4.4 microg/ml proving its efficient antioxidant property. Garlic administration at 250 and 500 mg/kg body wt. significantly normalized the blood glucose in the diabetic rats. Biochemical analysis revealed a pronounced oxidative stress in STZ-rats (G-II) consequent to hyperglycemia as seen by a significant (P < 0.05 and 0.01) rise in malondialdehyde, protein carbonyls; accumulation of glycation products; disintegration of protein integrity (tryptophan fluorescence) followed by a decrease in reduced glutathione, antioxidant (GPx and CAT) enzymes culminating in apoptosis. Garlic administration in a dose-dependent manner has been found to restore and normalize significantly the above changes and thus restoring a normal functional integrity. These beneficial effects are prominent with 500 mg/kg body wt. dosage of garlic in comparison with 250 mg/kg body wt. dosage. But, 500 mg/kg body wt. dosage is not totally free from side effects as the decrease in body weight and increased intestinal tissue apoptosis were also found in control rats administered with garlic extract at 500 mg/kg body wt. along with diabetic rats. Based on these findings it is suggested that consumption of garlic at a lower dose is beneficial in terms of defensive action against oxidative stress.
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Affiliation(s)
- V Rajani Kanth
- Physiology Division, Department of Zoology, University College of Science, Osmania University, Hyderabad 500 007, India
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Herbach N, Göke B, Wolf E, Wanke R. Diets influence the diabetic phenotype of transgenic mice expressing a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPRdn). ACTA ACUST UNITED AC 2007; 146:260-70. [PMID: 18031839 DOI: 10.1016/j.regpep.2007.10.005] [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: 05/10/2007] [Revised: 10/10/2007] [Accepted: 10/15/2007] [Indexed: 12/25/2022]
Abstract
Transgenic mice overexpressing a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn)) have recently been shown to develop diabetes mellitus due to disturbed postnatal development of the endocrine pancreas. In this study, the effects of feeding a high fibre/low calorie diet on the diabetic phenotype of GIPR(dn) transgenic mice were examined. Transgenic and control animals received either a conventional breeding diet (BD) or a high fibre diet (HF). Both fasting and postprandial blood glucose levels and HbA1C levels were largely elevated in transgenic mice vs. controls (p<0.05), irrespective of the diet fed. Food and water intake and the daily urine volume of GIPR(dn) transgenic mice were higher than that of control mice (p<0.05). Transgenic animals receiving the HF diet showed significantly lower blood glucose and HbA1C levels as well as less food and water intake than transgenic mice fed BD. The 365-day survival of transgenic mice was significantly lower than that of control mice. Transgenic animals fed the HF diet lived significantly longer than their counterparts receiving BD. GIPR(dn) transgenic mice develop a severe diabetic phenotype which can be ameliorated by a HF diet, thereby resembling some aspects of the pathophysiology of human type 2 diabetes mellitus.
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Affiliation(s)
- Nadja Herbach
- Institute of Veterinary Pathology, Veterinaerstr. 13, 80539 Munich, Germany.
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Frokjaer JB, Andersen SD, Ejskjaer N, Funch-Jensen P, Drewes AM, Gregersen H. Impaired contractility and remodeling of the upper gastrointestinal tract in diabetes mellitus type-1. World J Gastroenterol 2007; 13:4881-90. [PMID: 17828820 PMCID: PMC4611767 DOI: 10.3748/wjg.v13.i36.4881] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate that both the neuronal function of the contractile system and structural apparatus of the gastrointestinal tract are affected in patients with longstanding diabetes and auto mic neuropathy.
METHODS: The evoked esophageal and duodenal contractile activity to standardized bag distension was assessed using a specialized ultrasound-based probe. Twelve type-1 diabetic patients with autonomic neuropathy and severe gastrointestinal symptoms and 12 healthy controls were studied. The geometry and biomechanical parameters (strain, tension/stress, and stiffness) were assessed.
RESULTS: The diabetic patients had increased frequency of distension-induced contractions (6.0 ± 0.6 vs 3.3 ± 0.5, P < 0.001). This increased reactivity was correlated with the duration of the disease (P = 0.009). Impaired coordination of the contractile activity in diabetic patients was demonstrated as imbalance between the time required to evoke the first contraction at the distension site and proximal to it (1.5 ± 0.6 vs 0.5 ± 0.1, P = 0.03). The esophageal wall and especially the mucosa-submucosa layer had increased thickness in the patients (P < 0.001), and the longitudinal and radial compressive stretch was less in diabetics (P < 0.001). The esophageal and duodenal wall stiffness and circumferential deformation induced by the distensions were not affected in the patients (all P > 0.14).
CONCLUSION: The impaired contractile activity with an imbalance in the distension-induced contractions likely reflects neuronal abnormalities due to autonomic neuropathy. However, structural changes and remodeling of the gastrointestinal tract are also evident and may add to the neuronal changes. This may contribute to the pathophysiology of diabetic gut dysfunction and impact on future management of diabetic patients with gastrointestinal symptoms.
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Affiliation(s)
- Jens Brondum Frokjaer
- Center for Visceral Biomechanics and Pain, Department of Radiology, Aalborg Hospital, DK-9100 Aalborg, Denmark.
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Shirpoor A, Ansari MHK, Salami S, Pakdel FG, Rasmi Y. Effect of vitamin E on oxidative stress status in small intestine of diabetic rat. World J Gastroenterol 2007; 13:4340-4. [PMID: 17708608 PMCID: PMC4250861 DOI: 10.3748/wjg.v13.i32.4340] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of vitamin E on oxidative stress status in the small intestine of diabetic rats.
METHODS: Twenty-four male Wistar rats were randomly divided into three groups: Control (C), non-treated diabetic (NTD) and vitamin E-treated diabetic (VETD) groups. The increases in lipid peroxidation, protein oxidation and superoxide dismutase (SOD) in these three groups was compared after 6 wk.
RESULTS: There was no significant difference in catalase activity between NTD and control rats. Compared to NTD rats, the treatment with vitamin E significantly decreased lipid peroxidation and protein oxidation, and also increased catalase activity and SOD.
CONCLUSION: The results revealed the occurrence of oxidative stress in the small intestine of diabetic rats. Vitamin E, as an antioxidant, attenuates lipid peroxidation and protein oxidation, and increases antioxidant defense mechanism.
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Affiliation(s)
- A Shirpoor
- Department of Physiology, Faculty of Medicine, Jaddeh Nazloo, Urmia, Iran.
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Yamada K, Hosokawa M, Fujimoto S, Nagashima K, Fukuda K, Fujiwara H, Ogawa E, Fujita Y, Ueda N, Matsuyama F, Yamada Y, Seino Y, Inagaki N. The spontaneously diabetic Torii rat with gastroenteropathy. Diabetes Res Clin Pract 2007; 75:127-34. [PMID: 16959364 DOI: 10.1016/j.diabres.2006.06.034] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2006] [Revised: 05/30/2006] [Accepted: 06/07/2006] [Indexed: 12/17/2022]
Abstract
The spontaneously diabetic Torii (SDT) rat was recently recognized as a new animal model of non-obese type 2 diabetes. As the severe diabetic ocular complications seen in SDT rats already have been investigated, we examined another common diabetic complication, gastroenteropathy. Male SDT rats developed diabetes at 20 weeks and diarrhea at 28 weeks of age. Gastrointestinal motility was evaluated at 28 weeks by measuring the distance of small intestinal transit by oral administration of the non-absorbed marker, arabic gum. SDT rats exhibited greater intestinal transit distance than control SD rats (54.1+/-2.6% versus 43.0+/-1.2%). Insulin treatment of SDT rats begun at 20 weeks of age produced improved stool and reduced intestinal transit distance (41.4+/-0.3%). Morphologically, the SDT rats exhibited longer villi and heavier weight of intestine compared to control SD rats. These results suggest that the SDT rat may be a useful animal model for studies of diabetic gastroenteropathy.
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Affiliation(s)
- Kotaro Yamada
- Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
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Sha H, Zhao JB, Zhang ZY, Zhou SP, Tong XL, Zhuang FY, Gregersen H. Effect of Kaiyu Qingwei Jianji on the morphometry and residual strain distribution of small intestine in experimental diabetic rats. World J Gastroenterol 2006; 12:7149-54. [PMID: 17131477 PMCID: PMC4087776 DOI: 10.3748/wjg.v12.i44.7149] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of a Chinese medicine, Kaiyu Qingwei Jianji (KYQWJJ) used for diabetic treatment, on the morphometry and residual strain distribution of the small intestine in streptozotocin (STZ) -induced diabetic rats. Correlation analysis was also performed between the opening angle and residual strain with the blood glucose level.
METHODS: Forty-two male Wistar rats weighing 220-240 g were included in this study. Thirty-two STZ-induced diabetic rats were subdivided into four groups (n = 8 in each group), i.e. diabetic control group (DM); high dose of KYQWJJ (T1, 36g/kg per day); low dose of KYQWJJ (T2, 17 g/kg per day) and Gliclazide (T3, 50 mg/kg per day). Another ten rats were used as non-diabetic control (CON). The medicines were poured directly into stomach lumen by gastric lavage twice daily. The rats of CON and DM groups were only poured the physiological saline. Blood glucose and plasma insulin levels were measured. Experimental period was 35 d. At the end of experiment, three 5-cm long segments were harvested from the duodenum, jejunum and ileum. Three rings of 1-2 mm in length for no-load and zero-stress state tests were cut from the middle of different segments. The morphometric data, such as the circumferential length, the wall thickness and the opening angle were measured from the digitized images of intestinal segments in the no-load state and zero-stress state. The residual strain was computed from the morphometry data. Furthermore, the linear regression analysis was performed between blood glucose level with morphometric and biomechanical data in the different intestinal segments.
RESULTS: The blood glucose level of DM group was consistent 4-fold to 5-fold higher than those in CON group during the experiment (16.89 ± 1.11 vs 3.44 ± 0.15 mmol/L, P < 0.001). The blood glucose level in the T1 (16.89 ± 1.11 vs 11.08 ± 2.67 mmol/L, P < 0.01) and T3 groups (16.89 ± 1.11 vs 13.54 ± 1.73 mmol/L, P < 0.05), but not in T2 group (P > 0.05) was significantly lower than those in DM group. The plasma insulin levels of DM, T1, T2 and T3 groups were significantly lower than those in CON group (10.98 ± 1.02, 12.52 ± 1.42,13.54 ± 1.56,10.96 ± 0.96 vs 17.84 ± 2.34 pmol/L respectively, P < 0.05), but no significantly difference among the groups with exception of CON group. The wet weight/cm and total wall thickness of duodenum, jejunum and ileum in DM group were significantly higher than those in CON group (wet weight (g/cm): duodenum 0.209 ± 0.012 vs 0.166 ± 0.010, jejunum 0.149 ± 0.008 vs 0.121 ± 0.004, ileum 0.134 ± 0.013 vs 0.112 ± 0.007; Wall thickness (mm): duodenum 0.849 ± 0.027 vs 0.710 ± 0.026, jejunum 0.7259 ± 0.034 vs 0.627 ± 0.025, ileum 0.532 ± 0.023 vs 0.470 ± 0.010, all P < 0.05), T1 and T3 treatment could partly restore change of wall thickness, but T2 could not. The opening angle and absolute value of inner and outer residual stain were significantly smaller in duodenal segment (188 ± 11 degrees, -0.31 ± 0.02 and 0.35 ± 0.03 vs 259 ± 15 degrees, -0.40 ± 0.02 and 0.43 ± 0.05) and larger in jejunal (215 ± 20 degrees, -0.30 ± 0.03 and 0.36 ± 0.06 vs 172 ± 19 degrees, -0.25 ± 0.02 and 0.27 ± 0.02) and ileal segments (183 ± 20 degrees, -0.28 ± 0.01 and 0.34 ± 0.05 vs 153 ± 14 degrees, -0.23 ± 0.03 and 0.29 ± 0.04) in DM group than in CON group (P < 0.01). T1 and T3 treatment could partly restore this biomechanical alteration, but strong effect was found in T1 treatment (duodenum 243 ± 14 degrees, -0.36 ± 0.02 and 0.42 ± 0.06, jejunum 180 ± 15 degrees, -0.26 ± 0.03 and 0.30 ± 0.06 and ileum 163 ± 17 degrees, -0.23 ± 0.03 and 0.30 ± 0.05, compared with DM, P < 0.05). The linear association was found between the glucose level with most morphometric and biomechanical data.
CONCLUSION: KYQWJJ (high dose) treatment could partly restore the changes of blood glucose level and the remodeling of morphometry and residual strain of small intestine in diabetic rats. The linear regression analysis demonstrated that the effect of KYQWJJ on intestinal opening angle and residual strain is partially through its effect on the blood glucose level.
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Affiliation(s)
- Hong Sha
- China-Japan Friendship Hospital, Beijing, China
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20
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Abstract
Gastrointestinal (GI) sensory-motor abnormalities are common in patients with diabetes mellitus and may involve any part of the GI tract. Abnormalities are frequently sub-clinical, and fortunately only rarely do severe and life-threatening problems occur. The pathogenesis of abnormal upper GI sensory-motor function in diabetes is incompletely understood and is most likely multi-factorial of origin. Diabetic autonomic neuropathy as well as acute suboptimal control of diabetes has been shown to impair GI motor and sensory function. Morphological and biomechanical remodeling of the GI wall develops during the duration of diabetes, and may contribute to motor and sensory dysfunction. In this review sensory and motility disorders of the upper GI tract in diabetes is discussed; and the morphological changes and biomechanical remodeling related to the sensory-motor dysfunction is also addressed.
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Affiliation(s)
- Jingbo Zhao
- Center of Excellence in Visceral Biomechanics and Pain, the Research Building room 404, Aalborg Hospital, Sdr. Skovvej 15, DK-9000 Aalborg, Denmark.
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Ringø E, Mathiesen SD, Storeheier PV, Mayhew TM, Myklebust R. Effects of natural winter pasture and commercial pellet on the ultrastructure of small intestinal epithelium in reindeer. Cell Tissue Res 2005; 320:355-9. [PMID: 15778852 DOI: 10.1007/s00441-004-1074-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2004] [Accepted: 12/13/2004] [Indexed: 12/01/2022]
Abstract
Segments of small intestine (duodenum, jejunum and ileum) from slaughtered reindeer (Rangifer tarandus tarandus) grazing natural winter pastures (n=3) and reindeer fed commercially available pellets (RF-80) in winter (n=5) were collected and immediately fixed in McDowell's fixative. Transmission electron microscopy was employed to investigate the ultrastructural features of the epithelium and lamina propria along the small intestine and to relate these to the different diets. Major differences in ultrastructural features were observed between the small intestinal enterocytes of reindeer fed the two diets. Enterocytes in reindeer fed the natural diet displayed a normal appearance with a dense cytoplasm and distinct microvilli. In contrast, reindeer fed the commercial diet showed damaged enterocytes amongst the normal cells. Abnormal changes included disintegration and loss of microvilli, cytoplasmic swelling, loss of membrane integrity and increases in the width of intercellular spaces, especially in the jejunum.
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Affiliation(s)
- E Ringø
- Section of Arctic Veterinary Medicine, Department of Food Safety and Infection Biology, Norwegian School of Veterinary Science, Tromsø.
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Abstract
PURPOSE OF REVIEW To review recently published studies presenting novel and relevant information on small intestinal motility in humans and animals. RECENT FINDINGS The reviewed studies covered a variety of topics with several themes emerging. The relation between bacterial overgrowth and altered intestinal motility gathers support in a variety of conditions including portal hypertension and senescence. The mechanisms of postoperative ileus are becoming better understood. Cannabinoids play an important role in ileus and this further highlights the importance of these compounds in intestinal motility. Luminal impedance appears to be an important tool for investigation of intestinal flow. SUMMARY Small intestinal motility remains an understudied area. Recent publications have shed additional light on myogenic, neural, and hormonal control mechanisms. Novel investigative techniques will likely further improve our understanding.
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Affiliation(s)
- Michael P Jones
- Division of Gastroenterology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
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23
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Bhor VM, Raghuram N, Sivakami S. Oxidative damage and altered antioxidant enzyme activities in the small intestine of streptozotocin-induced diabetic rats. Int J Biochem Cell Biol 2004; 36:89-97. [PMID: 14592535 DOI: 10.1016/s1357-2725(03)00142-0] [Citation(s) in RCA: 137] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The small intestine exhibits numerous morphological and functional alterations during diabetes. Oxidative stress, a factor implicated in the pathogenesis of diabetic complications may contribute towards some of these alterations. We therefore investigated the occurrence of oxidative stress in the small intestine during diabetes by measuring the extent of oxidative damage as well as the status of the antioxidant defense system. Significant increases in lipid peroxidation (four-fold) as measured by TBARS and protein oxidation (38%) as measured by protein carbonyl content were observed after 6 weeks of diabetes. A distinct elevation in the activities of catalase (123.9%) and superoxide dismutase (71.9%) and a decline in the activity of glutathione peroxidase (67.7%) were also observed. The steady state mRNA levels of these enzymes measured by RT-PCR were, however, unchanged suggesting the absence of transcriptional control. In contrast, no changes in the levels of protein and non-protein thiols as well as the activities of glutathione reductase and glutathione-S-transferase were detected. Interestingly, decreases in the activities of xanthine oxidase (XO; 25.7%) and xanthine dehydrogenase (XDH; 42.6%) indicate that they do not contribute significantly to oxidative damage. The results thus reveal the occurrence of oxidative stress in the small intestine during diabetes and suggest its possible involvement in some of the accompanying functional alterations.
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Affiliation(s)
- V M Bhor
- Department of Life Sciences, University of Mumbai, Santacruz (East), Mumbai 400098, India
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24
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Bhor VM, Sivakami S. Regional variations in intestinal brush border membrane fluidity and function during diabetes and the role of oxidative stress and non-enzymatic glycation. Mol Cell Biochem 2004; 252:125-32. [PMID: 14577585 DOI: 10.1023/a:1025599126840] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The physical state (fluidity) of lipids modulates the activities of several membrane bound enzymes and transport proteins. Alteration of brush border membrane (BBM) fluidity is one of the several changes exhibited by the small intestine during diabetes. In the present study, an investigation of the diabetes induced regional changes in fluidity, oxidative damage, non-enzymatic glycation as well as the activities and the kinetic parameters of the enzymes alkaline phosphatase and gamma-glutamyl transpeptidase was carried out on the intestinal BBM. At the end of 6 weeks of diabetes, significant increases in the extent of both oxidative damage and non-enzymatic glycation were observed along the length of the intestine along with a simultaneous decrease in membrane fluidity. A significant correlation between the decrease in BBM fluidity and increase in non-enzymatic glycation was observed in the duodenum and jejunum. Additionally regional variations in the activities and kinetic parameters of both the enzymes were observed.
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Affiliation(s)
- V M Bhor
- Department of Life Sciences, University of Mumbai, Santacruz (East), Mumbai 400 098, India
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25
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Zhao J, Yang J, Gregersen H. Biomechanical and morphometric intestinal remodelling during experimental diabetes in rats. Diabetologia 2003; 46:1688-97. [PMID: 14593459 DOI: 10.1007/s00125-003-1233-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2003] [Revised: 07/28/2003] [Indexed: 12/19/2022]
Abstract
AIMS/HYPOTHESIS Morphometric and passive biomechanical properties were studied in the duodenum, jejunum and ileum in 10 non-diabetic and 40 streptozotocin-induced diabetic rats. METHODS The diabetic rats were divided into groups living 4 days, 1, 2, and 4 weeks after diabetes was induced ( n=10 for each groups). The mechanical test was done as a ramp distension experiment. The intestinal diameter and length were obtained from digitised images of the intestinal segments at pre-selected pressures 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 and from the zero-stress state geometry. RESULTS The blood glucose concentration increased four- to fivefold in the diabetic rats. Streptozotocin-induced diabetes generated pronounced increase in the weight per centimetre length, wall thickness and wall cross-sectional area in all intestinal segments during diabetes ( p<0.05). Histological analysis showed that the thickness of the intestinal layers was increased in all segments during diabetes ( p<0.05). In the duodenum the opening angle did not change in the first 2 weeks and decreased after 4 weeks ( p<0.05). In the jejunum and ileum the opening angle increased after 1 week in the diabetic group. The residual strain showed the same pattern as the opening angle. Furthermore, it was found that the circumferential and longitudinal stiffness of the intestinal wall increased with the duration of diabetes ( p<0.05 and p<0.01). CONCLUSION/INTERPRETATION Morphological and biomechanical remodelling of the small intestine occurred during the development of diabetes.
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Affiliation(s)
- J Zhao
- Centre of Sensory-Motor Interaction, Aalborg University, Denmark
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Zhao J, Sha H, Zhou S, Tong X, Zhuang FY, Gregersen H. Remodelling of zero-stress state of small intestine in streptozotocin-induced diabetic rats. Effect of gliclazide. Dig Liver Dis 2002; 34:707-16. [PMID: 12469798 DOI: 10.1016/s1590-8658(02)80022-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Biomechanical properties in terms of residual strains in diabetic small intestine have not been studied. Furthermore, no data have been reported on affect of gliclazide on gastrointestinal complications of diabetes. AIMS To determine remodelling of zero-stress state of small intestine in streptozotocin-induced diabetic rats and effect of gliclazide treatment. MATERIALS Morphological properties and residual strains were studied in duodenum, jejunum and ileum obtained from diabetic rats, gliclazide-treated diabetic rats and normal rats (n = 8 each group). METHODS Diabetes was induced by single intraperitoneal injection of 65 mg/kg streptozotocin. Gliclazide (10 mg kg(-1) day(-1) was injected directly into stomach lumen by intragastric gavage twice daily. Experimental period was 35 days. To approach no-load state; intestinal segments were surgically excised and cut transversely into short ring-shaped segments. Each ring was cut radially to obtain geometry of zero-stress state. Circumferential length, the wall thickness and opening angle were measured from digital images of each specimen and residual strains were computed. RESULTS Blood glucose level of diabetic group (approximately 20 mmol/l) was consistently higher than that in normal group (approximately 4 mmol/l) after induction of diabetes (p < 0.001). Gliclazide lowered average blood glucose level to between 10 and 15 mmol/l (p < 0.001). Plasma insulin levels of both diabetic groups (average between 10 and 15 pmol/l) were significantly lower than those in normal group (average approximately 18 pmol/l, p < 0.05). Wet weight per unit length and wall thickness of duodenum, jejunum and ileum were significantly higher in Diabetes group than those in Normal group (p < 0.05). Opening angle and absolute value of residual strain were significantly smaller in duodenum and larger in jejunum and ileum in Diabetes group than in Normal group (p < 0.001). Gliclazide treatment partly restored these changes (p < 0.05). CONCLUSIONS Diabetes induced morphometric and biomechanical remodelling in intestine. Gliclazide partly restored these changes.
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Affiliation(s)
- J Zhao
- China-Japan Friendship Hospital, Beijing, PR China
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Jehle PM, Fussgaenger RD, Angelus NK, Jungwirth RJ, Saile B, Lutz MP. Proinsulin stimulates growth of small intestinal crypt-like cells acting via specific receptors. THE AMERICAN JOURNAL OF PHYSIOLOGY 1999; 276:E262-8. [PMID: 9950785 DOI: 10.1152/ajpendo.1999.276.2.e262] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The mechanisms that regulate cell turnover in the intestinal epithelium are incompletely understood. Here we tested the hypothesis that proinsulin, present in serum and pancreatic juice in picomolar concentrations, stimulates growth of the rat small intestinal crypt-like cell line IEC-6 under serum-free conditions. Proinsulin binding was assessed by competitive ligand binding studies. Proinsulin and insulin-like growth factor I (IGF-I) stimulated cell proliferation up to threefold above controls, with half-maximal action already in the picomolar range and with additive effects. In early confluent cell monolayers, proinsulin bound with higher affinity (IC50 1.3 +/- 0.05 nM) and capacity (87,200 +/- 2,500 receptors/cell) than IGF-I (4.0 +/- 0.6; 23,700 +/- 2,200, P < 0. 05). C-peptide competed with 10-fold lower affinity for binding of 125I-proinsulin but not for 125I-IGF-I or 125I-insulin, suggesting a specific binding epitope of the proinsulin molecule within or close to the C-peptide region. In contrast, insulin showed approximately 100-fold lower binding affinity and growth-promoting potency than proinsulin or IGF-I. We conclude that proinsulin stimulates growth of small intestinal crypt cells through specific binding and may play a physiological role in the regulation of intestinal epithelial cell proliferation.
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Affiliation(s)
- P M Jehle
- Division of Nephrology, Departments of Internal Medicine I and II, University of Ulm, 89070 Ulm, Germany
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Adachi T, Takenoshita M, Katsura H, Yasuda K, Tsuda K, Seino Y, Enomoto T, Yamaji R, Miyatake K, Inui H, Nakano Y. Disordered expression of the sucrase-isomaltase complex in the small intestine in Otsuka Long-Evans tokushima fatty rats, a model of non-insulin-dependent diabetes mellitus with insulin resistance. BIOCHIMICA ET BIOPHYSICA ACTA 1999; 1426:126-32. [PMID: 9878708 DOI: 10.1016/s0304-4165(98)00150-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
To clarify the relationship between diabetes mellitus and carbohydrate digestion, the activities of sucrase and isomaltase, which form a complex enzyme (SI complex) on the brush border membranes, were compared in the progression of diabetes mellitus in Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of human non-insulin-dependent diabetes mellitus with insulin resistance, and Long-Evans Tokushima Otsuka (LETO) rats as non-diabetic controls. Until 40 weeks of age, OLETF rats were obese and had a high plasma glucose level, compared to age-matched LETO rats, but the sucrase and isomaltase activities showed no significant differences between the two strains. Oral glucose tolerance test revealed that during 40-48 weeks of age, NIDDM became very severe with advancing insulin resistance in OLETF rats. In OLETF rats, in contrast to LETO rats, at 48 weeks of age, abnormal increases in the sucrase and isomaltase activities occurred, along with a remarkable decrease in body weight and a further great increase in the plasma glucose level in the non-fasting state. Hyperinsulinemia occurred in 20-week-old OLETF rats; however, at 40 and 48 weeks of age, the plasma insulin level in the non-fasting state in OLETF rats was not significantly different from that in LETO rats. The level of mRNA encoding the SI complex increased abnormally in 48-week-old OLETF rats. These results suggest that the advance of insulin resistance leads to an increase in the expression of the SI complex on the transcriptional level.
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Affiliation(s)
- T Adachi
- Laboratory of Metabolism, Kyoto University Graduate School of Human and Environmental Studies, Kyoto 606-8501, Japan
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Abstract
BACKGROUND Selection for body weight provides important animal models for studying mechanisms of growth regulation. This study evaluated growth responses of the gastrointestinal tract (GIT) to long-term selection of mice for high (H line) or low (L line) 8-week body weight as compared with random-bred controls (C line). METHODS Weights and dimensions of the various parts of the GIT were recorded from 8-month-old mice. For light microscopic stereological analyses, samples were taken from eight equidistant locations covering the whole jejunum/ileum. Vertical sections were used for estimation of fractional volumes of mucosa, submucosa, and muscularis and of villous surface area density and for measurement of villus length. RESULTS Differences between groups in weights and dimensions of the various parts of the GIT were more pronounced in the proximal than in the distal segments, with greatest values in H, followed by C and L mice. Relative to body weight, intestinal growth was similar in the three lines, except for significantly (P < 0.001) increased relative weights of jejunum/ ileum, caecum, and colon in L mice. The fractional volume of mucosa and villus length decreased, whereas the fractional volumes of submucosa and muscularis increased from the proximal to the distal locations. The absolute volume of mucosa was greatest in H mice, followed by C and L mice. Relative to body weight, the volume of mucosa was significantly (P < 0.01) greater in L mice than in the two other lines. The mean total villous surface area of jejunum/ileum was significantly (P < 0.01) different among the three lines (L line: 144 cm2; C line: 227 cm2; H line: 304 cm2) but proportionate to differences in metabolic body weight. CONCLUSIONS Selection for body weight affected various parts of the GIT to a different extent. The parameters investigated changed markedly along the small intestine, demonstrating the need for systematic sampling. Vertical section stereology provides unbiased estimates of total villous surface area, which is a parameter of major biological significance.
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Affiliation(s)
- L Ogiolda
- Lehrstuhl für Molekulare Tierzucht und Haustiergenetik/Genzentrum, Ludwig-Maximilians-Universität, München, Germany
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Ettarh RR, Carr KE. A morphological study of the enteric mucosal epithelium in the streptozotocin-diabetic mouse. Life Sci 1997; 61:1851-8. [PMID: 9365232 DOI: 10.1016/s0024-3205(97)00809-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
In the acutely diabetic rat, the polyphagia-induced increase in the weight of the small intestine is associated with reported increases in mucosal mass. Whereas, some of the individual mucosal components in the rat have been studied, comparable information for the acutely streptozotocin-diabetic mouse is lacking. A detailed morphological comparison of the epithelium of the small intestinal mucosa in control and untreated streptozotocin-diabetic mice was therefore undertaken. Samples from three small intestinal sites were examined by light and scanning electron microscopy and quantitative data obtained from histological sections. Although the morphological appearance of the small intestine in acutely diabetic mice was similar in many respects to literature accounts for the diabetic rat, infestation with filamentous microorganisms was present in the jejunum and ileum. The quantitative data showed that these sites also contained distorted villi, fewer crypt profiles, more goblet and Paneth cell profiles and a smaller epithelial volume in comparison to controls. These findings may represent differences between the rat and mouse models of streptozotocin-induced diabetes mellitus.
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Affiliation(s)
- R R Ettarh
- Department of Anatomy, University College, Dublin, Ireland.
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Zoubi SA, Williams MD, Mayhew TM, Sparrow RA. Number and ultrastructure of epithelial cells in crypts and villi along the streptozotocin-diabetic small intestine: a quantitative study on the effects of insulin and aldose reductase inhibition. Virchows Arch 1995; 427:187-93. [PMID: 7582250 DOI: 10.1007/bf00196525] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
This study has quantified the effects of insulin treatment with and without aldose reductase inhibitor (ponalrestat) on intestinal epithelial cell morphology in streptozotocin-diabetic rats. Epithelial volumes, villous and microvillous surface areas and mean volumes of cells (and their nuclei) in crypts and villi were estimated in each of four segments and in the entire intestine. We derived total numbers of cells, quantified the ultrastructural features of average cells and explored variation along the intestine and between experimental groups. In crypts, insulin and ponalrestat had significant effects on cell number (reduced towards normal values) and size (volume and apex area increased beyond normal values). There were interaction effects between insulin and ponalrestat for cell volume and apex area (insulin producing more exaggerated effects when given without ponalrestat). On villi, insulin and ponalrestat returned cell numbers towards normal values but neither treatment normalised cell size or the number and area of microvilli per cell. Indeed, ponalrestat increased microvillous number and area beyond values found in untreated diabetic animals. Again, there were interaction effects between insulin and ponalrestat. Patterns of segmental variation seen in crypts of normal rats (values tending to be higher in proximal or mid-intestinal regions) were not preserved, and only some of the segmental differences seen on villi (higher values at proximal or mid-intestinal sites) were maintained during therapy. Apart from reducing the abnormally high numbers of cells in untreated diabetic rats, these results show that insulin and ponalrestat treatment fail to restitute epithelial cell morphology in the small intestines of experimental diabetic rats.
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Affiliation(s)
- S A Zoubi
- Department of Human Morphology, Queen's Medical Centre, University of Nottingham, UK
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