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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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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. 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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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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Abstract
Intestinal failure is a condition characterized by malnutrition and/or dehydration as a result of the inadequate digestion and absorption of nutrients. The most common cause of intestinal failure is short bowel syndrome, which occurs when the functional gut mass is reduced below the level necessary for adequate nutrient and water absorption. This condition may be congenital, or may be acquired as a result of a massive resection of the small bowel. Following resection, the intestine is capable of adaptation in response to enteral nutrients as well as other trophic stimuli. Identifying factors that may enhance the process of intestinal adaptation is an exciting area of research with important potential clinical applications.
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Thiesen A, Drozdowski L, Iordache C, Neo CC, Woudstra TD, Xenodemetropoulos T, Keelan M, Clandinin MT, Thomson ABR, Wild G. Adaptation following intestinal resection: mechanisms and signals. Best Pract Res Clin Gastroenterol 2003; 17:981-95. [PMID: 14642861 DOI: 10.1016/s1521-6918(03)00097-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The intestine has an inherent ability to adapt morphologically and functionally in response to internal and external environmental changes. The functional adaptations encompass modifications of the brush border membrane fluidity and permeability, as well as up- or down-regulation of carrier-mediated transport. Intestinal adaptation improves the nutritional status following the loss of a major portion of the small intestine, following chronic ingestion of ethanol, following sublethal doses of abdominal irradiation, in diabetes, in pregnancy and lactation, with ageing, and with fasting and malnutrition. Following intestinal resection, morphological and functional changes occur depending upon the extent of the intestine removed, the site studied, and the lipid content of the diet. Therefore, intestinal adaptation has important implications in the survival potential and welfare of the host. An understanding of the mechanisms of, and signals for, intestinal adaptation in the experimental setting forms the basis for the use of management strategies in humans with the short-bowel syndrome.
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Affiliation(s)
- A Thiesen
- Nutrition and Metabolism Research Group, Division of Gastroenterology, Department of Medicine, University of Alberta, 519 Newton Research Building, 205 College Plaza, 8215-112 Street, Edmonton, Alta, Canada T6G 2C2.
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Thiesen AL, Tappenden KA, McBurney MI, Clandinin MT, Keelan M, Thomson BK, Wild GE, Thomson AB. Dietary lipids alter the effect of steroids on the transport of glucose after intestinal resection: Part I. Phenotypic changes and expression of transporters. J Pediatr Surg 2003; 38:150-60. [PMID: 12596094 DOI: 10.1053/jpsu.2003.50034] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND/PURPOSE Glucocorticosteroids alter the function of the intestine. This study was undertaken to assess the effect on D-glucose uptake of budesonide (Bud), prednisone (Pred), or dexamethasone (Dex) in animals with a 50% intestinal resection and fed chow or a diet enriched with saturated (SFA) or polyunsaturated fatty acids (PUFA). METHODS In vitro ring uptake technique, Western blots, and Northern blots were performed. RESULTS Bud increased the jejunal D-glucose uptake, and this effect was prevented by feeding PUFA. SGLT1 and Na+/K+ ATPase protein and mRNA abundance did not correlate with the change in the rate of uptake of glucose. CONCLUSIONS (1) Bud increased the jejunal glucose uptake, (2) the activity of the sugar transporter does not correlate with the abundance of protein or their respective mRNAs, (3) th Bud effect on glucose uptake is prevented by feeding PUFA. Thus, the desired intestinal adaptive response after intestinal resection may be enhanced further by the administration of the locally acting steroid budesonide and by feeding a saturated compared with a polyunsaturated fatty acid diet.
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Affiliation(s)
- Aducio L Thiesen
- Nutrition and Metabolism Research Group, Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada
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Abstract
Phospholipids constitute an important part of cellular membranes, and membrane fluidity and permeability are dependent on the fatty acid composition of the phospholipid. The composition, which changes with aging and disease is, to a large degree, influenced by nutrient supply. Phospholipids have been effective in protecting cellular membranes such as those of the gastrointestinal tract to an extent not much different from that observed with external supply of established mucosa-protective drugs such as misoprostol and sucralfate. Polar lipids have also been shown to be effective in preventing microbial translocation. The effect is further potentiated by an external supply of probiotic fibers such as pectin, guar gum, and oat gum. These and many other fibers also have documented strong mucosa preventive effects. Prebiotic bacteria such as Lactobacillus plantarum have demonstrated a strong ability to preserve food and prevent spoilage. In addition, L. plantarum seems to not only preserve key nutrients such as omega-3 fatty acids, but also increases its content during storage conditions. L. plantarum alone or in combination with various fibers has demonstrated a strong ability to reduce and eliminate potentially pathogenic microorganisms both in vitro and in vivo. It has recently been shown that L. plantarum possesses the ability to adhere to and colonize intestinal mucosa. It seems unique among the lactobacilli for L. plantarum to use mannose-specific adhesins, uncommon among gram-positive, but common among gram-negative bacteria, which makes it possible that L. plantarum competes with gram-negative other potential pathogens for receptor sites at the mucosal cell surfaces. Additionally, L. plantarum seems to be effective in eliminating nitrate and producing nitric oxide. These functions of L. plantarum are among the reasons why it has been used in combination with various fibers and polar lipids to recondition the gastrointestinal mucosa. For the purpose of a L. plantarum-containing formula being produced and tried, a treatment policy is regarded as an extension of the immunonutrition program and called ecoimmunonutrition.
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Affiliation(s)
- S Bengmark
- Lund University, Ideon Research Center, Sweden
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Thomson AB, De Pover A, Keelan M, Jarocka-Cyrta E, Clandinin MT. Inhibition of lipid absorption as an approach to the treatment of obesity. Methods Enzymol 1997; 286:3-44. [PMID: 9309643 DOI: 10.1016/s0076-6879(97)86003-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
A reduction in fat intake may be achieved by making educated choices to reduce total calorie intake, to consume a lower quantity of total fats, or to modify the ratio of saturated-to-polyunsaturated lipids. Leptin agonists or NPY or CCK antagonists may prove to be useful to diminish appetite and thereby reduce the total intake of food. But eating has such cultural, social, and hedonistic attributes that such a single-pronged approach is unlikely to be successful. The use of fat substitutes may prove to be popular to provide a wide range of snack food options, but these are likely to be of minimal use in weight reduction programs because of their distribution of additives in only a limited number of foods. The inhibitors of lipid digestion will be modestly successful in the short term; their long-term success will be influenced by gastrointestinal adverse effects and the need to consume fat-soluble vitamin supplements to prevent the development of fat-soluble vitamin deficiencies. The inhibition of lipid absorption is an attractive targeted approach for the treatment of obesity, since this would reduce the uptake of visible as well as invisible fats, which would potentially offer convenient dosing, and could also be a means to inhibit secondarily the uptake of carbohydrate calories.
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Affiliation(s)
- A B Thomson
- Department of Medicine, University of Alberta, Edmonton, Canada
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Keelan M, Clandinin MT, Thomson AB. Refeeding varying fatty acid and cholesterol diets alters phospholipids in rat intestinal brush border membrane. Lipids 1997; 32:895-901. [PMID: 9270983 DOI: 10.1007/s11745-997-0115-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Refeeding a diet initially given shortly after weaning results in a different adaptive change in the in vitro intestinal uptake of sugars and lipids than if the diet is given for the first time at a later age. This study was undertaken in rats to test the hypothesis that changes in nutrient uptake associated with refeeding diets containing beef tallow (S), beef tallow plus 1% cholesterol (Sc), fish oil (F), or fish oil plus cholesterol (Fc) are associated with changes in the brush border membrane (BBM) phospholipids and phospholipid fatty acids. Weanling Sprague-Dawley rats were fed ad libitum one of the four diets. At 35 d of age (about 2 wk after weaning), the rats were maintained on either the same diet used at weaning, or were switched to one of the other semisynthetic diets which were then fed for a further 7 wk. At week nine (2 + 7) the rats were either continued on the same diet or were switched back to the original diet for 2 wk (2 + 7 + 2). The groups of animals which were compared included SSSc vs. ScSSc; ScScS vs. SScS; FFFc vs. FcFFc; and FcFcF vs. FFcF. Refeeding S, Sc, F, or Fc had no effect on food consumption or on body weight gain. Refeeding Fc resulted in increased ileal BBM total phospholipids, whereas rechallenge with F resulted in a decline in the jejunal BBM ratio of phospho-lipid/cholesterol. Refeeding Sc resulted in a decrease in the ileal BBM phosphatidylcholine (PC). In rats rechallenged with Fc, there was increased ileal BBM sphingomyelin (SM), increased ileal BBM phosphatidylethanolamine (PE), decreased ileal BBM PC/PE, and an increased ileal BBM SM/PC. Refeeding had no effect on the fatty acyl constituents of the jejunal of ileal BBM PC or PE. These results suggest that there are late effects of the early introduction of dietary cholesterol on intestinal BBM phospholipid content and composition that may contribute to the previously reported changes in intestinal nutrient absorption.
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Affiliation(s)
- M Keelan
- Department of Medicine, University of Alberta, Edmonton, Canada
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Arnold RS, Newton AC. Inhibition of the insulin receptor tyrosine kinase by phosphatidic acid. J Cell Biochem 1996; 62:516-28. [PMID: 8891897 DOI: 10.1002/(sici)1097-4644(19960915)62:4%3c516::aid-jcb9%3e3.0.co;2-p] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The lipid second messenger, phosphatidic acid, inhibits the intrinsic tyrosine kinase activity of the insulin receptor in detergent-lipid mixed micelles or in reconstituted membranes. Enzymatic studies revealed that this lipid second messenger inhibits the catalytic activity of partially purified insulin receptor without affecting the affinity of the receptor for insulin. Selectivity in the protein-lipid interaction is suggested by the inability of several other acidic lipids to affect the kinase activity of the receptor and by the relative insensitivity of the inhibition to increasing ionic strength and, in some cases, micelle surface charge. Lysophosphatidic acid and phosphatidic acids with short acyl chains do not affect significantly the receptor's kinase activity, suggesting that hydrophobic interactions are involved in the inhibition. Thus, both a high affinity interaction of the insulin receptor with the phosphate headgroup and a stabilizing hydrophobic interaction with the acyl chains contribute to the inhibitory protein-lipid interaction. The selective sensitivity of the insulin receptor to phosphatidic acid suggests that the receptor-mediated generation of this lipid in the plasma membrane could negatively modulate insulin receptor function.
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Affiliation(s)
- R S Arnold
- Department of Pharmacology, University of California at San Diego, La Jolla 92093-0640, USA
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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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Zoubi SA, Mayhew TM, Sparrow RA. The small intestine in experimental diabetes: cellular adaptation in crypts and villi at different longitudinal sites. Virchows Arch 1995; 426:501-7. [PMID: 7633660 DOI: 10.1007/bf00193174] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Intestinal adaptation at the cellular level was examined in groups of streptozotocin-diabetic and age-matched control rats. Small intestines were removed and divided into four segments of roughly equal length. For each segment, epithelial volume, villous and microvillous surface areas and the mean volumes of epithelial cells in crypts and villi were estimated. From these data, we were able to estimate total numbers of epithelial cells in crypts and villi, assess adaptation at the level of the average cell and explore variation along the crypt-villus axis, between segments and between groups. Whilst the villus:crypt cell ratio did not change, diabetic animals contained about 80% more epithelial cells than control rats. The morphophenotype of villous epithelial cells (represented by nuclear volume, cell height, area and volume, and number and surface area of microvilli) was basically the same as that in controls. By contrast, crypt cells and their nuclei were 40-50% bigger in diabetic rats. Significant differences between segments were confined to the numbers and sizes of crypt cells and their nuclei. We conclude that experimental diabetes leads to both proliferative and hypertrophic responses within crypts. Crypt cells become fatter but not taller. Crypt hyperplasia is accompanied by an equiproportionate increase in villous epithelial cells, but these are of essentially normal morphophenotype.
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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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15
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Schedl HP, Christensen KK, Ronnenberg WC. Effects of diabetes on calcium uptake by rat brush border membrane vesicles. Clin Exp Pharmacol Physiol 1995; 22:272-6. [PMID: 7671439 DOI: 10.1111/j.1440-1681.1995.tb01993.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
1. We investigated the mechanism of decreased transmucosal calcium transport in the gut of the diabetic rat by comparing calcium uptake by brush border membrane vesicles from control and streptozotocin diabetic rats at 5 days. Brush border calcium uptake consists of saturable and non-saturable components. Saturable uptake is mediated by a specific mobile carrier mechanism and is defined by Vmax (saturable uptake of calcium at infinite medium calcium concentration) and KT (calcium concentration at Vmax/2). Non-saturable uptake is defined by kD (rate constant for non-saturable uptake per unit calcium concentration), and comprises both diffusive and surface binding components of calcium uptake. 2. We found both saturable and non-saturable calcium uptake to be decreased (P < 0.05) in diabetes. Comparing control and diabetic, Vmax was 247 compared to 152 (data are pmol/mg protein per 3 s); kD was 285 compared to 172 (data are pmol/mg protein per 3 s at 1 mmol/L calcium); and KT (mmol/L) did not differ between groups, 0.070 compared to 0.057. 3. The decreased Vmax in the setting of unchanged KT in vesicles from diabetics is consistent with decreased calcium transporter specific activity, rather than with altered transporter function. 4. Since (i) Vmax is decreased by vitamin D deficiency in the normal rat, and (ii) circulating 1 alpha, 25-dihydroxycholecalciferol is decreased in the diabetic rat, decreased Vmax in the diabetic may be related to the low 1 alpha,25-dihydroxycholecalciferol.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- H P Schedl
- Medical Service, VA Medical Center, Iowa City, Iowa, USA
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Keelan M, Doring K, Tavernini M, Wierzbicki E, Clandinin MT, Thomson AB. Dietary omega 3 fatty acids and cholesterol modify enterocyte microsomal membrane phospholipids, cholesterol content and phospholipid enzyme activities in diabetic rats. Lipids 1994; 29:851-8. [PMID: 7854011 DOI: 10.1007/bf02536253] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Diabetes-associated changes in intestinal uptake of nutrients are modified by isocaloric variations in the type of dietary lipids, and are associated with alterations in the phospholipid and fatty acyl content of the intestinal brush border membrane. The present study was designed to test the hypothesis that diet- and diabetes-associated changes in enterocyte microsomal membrane phospholipids are due to variations in the activity of two phospholipid metabolizing enzymes, 1,2-diacylglycerol:CDPcholine cholinephosphotransferase (CPT) and phosphatidylethanolamine methyltransferase (PEMT). Adult female Wistar rats were fed one of four semisynthetic diets--beef tallow low in cholesterol (BT), beef tallow high in cholesterol (BTC), fish oil low in cholesterol (FO) or fish oil high in cholesterol. In half of the animals, diabetes mellitus was produced by injection of streptozotocin. Jejunal and ileal enterocyte microsomes (EMM) were isolated and analyzed for cholesterol and phospholipids, as well as for CPT and PEMT activities. In control animals, feeding FO reduced EMM total phospholipids including phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol. Feeding FO resulted in a greater than 95% reduction in the activity of CPT. Diabetes was associated with increased jejunal EMM total phospholipids including sphingomyelin (SM) and PE, without associated changes in CPT or PEMT. Dietary cholesterol supplementation did not affect EMM total cholesterol or phosphlipid composition in control rats fed BT or FO, but was associated with an increase in EMM cholesterol in diabetic rats fed BT or FO. A decrease in total phospholipids due to a decline in SM, PC and PE in diabetic rats fed FO was not associated with changes in the activities of CPT or PEMT in EMM.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- M Keelan
- Department of Medicine, University of Alberta, Edmonton, Canada
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Ruiz-Gutiérrez V, Vazquez CM. Characterization of the lipid and fatty acid composition of rat caecal mucosa: effect of intestinal resection. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 1993; 45:183-8. [PMID: 8329869 DOI: 10.1016/s0940-2993(11)80503-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The lipid composition and the fatty acid profile of the lipid fraction (phospholipid, triacylglycerol, diacylglycerol and cholesterol ester) of the caecum were studies 6 weeks after both 50% and 75% distal small bowel resection (DSBR). Triacylglycerol (TG) and cholesterol ester (CE) levels were decreased after resection but the total phospholipid (PL), free cholesterol (FC), and diacylglycerol (DG) contents were not significantly modified after the operation. Different fatty acid changes in the caecum lipid fractions were found after the surgical operation, with the greatest differences after 75% DSBR. Saturated fatty acids were increased in PL, TG and CE fractions as a consequence of DSBR. Similarly, these fractions presented the lowest amounts of n-6 and polyunsaturated fatty acids after resection. On the contrary, the levels of saturated fatty acids was decreased and both n-6 and polyunsaturated fatty acid levels increased in the DG fraction of resected animals. These results are discussed in terms of adaptation to intestinal resection.
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Affiliation(s)
- V Ruiz-Gutiérrez
- Instituto de la Grasa y sus Derivados, (C.S.I.C.), Sevilla, Spain
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18
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Tosco M, Orsenigo MN, Faelli A. d-glucose transport systems in rat jejunal brush border membrane: Influence of ageing. Mech Ageing Dev 1992; 63:131-46. [PMID: 1351123 DOI: 10.1016/0047-6374(92)90059-m] [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] [Indexed: 12/25/2022]
Abstract
Jejunal brush border membranes were isolated from rats of different ages (very young, young, adult and old); the gamma-GT specific activity and the vesicle volumes were unaffected by ageing, whilst protein content was significantly reduced in brush border from old rats. Vesicles were used to investigate the kinetics of Na-glucose cotransport under voltage-clamped and zero-trans conditions over a wide range of D-glucose concentrations (0.005-70 mM). Results provide evidence that in all the ages tested D-glucose can cross the brush border membrane both by a passive diffusional component and by two Na-dependent saturable transport systems, namely one with high-affinity and low-capacity and the other with low-affinity and high-capacity. However, in some old rats only one saturable and a very small passive component occur. The two Na-dependent transport systems were analyzed to define the stoichiometry of coupling between Na and glucose fluxes. In all the ages tested the Na:glucose ratio is higher in the high-affinity system than in the low-affinity one. Accordingly the effect of a superimposed membrane potential is more evident for the high-affinity transport mechanism. In conclusion, D-glucose transport systems seem to be unaffected by ageing from very young to adult rats; only in old animals age-related alterations can be observed.
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Affiliation(s)
- M Tosco
- Dipartimento di Fisiologia e Biochimica Generali, Università di Milano, Italy
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Abstract
In addition to the well-known (Na,K)-ATPase activity, an ouabain-insensitive Na-ATPase has been evidenced in the basolateral membrane of intestinal and renal cells from different mammals. Basolateral membranes of jejunal enterocytes from rats of different ages, i.e., very young, young, adult and old were separated by self-orienting, Percoll-gradient centrifugation. The total protein content and both Na- and (Na,K)-ATPase activities in initial homogenate and final pellets were analyzed. The dry weight of homogenate and pellet was also determined. The two ATPase activities and the protein content of the basolateral membrane fraction decrease with age when referred to the dry weight of the pellet. This diminution is also evident in the initial homogenate. The activation curve of Na-ATPase, hyperbolic in shape, gives Km and Vmax values unaffected by aging. The same behaviour is true for the kinetic parameters of (Na,K)-ATPase, which has a sigmoidal velocity curve. From these results, it seems that both Na- and (Na,K)-ATPase have the same characteristics in the basolateral membrane of the enterocyte throughout the life span of the animal, but they decrease quantitatively with aging.
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Affiliation(s)
- M Tosco
- Dipartimento di Fisiologia e Biochimica Generali, Universita' di Milano, Italy
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20
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Thomson AB, Keelan M, Garg ML, Clandinin MT. Influence of dietary fat composition on intestinal absorption in the rat. Lipids 1989; 24:494-501. [PMID: 2549323 DOI: 10.1007/bf02535128] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Omega-3 fatty acids influence the function of the intestinal brush border membrane. For example, the omega-3 fatty acid eicosapentaenoic acid (20:5 omega 3) has an antiabsorptive effect on jejunal uptake of glucose. This study was undertaken to determine whether the effect of feeding alpha-linolenic acid (18:3 omega 3) or EPA plus docosahexaenoic acid (22:6 omega 3) on intestinal absorption of nutrients was influenced by the major source of dietary lipid, hydrogenated beef tallow or safflower oil. The in vitro intestinal uptake of glucose, fatty acids and cholesterol was examined in rats fed isocaloric diets for 2 weeks: beef tallow, beef tallow + linolenic acid, beef tallow + eicosapentaenoic acid/docosahexaenoic acid, safflower oil, safflower oil + linolenic acid, or safflower oil + eicosapentaenoic acid/docosahexaenoic acid. Eicosapentaenoic acid/docosahexaenoic acid reduced jejunal uptake of 10 and 20 mM glucose only when fed with beef tallow, and not when fed with safflower oil. Linolenic acid had no effect on glucose uptake, regardless of whether it was fed with beef tallow or safflower oil. The jejunal uptake a long-chain fatty acids (18:0, 18:2 omega 6, 18:3 omega 3, 20:4 omega 6, 20:5 omega 3 and 22:6 omega 3) and cholesterol was lower in safflower oil than with beef tallow. When eicosapentaenoic acid/docosahexaenoic acid was given with beef tallow (but not with safflower oil), there was lower uptake of 18:0, 20:5 omega 3 and cholesterol. The demonstration of the inhibitory effect of linolenic acid or eicosapentaenoic acid/docosahexaenoic acid on cholesterol uptake required the feeding of a saturated fatty acid diet (beef tallow).(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- A B Thomson
- Department of Medicine, University of Alberta, Edmonton, Canada
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Gupta R, Sidhu H, Rattan V, Thind SK, Nath R. Oxalate uptake in intestinal and renal brush-border membrane vesicles (BBMV) in vitamin B6-deficient rats. BIOCHEMICAL MEDICINE AND METABOLIC BIOLOGY 1988; 39:190-8. [PMID: 3377907 DOI: 10.1016/0885-4505(88)90076-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Acute, subclinical, and chronic pyridoxine deficiency did not modify the oxalate influx in rat intestinal BBMV but elevated the oxalate reabsorption by renal tubular cells. The Na+ and K+ ions did not affect oxalate uptake in either intestinal or renal BBMV. Although thiol group blocking agents did not affect intestinal uptake of oxalate they significantly altered oxalate translocation across the renal tubular cells. Following pyridoxine deficiency the rat kidneys appear to be more specific for inducing oxalate lithiasis as compared to oxalate influx through the intestine.
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Affiliation(s)
- R Gupta
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Lee JA, Cossins AR. Adaptation of intestinal morphology in the temperature-acclimated carp, Cyprinus carpio L. Cell Tissue Res 1988; 251:451-6. [PMID: 3345555 DOI: 10.1007/bf00215854] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The effects of temperature and photoperiod acclimation upon the morphology of carp intestinal mucosa have been studied using morphometric techniques. Carp intestine showed an absence of anatomical regionalisation. There was a gradual reduction in the dimensions of villi along the tract. The decrease in the dimensions of the villi was greatest in the anterior half. Temperature acclimation had no effect on intestinal-somatic indices. Acclimation to 10 degrees C or 30 degrees C resulted in large differences in the dimensions of villi. Cold acclimation produced significant increases in mean villus height and breadth along the entire intestine. These villus shape changes resulted in a 58% increase in total mucosal surface area and a 102% increase in total volume of villi in cold-acclimated fish relative to warm-acclimated fish. Surface area of the unmodified intestinal tube increased with cold acclimation by 28%. The total number of villi remained unchanged by thermal acclimation. Because normalisation to a nominal surface area does not take account of the possibility of differentially developed mucosal surfaces in differently acclimated animals, experiments comparing transepithelial transport rates of differently-acclimated fish, using unstripped preparations, overestimates the differences in area-specific transport capacity.
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Affiliation(s)
- J A Lee
- Department of Zoology, University of Liverpool, United Kingdom
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Thomson AB, Keelan M, Clandinin MT, Rajotte RV, Cheeseman CI, Walker K. Treatment of the enhanced intestinal uptake of glucose in diabetic rats with a polyunsaturated fatty acid diet. BIOCHIMICA ET BIOPHYSICA ACTA 1987; 905:426-34. [PMID: 3689786 DOI: 10.1016/0005-2736(87)90472-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Intestinal absorption of most nutrients is enhanced in diabetic rats. We wished to test the hypothesis that manipulation of dietary fatty acids will modify enhanced uptake of glucose in rats with established streptozotocin-diabetes. Chow-fed control rats or animals with one week of streptozotocin-diabetes were continued on chow or were fed ad libitum for three weeks with semisynthetic isocaloric diets containing a high content of either essential polyunsaturated or non-essential saturated fatty acids. The jejunal and ileal in vitro uptake of varying concentrations of glucose was much higher in diabetic than control rats fed chow or the saturated fatty acid diet. In contrast, the enhanced uptake of this sugar was reduced or normalized in diabetic rats fed the polyunsaturated fatty acid diet. Feeding the polyunsaturated fatty acid diet was associated with increased brush-border membrane activity of alkaline phosphatase in diabetic jejunum and ileum, but neither the saturated fatty acid diet nor the polyunsaturated fatty acid diet altered brush-border membrane cholesterol or phospholipids in control or in diabetic rats. Mucosal surface area was similar in diabetic rats fed the saturated fatty acid diet or the polyunsaturated fatty acid diet. Thus, (1) feeding the polyunsaturated fatty acid diet diminishes the enhanced jejunal and ileal uptake of glucose in diabetic rats, and (2) the influence of the polyunsaturated fatty acid diet on uptake in diabetic rats was not explained by alterations in intestinal morphology or brush-border membrane content of cholesterol or phospholipids. This study suggests that manipulation of dietary lipids may play a role in the normalization of the enhanced intestinal glucose uptake in rats with established diabetes.
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Affiliation(s)
- A B Thomson
- Department of Medicine, University of Alberta, Edmonton, Canada
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Thomson AB, Keelan M. Late effects of early feeding of a low cholesterol diet on the intestinal active and passive transport properties in the rabbit. Mech Ageing Dev 1987; 40:157-70. [PMID: 3431158 DOI: 10.1016/0047-6374(87)90015-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
It has previously been demonstrated that a short period of feeding of a low cholesterol diet (LCD) alters the active and passive transport properties of the intestine. This study was undertaken to determine the late effect of early nutrition with LCD. An in vitro technique was used to determine the uptake of glucose, galactose, leucine, medium- and long-chain fatty acids, cholesterol and bile acids into the jejunum, ileum and colon of rabbits. Five dietary groups were used: group A was fed chow for 16 weeks; group B was fed chow for 14 weeks followed by LCD for 2 weeks; group C was fed chow for 2 weeks, LCD for 2 weeks, chow for 10 weeks, and LCD for 2 weeks; group D was fed chow for 2 weeks and LCD for 14 weeks; and group E was fed chow for 2 weeks, LCD for 2 weeks and chow for 14 weeks. Animals fed LCD for 2 weeks at an early age demonstrated different alterations in the active and passive transport of these solutes as compared with animals exposed to LCD for only 2 weeks at a later age (group C vs. group D). Feeding the animals chow for 12 weeks after 2 weeks of LCD (group E) did not result in a normalization of the altered intestinal transport. The transport changes were progressive, with qualitative and quantitative differences in animals fed LCD for 2 weeks (group B) as compared with animals fed LCD for 14 weeks (group D). These changes in intestinal transport were not due to differences in food consumption or mucosal weight but were likely of nutritional significance, since the animals' body weight gain differed in animals fed chow as compared with those fed LCD. Thus, (1) feeding LCD is associated with alterations in the active and passive jejunal, ileal and colonic uptake of nutrients; (2) these alterations are influenced by the duration of feeding LCD; (3) the effects of LCD persist for at least 10 weeks after the diet is stopped and feeding with chow is restored; and (4) rechallenge with LCD following an earlier exposure to LCD is associated with an accentuation of the intestinal effects of LCD. It is concluded that these late effects of early nutrition with a low cholesterol diet upon intestinal transport function may have an important impact on the nutritional status of the animal.
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Affiliation(s)
- A B Thomson
- Department of Medicine, University of Alberta, Edmonton, Canada
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Thomson AB, Keelan M, Clandinin MT. Onset and persistence of changes in intestinal transport following dietary fat manipulation. Lipids 1987; 22:22-7. [PMID: 3821398 DOI: 10.1007/bf02534870] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
In this study we determined the time-course for the onset and the loss of the effect of short-term feeding rats isocaloric semisynthetic diets containing a high content of saturated (HS) or polyunsaturated (HP) fatty acids on the jejunal and ileal uptake of medium- and long chain fatty acids, cholesterol and glucose. Animals were fed HP or HS for 3, 7 or 14 days; then the diet was switched to standard Purina rat chow for a further 3, 7 or 14 days. The uptake of medium chain fatty acids was unchanged. The differences between HP and HS in glucose uptake occurred within 3 days, but persisted for 14 days, whereas there were qualitative as well as quantitative changes in the pattern of lipid uptake: differences in uptake of stearic, oleic, linoleic and linolenic acids and cholesterol occurred after 7 days of feeding HP or HS. Jejunal uptake of linoleic acid was greater in HP than HS on day 7, but HS was greater than HP on day 14. The effect of diet on lipid uptake was similar in the jejunum and ileum. The altered uptake of stearic and oleic acids persisted after the rats were switched back to chow, whereas the uptake of the other nutrients became similar. Thus, changes in dietary content of saturated and polyunsaturated fatty acids have early effects on intestinal transport function; some of these changes persist even when animals are returned to feeding on chow; and glucose transport is rapidly altered by dietary changes, whereas lipid uptake changes only after 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)
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