Skip to main content

Advertisement

SpringerLink
Log in

Up-Regulated Expression of Advanced Glycation End-Products and Their Receptor in the Small Intestine and Colon of Diabetic Rats

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Nair M. Diabetes mellitus, part 1: physiology and complications. Br J Nurs. 2007;16:184–188.

    PubMed  Google Scholar 

  2. Horowitz M, Samsom M. Gastrointestinal function in diabetes mellitus. Chichester: Wiley; 2004.

    Book  Google Scholar 

  3. Zhao J, Frøkjaer JB, Drewes AM, Ejskjaer N. Upper gastrointestinal sensory-motor dysfunction in diabetes mellitus. World J Gastroenterol. 2006;12:2846–2857.

    PubMed  Google Scholar 

  4. Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review. Diabetologia. 2001;44:129–146.

    Article  PubMed  CAS  Google Scholar 

  5. Bierhaus A, Humpert PM, Morcos M. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med. 2005;83:876–886.

    Article  PubMed  CAS  Google Scholar 

  6. Stern DM, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes. Ageing Res Rev. 2002;1:1–15.

    Article  PubMed  CAS  Google Scholar 

  7. Goh SY, Cooper ME. Clinical review: the role of advanced glycation end products in progression and complications of diabetes. J Clin Endocrinol Metab. 2008;93:1143–1152.

    Article  PubMed  CAS  Google Scholar 

  8. Kato T, Yamashita T, Sekiguchi A, et al. AGEs-RAGE system mediates atrial structural remodeling in the diabetic rat. J Cardiovasc Electrophysiol. 2008;19:415–420.

    Article  PubMed  Google Scholar 

  9. Chen BH, Jiang DY, Tang LS. Advanced glycation end-products induce apoptosis involving the signaling pathways of oxidative stress in bovine retinal pericytes. Life Sci. 2006;79:1040–1048.

    Article  PubMed  CAS  Google Scholar 

  10. Sugiyama T, Okuno T, Fukuhara M, et al. Angiotensin II receptor blocker inhibits abnormal accumulation of advanced glycation end products and retinal damage in a rat model of type 2 diabetes. Exp Eye Res. 2007;85:406–412.

    Article  PubMed  CAS  Google Scholar 

  11. Fukami K, Yamagishi S, Ueda S, Okuda S. Role of AGEs in diabetic nephropathy. Curr Pharm Des. 2008;14:946–952.

    Article  PubMed  CAS  Google Scholar 

  12. Suzuki D, Toyoda M, Yamamoto N, et al. Relationship between the expression of advanced glycation end-products (AGE) and the receptor for AGE (RAGE) mRNA in diabetic nephropathy. Intern Med. 2006;45:435–441.

    Article  PubMed  Google Scholar 

  13. Tan AL, Forbes JM, Cooper ME. AGE, RAGE, and ROS in diabetic nephropathy. Seminars in Nephrology. 2007;27:130–143.

    Article  PubMed  CAS  Google Scholar 

  14. Basta G. Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications. Atherosclerosis. 2008;196:9–21.

    Article  PubMed  CAS  Google Scholar 

  15. Peppa M, Raptis SA. Advanced glycation end products and cardiovascular disease. Curr Diabetes Rev. 2008;4:92–100.

    Article  PubMed  CAS  Google Scholar 

  16. Ling X, Nagai R, Sakashita N, et al. Immunohistochemical distribution and quantitative biochemical detection of advanced glycation end products in fetal to adult rats and in rats with streptozotocin- induced diabetes. Lab Invest. 2001;81:845–861.

    PubMed  CAS  Google Scholar 

  17. 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. 2003;252:125–132.

    Article  PubMed  CAS  Google Scholar 

  18. Jeyabal PV, Kumar R, Gangula PR, et al. Inhibitors of advanced glycation end-products prevent loss of enteric neuronal nitric oxide synthase in diabetic rats. Neurogastroenterol Motil. 2008;20:253–261.

    Article  PubMed  CAS  Google Scholar 

  19. Wada R, Yagihashi S. Role of advanced glycation end products and their receptors in development of diabetic neuropathy. Ann N Y Acad Sci. 2005;1043:598–604.

    Article  PubMed  CAS  Google Scholar 

  20. Nazratun N, Mahmood AA, Kuppusamy UR, et al. Diabetes mellitus exacerbates advanced glycation end product accumulation in the veins of end-stage renal failure patients. Vasc Med. 2006;11:245–250.

    Article  PubMed  CAS  Google Scholar 

  21. Esposito C, Gerlach H, Brett J, et al. Endothelial receptor-mediated binding of glucose modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties. J Exp Med. 1989;170:1387–1407.

    Article  PubMed  CAS  Google Scholar 

  22. Schmidt AM, Hori O, Brett J, et al. Cellular receptors for advanced glycation endproducts: implications for induction of oxidative stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb. 1994;14:1521–1528.

    Article  PubMed  CAS  Google Scholar 

  23. Vlassara H. Receptor mediated interactions of advanced glycosylation endproducts with cellular components within diabetic tissues. Diabetes. 1991;41:52–56.

    Google Scholar 

  24. Vlassara H, Bucala R, Striker LJ. Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest. 1994;70:138–151.

    PubMed  CAS  Google Scholar 

  25. 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;426:501–507.

    Article  PubMed  CAS  Google Scholar 

  26. Mayhew TM, Carson FL. Mechanisms of adaptation in rat small intestine: regional differences in quantitative morphology during normal growth and experimental hypertrophy. J Anat. 1995;164:189–200.

    Google Scholar 

  27. Zhou G, Li C, Cai L. Advanced glycation end-products induce connective tissue growth factor-mediated renal fibrosis predominantly through transforming growth factor β-independent pathway. Am J Pathol. 2004;165:2033–2043.

    Article  PubMed  CAS  Google Scholar 

  28. Murata T, Nagai R, Ishibashi T, et al. The relationship between accumulation of advanced glycation end products and expression of vascular endothelial growth factor in human diabetic retinas. Diabetologia. 1997;40:764–769.

    Article  PubMed  CAS  Google Scholar 

  29. Rumble JR, Cooper ME, Soulis T, et al. Vascular hypertrophy in experimental diabetes. Role of advanced glycation end products. J Clin Invest. 1997;99:1016–1027.

    Article  PubMed  CAS  Google Scholar 

  30. Oldfield MD, Bach LA, Forbes JM, et al. Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest. 2001;108:1853–1863.

    PubMed  CAS  Google Scholar 

  31. Seki N, Hashimoto N, Sano H, et al. Mechanisms involved in the stimulatory effect of advanced glycation end products on growth of rat aortic smooth muscle cells. Metabolism. 2003;52:1558–1563.

    Article  PubMed  CAS  Google Scholar 

  32. Handa JT, Reiser KM, Matsunaga H, Hjelmeland LM. The advanced glycation endproduct pentosidine induces the expression of PDGF-B in human retinal pigment epithelial cells. Exp Eye Res. 1998;66:411–419.

    Article  PubMed  CAS  Google Scholar 

  33. Chandrasekharan B, Srinivasan S. Diabetes and the enteric nervous system. Neurogastroenterol Motil. 2007;19:951–960.

    PubMed  CAS  Google Scholar 

  34. Guyton AC, Hall JE. Textbook of medical physiology. 10th ed. USA: W.B. Saunders Company; 2000:754–763.

    Google Scholar 

  35. Brasitus TA, Dudeja PK. Correction of abnormal lipid fluidity and composition of rat ileal microvillus membranes in chronic streptozotocin induced diabetes by insulin therapy. J Biol Chem. 1985;260:12405–12409.

    PubMed  CAS  Google Scholar 

  36. Olsen WA, Korsmo H. The intestinal brush border membrane in diabetes. Studies of sucrase-isomaltase metabolism in rats with streptozotocin diabetes. J Clin Invest. 1977;60:181–188.

    Article  PubMed  CAS  Google Scholar 

  37. Keelan M, Walker K, Thomson AB. Intestinal brush border membrane marker enzymes, lipid composition and villus morphology: effect of fasting and diabetes mellitus in rats. Comp Biochem Physiol A Comp Physiol. 1985;82:83–89.

    Article  PubMed  CAS  Google Scholar 

  38. Phillips LK, Rayner CK, Jones KL, Horowitz M. An update on autonomic neuropathy affecting the gastrointestinal tract. Curr Diab Rep. 2006;6:417–423.

    Article  PubMed  CAS  Google Scholar 

  39. King RH. The role of glycation in the pathogenesis of diabetic polyneuropathy. Mol Pathol. 2001;54:400–408.

    PubMed  CAS  Google Scholar 

  40. Sourris KC, Forbes JM. Interactions between advanced glycation end-products (AGE) and their receptors in the development and progression of diabetic nephropathy—are these receptors valid therapeutic targets. Curr Drug Targets. 2009;10:42–50.

    Article  PubMed  CAS  Google Scholar 

  41. Toth C, Martinez J, Zochodne DW. RAGE, diabetes, and the nervous system. Curr Mol Med. 2007;7:766–776.

    Article  PubMed  CAS  Google Scholar 

  42. Russo A, Fraser R, Adachi K, et al. Evidence that nitric oxide mechanisms regulate small intestinal motility in humans. Gut. 1999;44:72–76.

    Article  PubMed  CAS  Google Scholar 

  43. Korenaga K, Micci MA, Taglialatela G, Pasricha PJ. Suppression of nNOS expression in rat enteric neurones by the receptor for advanced glycation end-products. Neurogastroenterol Motil. 2006;18:392–400.

    Article  PubMed  CAS  Google Scholar 

  44. Toth C, Rong LL, Yang C, et al. Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy. Diabetes. 2008;57:1002–1017.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Karen Elise Jensens Foundation for Jingbo Zhao supported this work.

Conflict of interest

The authors have no proprietary, financial, professional, or other personal interest related to this research.

Author information

Authors and Affiliations

  1. Mech-Sense, Aalborg Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark

    Pengmin Chen & Jingbo Zhao

  2. Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Jingbo Zhao

  3. Department of Molecular Biology, Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China

    Pengmin Chen

  4. Sino-Danish Centre for Education and Research, Aarhus University, Aarhus, Denmark

    Hans Gregersen

Authors
  1. Pengmin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingbo Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hans Gregersen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jingbo Zhao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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 57, 48–57 (2012). https://doi.org/10.1007/s10620-011-1951-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-011-1951-0

Keywords

Search

Navigation