Top

International Journal of Diabetes in Developing Countries

Published in:

01-04-2020 | Gestational Diabetes | Original Article

Association of advanced glycation end products (AGEs) with endothelial dysfunction, oxidative stress in gestational diabetes mellitus (GDM)

Authors: Sundar Krishnasamy, Barathi Rajaraman, Vidya Ravi, Rashmi Rajagopal, Arunkumar Ganeshprasad, Ashok Ayyappa Kuppuswamy, Atima Pathak, C. S. Dhevasena, Krishnan Swaminathan, Mohanraj Sundaresan, Nirupama Ramadas, Srinivasan Vedantham

Published in: International Journal of Diabetes in Developing Countries | Issue 2/2020

Abstract

Background

Advanced glycation end products (AGEs) are major risk factors for vascular complications in diabetes. Its role in gestational diabetes mellitus (GDM) and vascular complications in GDM is not known.

Objective

The present study was aimed to study the association of AGEs with GDM and vascular inflammation.

Methods

Plasma samples from normal pregnant and GDM women (n = 50 each) were obtained from two tertiary referral centers in Tamil Nadu, India. Quantification of AGEs, methylglyoxal (MGO), ICAM-1, and malondialdehyde (MDA) were performed by commercially available ELISA kits.

Results and conclusions

The third trimester fasting blood sugar (101.35 ± 26.15 vs. 81.63 ± 6.14, p < 0.002) and postprandial blood sugar (150.69 ± 23.07 vs 105.79 ± 11.99, p < 0.0001) were significantly high in GDM women compared to normal pregnant women. The concentrations of AGEs (13.18 ± 8.74, p < 0.001), MGO (15.7 ± 13.54, p < 0.02), and ICAM-1 (217.8 ± 86.92, p = 0.005) were significantly higher in GDM women compared to AGEs (2.68 ± 0.89), MGO (9.26 ± 5.38), and ICAM-1 (142.3 ± 38.21) in normal pregnant women. Further, elevated levels of MDA concentration (0.64 ± 0.08, p < 0.002) and low GSH levels (0.19 ± 0.1, p < 0.0001) in the GDM women were indicative of oxidative stress. AGE levels significantly correlated with MDA concentration which indicates AGEs may be responsible for oxidative stress in GDM women. Further, elevated level of ICAM-1 in GDM women suggests endothelial activation which may impact endothelial function. Thus, AGEs may be used as a biomarker during pregnancy to predict vascular complications due to GDM.

Available only for authorised users

Seshiah V, Balaji V, Balaji MS, Sanjeevi CB, Green A. Gestational diabetes mellitus in India. J Assoc Physicians India. 2004;52:707–11.PubMed

Damm P, Houshmand-Oeregaard A, Kelstrup L, Lauenborg J, Mathiesen ER, Clausen TD. Gestational diabetes mellitus and long-term consequences for mother and offspring: a view from Denmark. Diabetologia. 2016;59(7):1396–9. https://doi.org/10.1007/s00125-016-3985-5.CrossRefPubMed

Booth AA, Khalifah RG, Todd P, Hudson BG. In vitro kinetic studies of formation of antigenic advanced glycation end products (AGEs) novel inhibition of post-Amadori glycation pathways. J Biol Chem. 1997;272(9):5430–7. https://doi.org/10.1074/jbc.272.9.5430.CrossRefPubMed

Brownlee M, Vlassara H, Cerami A. Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann Intern Med. 1984;101(4):527–37. https://doi.org/10.7326/0003-4819-101-4-527.CrossRefPubMed

Forbes JM, Thallas V, Thomas MC, Founds HW, Burns WC, Jerums G, et al. The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. FASEB J. 2003;17(12):1762–4. https://doi.org/10.1096/fj.02-1102fje.CrossRefPubMed

Wendt T, Bucciarelli L, Qu W, Lu Y, Yan SF, Stern DM, et al. Receptor for advanced glycation end products (RAGE) and vascular inflammation: insights into the pathogenesis of macrovascular complications in diabetes. Curr Atheroscler Rep. 2002;4(3):228–37.CrossRef

Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res. 1998;37(3):586–600. https://doi.org/10.1016/s0008-6363(97)00233-2.CrossRefPubMed

Loughlin DT, Artlett CM. Precursor of advanced glycation end products mediates ER-stress-induced caspase-3 activation of human dermal fibroblasts through NAD(P)H oxidase 4. PLoS One. 2010;5(6):e11093. https://doi.org/10.1371/journal.pone.0011093.CrossRefPubMedPubMedCentral

Wautier JL, Zoukourian C, Chappey O, Wautier MP, Guillausseau PJ, Cao R, et al. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest. 1996;97(1):238–43. https://doi.org/10.1172/JCI118397.CrossRefPubMedPubMedCentral

10.

Yamagishi S, Nakamura N, Suematsu M, Kaseda K, Matsui T. Advanced glycation end products: a molecular target for vascular complications in diabetes. Mol Med. 2015;21(Suppl 1):S32–40. https://doi.org/10.2119/molmed.2015.00067.CrossRefPubMedPubMedCentral

11.

Ueda S, Yamagishi S, Yokoro M, Okuda S. Role of asymmetric dimethylarginine in cardiorenal syndrome. Curr Pharm Des. 2014;20(14):2448–55.CrossRef

12.

Ojima A, Ishibashi Y, Matsui T, Maeda S, Nishino Y, Takeuchi M, et al. Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression. Am J Pathol. 2013;182(1):132–41. https://doi.org/10.1016/j.ajpath.2012.09.016.CrossRefPubMed

13.

Ando R, Ueda S, Yamagishi S, Miyazaki H, Kaida Y, Kaifu K, et al. Involvement of advanced glycation end product-induced asymmetric dimethylarginine generation in endothelial dysfunction. Diab Vasc Dis Res. 2013;10(5):436–41. https://doi.org/10.1177/1479164113486662.CrossRefPubMed

14.

Litwinoff E, Hurtado Del Pozo C, Ramasamy R, Schmidt AM. Emerging targets for therapeutic development in diabetes and its complications: the RAGE signaling pathway. Clin Pharmacol Ther. 2015;98(2):135–44. https://doi.org/10.1002/cpt.148.CrossRefPubMedPubMedCentral

15.

Rabbani N, Thornalley PJ. Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino Acids. 2012;42(4):1133–42. https://doi.org/10.1007/s00726-010-0783-0.CrossRefPubMed

16.

Dupont WD, Plummer WD Jr. Power and sample size calculations for studies involving linear regression. Control Clin Trials. 1998;19(6):589–601.CrossRef

17.

International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676–82. https://doi.org/10.2337/dc09-1848.CrossRefPubMedCentral

18.

Deepa M, Pradeepa R, Rema M, Mohan A, Deepa R, Shanthirani S, et al. The Chennai Urban Rural Epidemiology Study (CURES)- study design and methodology (urban component) (CURES-1). J Assoc Physician India. 2003;51:863–70.

19.

Kelstrup L, Damm P, Mathiesen ER, Hansen T, Vaag AA, Pedersen O, et al. Insulin resistance and impaired pancreatic β-cell function in adult offspring of women with diabetes in pregnancy. J Clin Endocrinol Metab. 2013 Sep;98(9):3793–801. https://doi.org/10.1210/jc.2013-1536.CrossRefPubMedPubMedCentral

20.

Luo ZC, Fraser WD, Julien P, Deal CL, Audibert F, Smith GN, et al. Tracing the origins of “fetal origins” of adult diseases: programming by oxidative stress? Med Hypotheses. 2006;66(1):38–44. https://doi.org/10.1016/j.mehy.2005.08.020.CrossRefPubMed

21.

Lappas M, Hiden U, Desoye G, Froehlich J, Hauguel-de Mouzon S, Jawerbaum A. The role of oxidative stress in the pathophysiology of gestational diabetes mellitus. Antioxid Redox Signal. 2011;15(12):3061–100. https://doi.org/10.1089/ars.2010.3765.CrossRefPubMed

22.

Rajaraman B, Ramadas N, Krishnasamy S, Ravi V, Pathak A, Devasena CS, et al. Hyperglycaemia cause vascular inflammation through advanced glycation end products/early growth response-1 axis in gestational diabetes mellitus. Mol Cell Biochem. 2019;456(1–2):179–90. https://doi.org/10.1007/s11010-019-03503-0.CrossRefPubMed

23.

Spranger J, Kroke A, Möhlig M, Hoffmann K, Bergmann MM, Ristow M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes. 2003;52(3):812–7. https://doi.org/10.2337/diabetes.52.3.812.CrossRefPubMed

24.

Monnier VM, Sell DR, Genuth S. Glycation products as markers and predictors of the progression of diabetic complications. Ann N Y Acad Sci. 2005;1043:567–81. https://doi.org/10.1196/annals.1333.065.CrossRefPubMed

25.

Sampathkumar R, Balasubramanyam M, Rema M, Premanand C, Mohan V. A novel advanced glycation index and its association with diabetes and microangiopathy. Metabolism. 2005;54(8):1002–7. https://doi.org/10.1016/j.metabol.2005.02.017.CrossRefPubMed

26.

Anitha B, Sampathkumar R, Balasubramanyam M, Rema M. Advanced glycation index and its association with severity of diabetic retinopathy in type 2 diabetic subjects. J Diabetes Complicat. 2008;22(4):261–6. https://doi.org/10.1016/j.jdiacomp.2007.05.005.CrossRefPubMed

27.

Gokulakrishnan K, Deepa R, Sampathkumar R, Balasubramanyam M, Mohan V. Association of leukocyte count with varying degrees of glucose intolerance in Asian Indians: the Chennai Urban Rural Epidemiology Study (CURES-26). Metab Syndr Relat Disord. 2009;7(3):205–10. https://doi.org/10.1089/met.2008.0024.CrossRefPubMed

28.

Uribarri J, Cai W, Woodward M, Tripp E, Goldberg L, Pyzik R, et al. Elevated serum advanced glycation endproducts in obese indicate risk for the metabolic syndrome: a link between healthy and unhealthy obesity? J Clin Endocrinol Metab. 2015;100(5):1957–66. https://doi.org/10.1210/jc.2014-3925.CrossRefPubMedPubMedCentral

29.

Mericq V, Piccardo C, Cai W, Chen X, Zhu L, Striker GE, et al. Maternally transmitted and food-derived glycotoxins a factor preconditioning the young to diabetes? Diabetes Care. 2010;33(10):2232–7. https://doi.org/10.2337/dc10-1058.CrossRefPubMedPubMedCentral

30.

Miyazawa N, Abe M, Souma T, Tanemoto M, Abe T, Nakayama M, et al. Methylglyoxal augments intracellular oxidative stress in human aortic endothelial cells. Free Radic Res. 2010;44(1):101–7. https://doi.org/10.3109/10715760903321788.CrossRefPubMed

31.

Yan SD, Schmidt AM, Anderson GM, Zhang J, Brett J, Zou YS, et al. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem. 1994;269(13):9889–97.PubMed

32.

Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab. 2001;280(5):E685–94.CrossRef

33.

Jialal I, Devaraj S, Venugopal SK. Oxidative stress, inflammation, and diabetic vasculopathies: the role of alpha tocopherol therapy. Free Radic Res. 2002;36(12):1331–6.CrossRef

34.

Morgan PE, Dean RT, Davies MJ. Inactivation of cellular enzymes by carbonyls and protein-bound glycation/glycoxidation products. Arch Biochem Biophys. 2002;403(2):259–69.CrossRef

35.

Deuther-Conrad W, Loske C, Schinzel R, Dringen R, Riederer P, Münch G. Advanced glycation endproducts change glutathione redox status in SH-SY5Y human neuroblastoma cells by a hydrogen peroxide dependent mechanism. Neurosci Lett. 2001;312(1):29–32. https://doi.org/10.1016/s0304-3940(01)02174-7.CrossRefPubMed

36.

Neumann A, Schinzel R, Palm D, Riederer P, Münch G. High molecular weight hyaluronic acid inhibits advanced glycation endproduct-induced NF-kappaB activation and cytokine expression. FEBS Lett. 1999;453(3):283–7. https://doi.org/10.1016/s0014-5793(99)00731-0.CrossRefPubMed

37.

Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res. 2004;63(4):582–92. https://doi.org/10.1016/j.cardiores.2004.05.001.CrossRefPubMed

38.

Kautzky-Willer A, Fasching P, Jilma B, Waldhäusl W, Wagner OF. Persistent elevation and metabolic dependence of circulating E-selectin after delivery in women with gestational diabetes mellitus. J Clin Endocrinol Metab. 1997;82(12):4117–21.CrossRef

39.

Sultan SA, Liu W, Peng Y, Roberts W, Whitelaw D, Graham AM. The role of maternal gestational diabetes in inducing fetal endothelial dysfunction. J Cell Physiol. 2015;230(11):2695–705. https://doi.org/10.1002/jcp.24993.CrossRefPubMed

40.

Poniedziałek-Czajkowska E, Mierzyński R, Szymula D, Leszczyńska-Gorzelak B, Oleszczuk J. Intercellular adhesion molecule and endogenous NOS inhibitor: asymmetric dimethylarginine in pregnant women with gestational diabetes mellitus. J Diabetes Res. 2016;2016:1342643. https://doi.org/10.1155/2016/1342643.CrossRefPubMedPubMedCentral

Title: Association of advanced glycation end products (AGEs) with endothelial dysfunction, oxidative stress in gestational diabetes mellitus (GDM)
Authors: Sundar Krishnasamy
Barathi Rajaraman
Vidya Ravi
Rashmi Rajagopal
Arunkumar Ganeshprasad
Ashok Ayyappa Kuppuswamy
Atima Pathak
C. S. Dhevasena
Krishnan Swaminathan
Mohanraj Sundaresan
Nirupama Ramadas
Srinivasan Vedantham
Publication date: 01-04-2020
Publisher: Springer India
Keywords: Gestational Diabetes
Gestational Diabetes
Hyperglycemia
Published in: International Journal of Diabetes in Developing Countries / Issue 2/2020
Print ISSN: 0973-3930
Electronic ISSN: 1998-3832
DOI: https://doi.org/10.1007/s13410-019-00766-7

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Objective

Methods

Results and conclusions

Please log in to get access to this content

Other articles of this Issue 2/2020

Assessment of risk for obstructive sleep apnea by using STOP-BANG questionnaire in type 2 diabetes mellitus

Irisin in elderly people with hypertension, diabetes mellitus type 2, and overweight and obesity

MACF1 gene variant rs2296172 is associated with T2D susceptibility in Mizo population from Northeast India

Phenotypic characterization of patients with type 2 diabetes mellitus

Lockdown—the only solution to defeat COVID-19

Changes in SFRP5, WNT5A, HbA1c, BMI, PBF, and insulin resistance in men with type 2 diabetes after 12 weeks of combined exercise (HIIT and resistance)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage