Subscribe to RSS
DOI: 10.1055/s-0028-1082085
© Georg Thieme Verlag KG Stuttgart · New York
Modulation of Insulin Action by Advanced Glycation Endproducts: A New Player in the Field
Publication History
received 27.10.2007
accepted 21.02.2008
Publication Date:
15 September 2008 (online)
![](https://www.thieme-connect.de/media/hmr/200809/lookinside/thumbnails/10.1055-s-0028-1082085-1.jpg)
Abstract
Insulin resistance is characterized by an impaired responsiveness to the action of insulin at its multiple target organs. The accumulation of advanced glycation endproducts (AGEs) has been demonstrated in clinical settings of insulin resistance such as in diabetes, hypertension, and obesity. In this review we have focused on advanced glycation as a modulator of insulin resistance. Structural and functional abnormalities of the insulin molecule by glycation and methylglyoxal may contribute to the pathogenesis of insulin resistance. In addition, it is likely that AGEs interfere in the complex molecular pathways of insulin signaling and as such in insulin resistance.
Key words
AGEs - insulin resistance - glycation
References
- 1 Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006; 7 85-96
- 2 Yudkin JS. Inflammation, obesity, and the metabolic syndrome. Horm Metab Res. 2007; 39 707-709
- 3 Clark MG, Wallis MG, Barrett EJ, Vincent MA, Richards SM, Clerk LH, Rattigan S. Blood flow and muscle metabolism: a focus on insulin action. Am J Physiol Endocrinol Metab. 2003; 284 E241-E258
- 4 Serne EH, IJzerman RG, Gans RO, Nijveldt R, Vries G De, Evertz R, Donker AJ, Stehouwer CD. Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia. Diabetes. 2002; 51 1515-1522
- 5 Accili D, Cama A, Barbetti F, Kadowaki H, Kadowaki T, Taylor SI. Insulin resistance due to mutations of the insulin receptor gene: an overview. J Endocrinol Invest. 1992; 15 857-864
- 6 Arner P, Pollare T, Lithell H, Livingston JN. Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1987; 30 437-440
- 7 Youngren JF. Regulation of insulin receptor function. Cell Mol Life Sci. 2007; 64 873-891
- 8 Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol. 2004; 24 816-823
- 9 Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006; 440 944-948
- 10 Davidson MB, Bouch C, Venkatesan N, Karjala RG. Impaired glucose transport in skeletal muscle but normal GLUT-4 tissue distribution in glucose-infused rats. Am J Physiol. 1994; 267 E808-E813
- 11 Koschinsky T, He CJ, Mitsuhashi T, Bucala R, Liu C, Buenting C, Heitmann K, Vlassara H. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci USA. 1997; 94 6474-6479
- 12 Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri J, Vlassara H. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc. 2004; 104 1287-1291
- 13 Giardino I, Edelstein D, Brownlee M. BCL-2 expression or antioxidants prevent hyperglycemia-induced formation of intracellular advanced glycation endproducts in bovine endothelial cells. J Clin Invest. 1996; 97 1422-1428
- 14 Giardino I, Edelstein D, Brownlee M. Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes. J Clin Invest. 1994; 94 110-117
- 15 Ruderman NB, Williamson JR, Brownlee M. Glucose and diabetic vascular disease. FASEB J. 1992; 6 2905-2914
- 16 Westwood ME, Thornalley PJ. Molecular characteristics of methylglyoxal-modified bovine and human serum albumins. Comparison with glucose-derived advanced glycation endproduct-modified serum albumins. J Protein Chem. 1995; 14 359-372
- 17 Shinohara M, Thornalley PJ, Giardino I, Beisswenger P, Thorpe SR, Onorato J, Brownlee M. Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J Clin Invest. 1998; 101 1142-1147
- 18 Phillips SA, Thornalley PJ. Formation of methylglyoxal and D-lactate in human red blood cells in vitro. Biochem Soc Trans. 1993; 21 163S
- 19 Thornalley PJ. Dicarbonyl intermediates in the maillard reaction. Ann N Y Acad Sci. 2005; 1043 111-117
- 20 Monnier VM, Stevens VJ, Cerami A. Maillard reactions involving proteins and carbohydrates in vivo: relevance to diabetes mellitus and aging. Prog Food Nutr Sci. 1981; 5 315-327
- 21 Baynes JW. The role of AGEs in aging: causation or correlation. Exp Gerontol. 2001; 36 1527-1537
- 22 Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review. Diabetologia. 2001; 44 129-146
- 23 Tilton RG. Diabetic vascular dysfunction: links to glucose-induced reductive stress and VEGF. Microsc Res Tech. 2002; 57 390-407
- 24 Thornalley PJ. Glycation in diabetic neuropathy: characteristics, consequences, causes, and therapeutic options. Int Rev Neurobiol. 2002; 50 37-57
- 25 Ahmed N. Advanced glycation endproducts – role in pathology of diabetic complications. Diabetes Res Clin Pract. 2005; 67 3-21
- 26 Smit AJ, Lutgers HL. The clinical relevance of advanced glycation endproducts (AGE) and recent developments in pharmaceutics to reduce AGE accumulation. Curr Med Chem. 2004; 11 2767-2784
- 27 Basta G, Lazzerini G, Massaro M, Simoncini T, Tanganelli P, Fu C, Kislinger T, Stern DM, Schmidt AM, Caterina R De. Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circulation. 2002; 105 816-822
- 28 Stitt AW, Bucala R, Vlassara H. Atherogenesis and advanced glycation: promotion, progression, and prevention. Ann N Y Acad Sci. 1997; 811 115-127
- 29 Vlassara H. Advanced glycation end-products and atherosclerosis. Ann Med. 1996; 28 419-426
- 30 Baynes JW, Thorpe SR. Glycoxidation and lipoxidation in atherogenesis. Free Radic Biol Med. 2000; 28 1708-1716
- 31 Sasaki N, Fukatsu R, Tsuzuki K, Hayashi Y, Yoshida T, Fujii N, Koike T, Wakayama I, Yanagihara R, Garruto R, Amano N, Makita Z. Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. Am J Pathol. 1998; 153 1149-1155
- 32 Munch G, Deuther-Conrad W, Gasic-Milenkovic J. Glycoxidative stress creates a vicious cycle of neurodegeneration in Alzheimer's disease – a target for neuroprotective treatment strategies?. J Neural Transm Suppl. 2002; 303-307
- 33 Yan SD, Schmidt AM, Stern D. Alzheimer's disease: inside, outside, upside down. Biochem Soc Symp. 2001; 15-22
- 34 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
- 35 Miyazaki A, Nakayama H, Horiuchi S. Scavenger receptors that recognize advanced glycation end products. Trends Cardiovasc Med. 2002; 12 258-262
- 36 Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest. 2001; 108 949-955
- 37 Uchida Y, Ohba K, Yoshioka T, Irie K, Muraki T, Maru Y. Cellular carbonyl stress enhances the expression of plasminogen activator inhibitor-1 in rat white adipocytes via reactive oxygen species-dependent pathway. J Biol Chem. 2004; 279 4075-4083
- 38 Unno Y, Sakai M, Sakamoto Y, Kuniyasu A, Nakayama H, Nagai R, Horiuchi S. Advanced glycation end products-modified proteins and oxidized LDL mediate down-regulation of leptin in mouse adipocytes via CD36. Biochem Biophys Res Commun. 2004; 325 151-156
- 39 Fan X, Subramaniam R, Weiss MF, Monnier VM. Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation. Arch Biochem Biophys. 2003; 409 274-286
- 40 Stirban A, Negrean M, Stratmann B, Gotting C, Salomon J, Kleesiek K, Tschoepe D. Adiponectin decreases postprandially following a heat-processed meal in individuals with type 2 diabetes: an effect prevented by benfotiamine and cooking method. Diabetes Care. 2007; 30 2514-2516
- 41 Makita Z, Vlassara H, Cerami A, Bucala R. Immunochemical detection of advanced glycosylation end products in vivo. J Biol Chem. 1992; 267 5133-5138
- 42 Chen S, Cohen MP, Ziyadeh FN. Amadori-glycated albumin in diabetic nephropathy: pathophysiologic connections. Kidney Int Suppl. 2000; 77 S40-S44
-
43 Schalkwijk CG, Lieuw-a-Fa M, Hinsbergh VW van, Stehouwer CD. Pathophysiological Role of Amadori-glycated proteins in diabetic microangiopathy. In: Michiel JJ, ed.
Diabetic angiopathy . New York: Thieme Medical Publishers 2002: 191-198 - 44 Schalkwijk CG, Ligtvoet N, Twaalfhoven H, Jager A, Blaauwgeers HG, Schlingemann RO, Tarnow L, Parving HH, Stehouwer CD, Hinsbergh VW van. Amadori albumin in type 1 diabetic patients: correlation with markers of endothelial function, association with diabetic nephropathy, and localization in retinal capillaries. Diabetes. 1999; 48 2446-2453
- 45 Schalkwijk CG, Chaturvedi N, Twaafhoven H, Hinsbergh VW van, Stehouwer CD. Amadori-albumin correlates with microvascular complications and precedes nephropathy in type 1 diabetic patients. Eur J Clin Invest. 2002; 32 500-506
- 46 Chaturvedi N, Schalkwijk CG, Abrahamian H, Fuller JH, Stehouwer CD. Circulating and urinary transforming growth factor beta1, Amadori albumin, and complications of type 1 diabetes: the EURODIAB prospective complications study. Diabetes Care. 2002; 25 2320-2327
- 47 Naitoh T, Kitahara M, Tsuruzoe N. Tumor necrosis factor-alpha is induced through phorbol ester – and glycated human albumin-dependent pathway in THP-1 cells. Cell Signal. 2001; 13 331-334
- 48 Miele C, Riboulet A, Maitan MA, Oriente F, Romano C, Formisano P, Giudicelli J, Beguinot F, Obberghen E Van. Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism. J Biol Chem. 2003; 278 47376-47387
- 49 Abdel-Wahab YH, O’Harte FP, Ratcliff H, MacClenaghan NH, Barnett CR, Flatt PR. Glycation of insulin in the islets of Langerhans of normal and diabetic animals. Diabetes. 1996; 45 1489-1496
- 50 Abdel-Wahab YH, O’Harte FP, Barnett CR, Flatt PR. Glycation of insulin in a cultured insulin-secreting cell line. Biochem Soc Trans. 1997; 25 128S
- 51 Abdel-Wahab YH, O’Harte FP, Barnett CR, Flatt PR. Characterization of insulin glycation in insulin-secreting cells maintained in tissue culture. J Endocrinol. 1997; 152 59-67
- 52 Abdel-Wahab YH, O’Harte FP, Boyd AC, Barnett CR, Flatt PR. Glycation of insulin results in reduced biological activity in mice. Acta Diabetol. 1997; 34 265-270
- 53 Lindsay JR, MacKillop AM, Mooney MH, O’Harte FP, Bell PM, Flatt PR. Demonstration of increased concentrations of circulating glycated insulin in human Type 2 diabetes using a novel and specific radioimmunoassay. Diabetologia. 2003; 46 475-478
- 54 O’Harte FP, Hojrup P, Barnett CR, Flatt PR. Identification of the site of glycation of human insulin. Peptides. 1996; 17 1323-1330
- 55 Boyd AC, Abdel-Wahab YH, MacKillop AM, MacNulty H, Barnett CR, O’Harte FP, Flatt PR. Impaired ability of glycated insulin to regulate plasma glucose and stimulate glucose transport and metabolism in mouse abdominal muscle. Biochim Biophys Acta. 2000; 1523 128-134
- 56 Hunter SJ, Boyd AC, O’Harte FP, MacKillop AM, Wiggam MI, Mooney MH, MacCluskey JT, Lindsay JR, Ennis CN, Gamble R, Sheridan B, Barnett CR, MacNulty H, Bell PM, Flatt PR. Demonstration of glycated insulin in human diabetic plasma and decreased biological activity assessed by euglycemic-hyperinsulinemic clamp technique in humans. Diabetes. 2003; 52 492-498
- 57 MacLellan AC, Thornalley PJ, Benn J, Sonksen PH. Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. Clin Sci (Lond). 1994; 87 21-29
- 58 Wu L, Juurlink BH. Increased methylglyoxal and oxidative stress in hypertensive rat vascular smooth muscle cells. Hypertension. 2002; 39 809-814
- 59 Chang T, Wu L. Methylglyoxal, oxidative stress, and hypertension. Can J Physiol Pharmacol. 2006; 84 1229-1238
- 60 Bourajjaj M, Stehouwer CD, Hinsbergh VW van, Schalkwijk CG. Role of methylglyoxal adducts in the development of vascular complications in diabetes mellitus. Biochem Soc Trans. 2003; 31 1400-1402
- 61 Yao D, Taguchi T, Matsumura T, Pestell R, Edelstein D, Giardino I, Suske G, Rabbani N, Thornalley PJ, Sarthy VP, Hammes HP, Brownlee M. High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. J Biol Chem. 2007; 282 31038-31045
- 62 Rosca MG, Mustata TG, Kinter MT, Ozdemir AM, Kern TS, Szweda LI, Brownlee M, Monnier VM, Weiss MF. Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol. 2005; 289 F420-F430
- 63 Jia X, Olson DJ, Ross AR, Wu L. Structural and functional changes in human insulin induced by methylglyoxal. FASEB J. 2006; 20 1555-1557
- 64 Riboulet-Chavey A, Pierron A, Durand I, Murdaca J, Giudicelli J, Obberghen E Van. Methylglyoxal impairs the insulin signaling pathways independently of the formation of intracellular reactive oxygen species. Diabetes. 2006; 55 1289-1299
- 65 Jia X, Wu L. Accumulation of endogenous methylglyoxal impaired insulin signaling in adipose tissue of fructose-fed rats. Mol Cell Biochem. 2007; 306 133-139
- 66 Hofmann MA, Drury S, Hudson BI, Gleason MR, Qu W, Lu Y, Lalla E, Chitnis S, Monteiro J, Stickland MH, Bucciarelli LG, Moser B, Moxley G, Itescu S, Grant PJ, Gregersen PK, Stern DM, Schmidt AM. RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immun. 2002; 3 123-135
- 67 Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H. Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake. Diabetes. 2005; 54 2314-2319
- 68 Stirban A, Negrean M, Stratmann B, Gawlowski T, Horstmann T, Gotting C, Kleesiek K, Mueller-Roesel M, Koschinsky T, Uribarri J, Vlassara H, Tschoepe D. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care. 2006; 29 2064-2071
- 69 Uribarri J, Stirban A, Sander D, Cai W, Negrean M, Buenting CE, Koschinsky T, Vlassara H. Single oral challenge by advanced glycation end products acutely impairs endothelial function in diabetic and nondiabetic subjects. Diabetes Care. 2007; 30 2579-2582
- 70 Ahmed N, Mirshekar-Syahkal B, Kennish L, Karachalias N, Babaei-Jadidi R, Thornalley PJ. Assay of advanced glycation endproducts in selected beverages and food by liquid chromatography with tandem mass spectrometric detection. Mol Nutr Food Res. 2005; 49 691-699
Correspondence
Dr. C. G. Schalkwijk
Department of Internal Medicine
University Hospital Maastricht
Debeyelaan 25
P.O. Box 5800
6202 AZ Maastricht
The Netherlands
Phone: +31/43/388 21 86
Fax: +31/43/387 50 06
Email: C.Schalkwijk@intmed.unimaas.nl