HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sandu, O. Articles by Vlassara, H. Search for Related Content PubMed PubMed Citation Articles by Sandu, O. Articles by Vlassara, H. Social Bookmarking                What's this?

Insulin Resistance and Type 2 Diabetes in High-Fat–Fed Mice Are Linked to High Glycotoxin Intake

¹ The Brookdale Department of Geriatrics, Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, New York, New York
² Department of Medicine, Division of Nephrology, Mount Sinai School of Medicine, New York, New York

	ABSTRACT

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

 
Dietary advanced glycosylation end products (AGEs) have been linked to insulin resistance in db/db⁽⁺⁺⁾ mice. To test whether dietary AGEs play a role in the progression of insulin resistance in normal mice fed high-fat diets, normal C57/BL6 mice were randomly assigned to high-fat diets (35% g fat), either high (HAGE-HF group; 995.4 units/mg AGE) or low (by 2.4-fold LAGE-HF group; 329.6 units/mg AGE) in AGE content for 6 months. Age-matched C57/BL6 and db/db⁽⁺⁺⁾ mice fed regular diet (5% g fat, 117.4 units/mg AGE) served as controls. After 6 months, 75% of HAGE-HF mice were diabetic and exhibited higher body weight (P < 0.001), fasting glucose (P < 0.001), insulin (P < 0.001), and serum AGEs (P < 0.01) than control mice, while none of the LAGE-HF mice were diabetic despite a similar rise in body weight and plasma lipids. The HAGE-HF group displayed markedly impaired glucose and insulin responses during glucose tolerance tests and euglycemic and hyperglycemic clamps and altered pancreatic islet structure and function compared with those of LAGE-HF mice, in which findings resembled those of control mice. The HAGE-HF group had more visceral fat (by two- and fourfold) and more AGE-modified fat (by two- and fivefold) than LAGE-HF and control mice, respectively. In the HAGE-HF group, plasma 8-isoprostane was higher (P < 0.01) and adiponectin lower (P < 0.001) than control mice, while in the LAGE-HF group, these were more modestly affected (P < 0.05). These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets.

Abbreviations: AGE, advanced glycation end product; ALE, advanced lipoxidation end product; ELISA, enzyme-linked immunosorbent assay

Insulin resistance, alone or as part of the metabolic syndrome, is becoming an increasingly common problem in modern society (1,2). Epidemiological studies (3,4) have demonstrated that populations with the same genetic background exhibit increased incidence of insulin resistance and type 2 diabetes whenever a western lifestyle and diet is adopted. Western diets are characterized by high fat and protein content (5). Nutrients, including fatty acids, have been shown to directly modulate insulin signaling and thus contribute to insulin resistance (6,7).

Advanced glycation end products (AGEs) as well as advanced lipoxidation end products (ALEs) are prooxidant and proinflammatory compounds that have recently been linked to impaired insulin sensitivity (8). These compounds continuously form in the body from the reaction of reducing sugars and reactive carbonyls with free amino groups (9), while amine-containing lipids are also generators of lipid peroxidation products (10–12). AGEs/ALEs can also originate exogenously, during heat processing of food (13–16), and become incorporated in body components after intestinal absorption (17). It has now become apparent that dietary AGEs represent a significant source of circulating and tissue AGEs, manifesting similar pathogenic properties to their endogenous counterparts (17–24). The restriction of the AGE content in standard mouse diets was found, among other effects, to markedly improve insulin resistance in obese db/db⁽⁺⁺⁾ mice (8).

Because fat-rich foods are also particularly rich in AGEs/ALEs (16), we postulated that the insulin resistance observed after chronic high-fat feeding (25) is related to the obligatory intake of large amounts of AGEs inherent in these diets. To test this hypothesis, we evaluated glucose and insulin responses, visceral adiposity, pancreatic islet morphology, and type 2 diabetes incidence in mice subjected to long-term feeding on high-fat diets but with either high or low AGE/ALE content. We also measured plasma 8-isoprostane as an index of systemic oxidant stress and plasma adiponectin as a molecule that has been found to be inversely correlated with insulin resistance.

	RESEARCH DESIGN AND METHODS

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

 
Six-week-old C57/BL6 female mice (The Jackson Laboratories, Bar Harbor, ME) were used in this study. The mice were divided into three groups (n = 20 per group), housed in a temperature-controlled animal facility (23°C) with a 12-h light/dark cycle, and provided with the respective diet and water ad libitum. After 1 week of adjustment, baseline body weight and blood and 24-h urine samples were obtained, and mice were randomly assigned for 6 months to one of two isocaloric high-fat diets (35% g fat, PicoLab Rodent Diet D12492) (Labdiet; Purina Mills, St. Louis, MO): one with high AGE content (HAGE-HF group; 6.8-fold higher than the regular diet, obtained by heating at 120°C x 30 min) and the other with 2.4-fold lower AGE content (LAGE-HF group) than the HAGE-HF group (Table 1). Age- and sex-matched C57/BL6 mice and, for certain studies, db/db⁽⁺⁺⁾ mice (n = 10) were placed on regular diet (PicoLab Rodent Diet D12450B; Labdiet; Purina Mills; 5% g fat, 117 units/mg AGE) and used as controls. Body weight and food intake (in grams of food per mouse) were monitored daily for 1 week and weekly thereafter throughout the duration of the study. Fasting blood glucose was monitored weekly. All procedures were approved by the institutional animal care and use committee.

Glucose tolerance test and glycemic clamps.
After 23 weeks on their respective diets, an intravenous glucose tolerance test was performed on all groups (n = 5 per group) by tail vein injection of glucose (1 g/kg) after an overnight fast (13–15 h). Blood samples for glucose testing were taken before glucose injection and at several intervals for a total of 120 min.

Following the period of exposure to the diets, euglycemic and hyperglycemic clamps were performed on all groups (n = 5 per group) (28,29). Three days before the testing, mice were anesthetized with intraperitoneal injection of ketamine and xylazin cocktail solution, and a catheter was inserted in the right jugular vein and externalized through an incision in a skin flap behind the head (28,29). Thus, studies were performed in awake, unstressed, chronically catheterized animals.

For the euglycemic clamp, insulin was infused continuously at 18 mU · kg^–1 · min^–1, while adjusting the rate of 10% glucose infusion to maintain plasma glucose levels steady at 90–100 mg/dl. Whole-body glucose disposal rate (equal to the amount of glucose infused in mg · kg^–1 · min^–1) was calculated during the last 60 min of the clamp. Since endogenous glucose production is negligible under such an hyperinsulinemic state, the amount of glucose infused is considered equivalent to whole-body glucose disposal. For the hyperglycemic clamp, glucose levels were maintained at 300–320 mg/dl for 1 h under different adjusted rates of glucose infusion.

Histological analysis.
After the animals were killed at the end of the study, visceral fat was separated, weighed, and stored at –80°C. Pancreatic samples were removed and fixed overnight in 10% formalin. Fixed tissues were processed for paraffin embedding. Sections were cut at a thickness of 4 µm, mounted on glass slides, and stained with hematoxylin and eosin. For detection of insulin, 10 consecutive paraffin-embedded sections of pancreas were stained with a guinea pig polyclonal anti-swine insulin antibody (Dako, Carpinteria, CA). Glucagon staining was performed using rabbit anti-glucagon antibody (Research Diagnostics, Flanders, NJ).

Statistical analysis.
Data are presented as means ± SE. Differences of means were analyzed by Student’s t test or ANOVA, followed by the Bonferroni correction, depending of the number of groups. Statistically significant difference was defined as a P value <0.05. All reported P values are based on two-sided tests. All data analyses were performed using the GraphPad Prism statistical program (GraphPad Software, San Diego, CA).

	RESULTS

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

 
Effect of diets on body weight, circulating AGEs, and fasting glucose, plasma insulin, and lipid levels.
Daily food consumption by both high-fat groups was identical for the 1st week and remained similar throughout the study (6 g/day vs. 5.5 g/day for control mice).

At the end of the study, both groups fed the high-fat diet had gained more weight than the controls (P < 0.001), while the HAGE-HF group weighed only slightly more than the LAGE-HF mice (P < 0.01) (Table 2). During the course of the study, serum AGE levels increased nearly threefold above baseline in the HAGE-HF group (P < 0.001), while in the LAGE-HF and control mice they rose by 2- and 1.6-fold (P < 0.01), respectively (Table 2). Levels of triglycerides and total cholesterol increased significantly from baseline in both groups fed the high-fat diet, while HDL cholesterol remained unchanged (Table 2). Interestingly, plasma insulin levels in the HAGE-HF group increased by 7.5-fold above baseline (P < 0.0001), but in the LAGE-HF group, these remained unchanged and similar to the control mice (Fig. 1B). A similar trend was observed with fasting blood glucose levels (Fig. 1A).

View larger version (21K): [in this window] [in a new window]   FIG. 1. Fasting plasma glucose (A) and insulin (B) levels in fat-fed mice are influenced by dietary AGE. Levels of fasting plasma glucose (A) and insulin (B) are expressed as means ± SE (mg/dl for glucose and ng/µ/l for insulin). *P < 0.01 between each marked group and C57/BL6 mice; #P < 0.01 between LAGE-HF and HAGE-HF.

View larger version (26K): [in this window] [in a new window]   FIG. 2. Glucose tolerance test and euglycemic and hyperglycemic clamps in fat-fed mice exposed to high or low dietary AGE. A: Intravenous glucose tolerance test (IGTT) was performed at 6 months of study in subgroups of mice (n = 5 per group): control (C57/BL6 mice, ), HAGE-HF (), LAGE-HF (), and db/db (). Data represent blood glucose concentrations before and after glucose injection for up to 120 min. Values are expressed as means ± SE (mg/dl). *P < 0.01 between each marked group and C57/BL6 mice; #P < 0.01 between LAGE-HF and HAGE-HF. Data on db/db mice are only shown as reference. B: Euglycemic clamps were performed at week 24 in all groups (n = 5 mice per group). Data represent the amount of glucose infused and are equivalent to whole-body glucose disposal. Values are expressed as means ± SE (mg · kg–1 · min–1). *P < 0.01 between each marked group and C57/BL6 mice; #P < 0.01 between LAGE-HF and HAGE-HF. Data on db/db mice are only shown as reference. C: Hyperglycemic clamps were performed at week 24 in all groups (n = 5 mice per group). Data represent plasma insulin levels and are expressed as means ± SE (ng/µl). *P < 0.01 between each marked group and C57/BL6 mice; #P < 0.01 between LAGE-HF and HAGE-HF. Data on db/db mice are only shown as reference.

Effect of diet on visceral fat, fat-AGE content, and circulating 8-isoprostane and adiponectin levels.
As expected, significant differences were observed in total visceral fat content between the two high-fat–fed groups and the regular diet–fed controls (Fig. 3A). Of note, however, the LAGE-HF group exhibited a significantly lower (50%) amount of visceral fat compared with that found in HAGE-HF mice (P < 0.001) (Fig. 3A). In addition, the amount of AGE-modified fat per gram of fat associated with the LAGE-HF group was significantly smaller compared with that of HAGE-HF mice (P < 0.001) (Fig. 3B). Consequently, the estimated amount of total AGE content present in visceral fat in the LAGE-HF mice was fourfold lower than that in the HAGE-HF mice (P = 0.000).

View larger version (25K): [in this window] [in a new window]   FIG. 3. Visceral adipose tissue accumulation and visceral AGE-modified fat content are reduced in mice fed a LAGE-HF diet. A: Visceral fat was isolated and weighed on mice from all groups (n = 5 mice per group) at the end of the study. Values are expressed as means ± SE (total grams of fat). *P < 0.01 between each marked group and C57/BL6 mice; #P < 0.01 between LAGE-HF and HAGE-HF; P < 0.05 between LAGE-HF and C57/BL6 mice. B: AGE content in visceral fat was assessed by a direct AGE-ELISA at the end of the study, as described in RESEARCH DESIGN AND METHODS, and data are expressed as means ± SE (AGE units/mg fat). *P < 0.01 between each marked group and C57/BL6 mice; #P < 0.01 between LAGE-HF and HAGE-HF; P < 0.05 between LAGE-HF and C57/BL6 mice.

View larger version (29K): [in this window] [in a new window]   FIG. 4. Plasma 8-isoprostane and adiponectin levels in mice exposed to either HAGE-HF or LAGE-HF diets. A: Plasma 8-isoprostane levels were assessed on all animals at the end of the study as described. Data represent means ± SE (pg/ml). *P < 0.01 between each marked group and C57/BL6 mice; #P < 0.01 between LAGE-HF and HAGE-HF; P < 0.05 between LAGE-HF and C57/BL6 mice. Data on db/db mice are only shown as reference. B: Serum adiponectin levels were determined at the end of the study. Values are expressed as means ± SE (ng/ml). *P < 0.01 between each marked group and C57/BL6 mice; #P < 0.01 between LAGE-HF and HAGE-HF; P < 0.05 between LAGE-HF and C57/BL6 mice. Data on db/db mice are only shown as reference.

Effect of diet on islet morphology.
Consistent with previous evidence based on the use of high-fat diets, pancreatic islets from the HAGE-HF mice after 6 months exhibited hyperplasia and hypertrophy combined with loss of islet structure and cellular homogeneity. However, such changes were only seen infrequently in islets from LAGE-HF mice (Fig. 5A and B). Instead, in the latter group, islet size appeared normal and well organized, with normal architecture and abundance of insulin- and glucagon-containing cells. In addition, islet degeneration and insulin- and glucagon-producing cell displacement from the periphery to the center of the islets were only evident in islets from the HAGE-HF and not the LAGE-HF mice.

View larger version (91K): [in this window] [in a new window]   FIG. 5. Insulin and glucagon immunostaining of pancreatic islets in mice exposed to either HAGE-HF or LAGE-HF diets. A: Insulin immunostaining of pancreatic tissue sections (4 mm) from C57/BL6, HAGE-HF, and LAGE-HF mice at 24 weeks of study, as described. Representative images are shown from 25 sections per group (n = 5 mice per group) (magnification x200). B: Glucagon immunostaining of pancreatic tissue sections (4 mm) from C57/BL6, HAGE-HF, and LAGE-HF mice at 24 weeks of study, as described. Representative images are shown from 25 sections per group (n = 5 mice per group) (magnification x200).

	DISCUSSION

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

In the present studies, high dietary fat intake by normal mice for the period between 1 and 7 months of age led to an increase in body weight of both high- and low-AGE groups, which was modest yet significantly higher in the HAGE-HF than in the LAGE-HF mice. Interestingly, a major proportion (75%) of the mice fed a HAGE-HF diet were diabetic by the end of the study compared with none of those exposed to the LAGE-HF diet, based on a fasting blood glucose level >130 mg/dl. The AGE-rich fatty diet resulted in a pattern of profound abnormalities in glucose tolerance, glucose disposal rate, and insulin responses closely resembling those of the diabetic db/db⁽⁺⁺⁾ mice (8). In contrast, exposure to the low-AGE fatty diet led to a pattern comparable with the normal metabolic profile associated with the standard (low-fat) diet. These findings suggest that dietary factors other than high fat content contribute to these metabolic changes.

Consistent with previous studies (8,18–24) and given the equal exposure to basic nutrients and energy provided by the two high-fat diets, the present evidence points to the different content in dietary AGEs/ALEs as the probable contributors to the metabolic effects described. As expected, both high-fat formulas (35% fat) contained greater N-carboxymethyllysine–immuno-epitopes than did the standard diet (4.5% fat), consistent with the fact that lipid-rich food products, often rich in amino-lipids, especially phospholipids, provide an extra source of reactants for the complex series of reactions leading to the formation of AGEs/ALEs (11,12,27) as well as of oxidized fatty acids, which further enhance the formation of AGEs/ALEs (30). Furthermore, the significant variance in AGE content between the HAGE-HF and LAGE-HF diets is attributable to the AGE-promoting methods and conditions used, e.g., exposure to elevated temperature and not to differences in nutrient composition (8,16). This was also clearly reflected in the higher circulating AGE levels in the HAGE-HF mice, relative to the other groups.

The identity of the AGE/ALE species responsible for the metabolic effects described remains speculative given the heterogeneity of these compounds. N-carboxymethyllysine, a chemically defined derivative of both glycoxidation and lipid peroxidation (27), however, is thought to contribute to oxidative stress and tissue damage and has proved a useful indicator of AGEs, correlating well with diabetes and aging (9,10,31) as well as with a range of diet-induced pathological conditions (18–22).

Of particular interest in these studies was the differential accumulation of visceral fat in the HAGE-HF group compared with the LAGE-HF mice, despite similar dietary fat intake and body weight gain by both groups. Of further interest was the marked accumulation of total AGEs/ALEs in the visceral fat of the HAGE-HF group, reaching the total of fourfold more than that of the LAGE-HF group. This novel finding reveals a potentially important relationship between diet-related glycoxidant and lipoxidant substances and visceral adiposity, a risk factor associated with insulin resistance and the metabolic syndrome (32,33).

Visceral adipose tissue expansion has been associated with increased production of inflammatory mediators, such as tumor necrosis factor- (34). Greater binding of AGE by proinflammatory AGE receptors, such as RAGE, could trigger oxidative stress and the release of cytokines such as tumor necrosis factor- (35,36), which is known to inhibit insulin action (37). This and a host of autocrine/paracrine inflammatory molecules released from adipose tissue or macrophages, migrating to AGE-rich visceral fat, could contribute to the insulin resistance exhibited by HAGE-HF mice but yet not seen in the LAGE-HF mice, most likely related to the lower amount of AGE fat in the latter group.

The histology of the pancreatic islets from both experimental groups reflected a similar pattern. Nearly normal glucose and insulin responses seen in the LAGE-HF group were consistent with well-preserved pancreatic islet morphology and function in this group and contrasted with islet enlargement, structure disorganization, and sparsity of insulin production displayed by the HAGE-HF mice. The near-normal appearance of islets from the LAGE-HF mice together with the metabolic findings strongly suggest a protective role for a low-AGE diet, even if the fat content is elevated. The islet changes were consistent with those seen in db/db mice fed high- versus low-AGE diets (8) and offered further in vivo support to reports associating glycoxidation with inhibition of insulin gene transcription (38) or promotion of ß-cell apoptosis in vitro (39). Thus, given the significant prooxidant and proinflammatory properties of AGEs/ALEs exhibited in the absence of chronic hyperglycemia, diet-derived AGEs/ALEs may represent diabetogenic substances worthy of further rigorous evaluation.

The significant rise in plasma 8-isoprostanes in the high-fat–fed groups, a finding consistent with a state of increased oxidant stress (40), may have also been the result of the higher supply of AGEs/ALEs in their diet (11). In agreement with this, adiponectin, a factor thought to play a role in regulating insulin sensitivity and to exert anti-inflammatory effects at large (41), correlated inversely with 8-isoprostane and with visceral adiposity and remained significantly higher only in the LAGE fat-fed mice. These findings reveal new aspects of the balance between prooxidant AGEs/ALEs and anti-inflammatory innate defense mechanisms. The positive relationship between ingested and circulating AGE levels found in the present studies has been previously also linked to acute-phase proteins (C-reactive protein) and vascular dysfunction (23,42). These properties are herein expanded to include manifestations of insulin resistance and are exemplified in the context of a diet high in fat. Thus, dietary AGE, forming at high rates in the presence of excess fat and commonly applied levels of temperature, may independently contribute to the subinflammatory state associated with insulin resistance and metabolic syndrome in humans as well. To date, AGEs/ALEs are the only food-derived compounds studied for their contribution to diabetic tissue toxicity, including insulin-producing cells (8). No other class of heat-enhanced substances has been studied for the intriguing array of cell effects exhibited by these substances, i.e., oxidant stress, nuclear facror-kB activation, cytokine (tumor necrosis factor-) induction, inflammation, and apoptosis (15,36).

In summary, during prolonged high-fat feeding, the AGE/ALE content of food may exert significant influence on the regulation of insulin secretion and action and visceral adiposity and may ultimately lead to type 2 diabetes. These results, taken together with previous work (8) on the effects of a high-in-AGE-but-low-in-fat diet on insulin resistance support the view that in addition to the fat, the high AGE/ALE content of food is significantly linked to the insulin-resistant state. While the mechanisms linking AGEs and the related deleterious metabolic effects are likely to be complex, the evidence indicates that lowering AGE/ALE content in fatty foods might be an intervention to control insulin resistance and prevent diabetes. Further long-term studies in humans are needed.

	ACKNOWLEDGMENTS

 
This work was funded by National Institutes of Health Grant AG 09453 (to H.V.).

We thank Ina Katz for excellent editorial assistance.

Received for publication November 3, 2004 and accepted in revised form May 6, 2005

	REFERENCES

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Hansen BC: The metabolic syndrome X. Ann N Y Acad Sci 892:1–24, 1999[Free Full Text]
2. Zimmet P, Alberti KG, Shaw J: Global and societal implications of the diabetes epidemic. Nature 414:782–787, 2001[Medline]
3. Ravussin E, Valencia ME, Esparza J, Bennet PH, Schulz LO: Effects of a traditional lifestyle on obesity in Pima Indians. Diabetes Care 17:1067–1074, 1994[Abstract]
4. Speakman JR: Obesity: the integrated roles of environment and genetics. J Nutr 134 (Suppl. 8):2090S–2105S, 2004
5. Mann N: Dietary lean red meat and human evolution. Eur J Nutr 39:71–79, 2000[Medline]
6. Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI: Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 277:50230–50236, 2002[Abstract/Free Full Text]
7. Shafrir E, Ziv E, Mosthaf L: Nutritionally induced insulin resistance and receptor defect leading to beta cell failure in animal models. Ann N Y Acad Sci 892:223–246, 1999[Abstract/Free Full Text]
8. Hofmann SM, Dong HJ, Li Z, Cai W, Altomonte J, Thung SN, Zeng F, Fisher EA, Vlassara H: Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse. Diabetes 51:2082–2089, 2002[Abstract/Free Full Text]
9. Singh R, Barden A, Mori T, Beilin L: Advanced glycoxylation end products: a review. Diabetologia 44:129–146, 2001[Medline]
10. Baynes JW, Thorpe SR: Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9, 1999[Abstract]
11. Bucala R, Makita Z, Koschinsky T, Cerami A, Vlassara H: Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci 90:6434–6438, 1993[Abstract/Free Full Text]
12. Bucala R, Makita Z, Vega G, Grundy S, Koschinsky T, Cerami A, Vlassara H: Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci U S A 91:9441–9445, 1994[Abstract/Free Full Text]
13. O’Brien J: Nutritional and toxicological aspects of the Maillard browning reaction in foods. Crit Rev Food Sci Nutr 28:211–248, 1989[Medline]
14. Lee T-C, Kimiagar M, Pintauro SJ, Chichester CO: Physiological and safety aspects of Maillard browning of foods. Prog Fd Nutr Sci 5:243–256, 1981
15. Cai W, Cao Q, Zhu L, Peppa M, He CJ, Vlassara H: Oxidative stress-inducing carbonyl compounds from common foods: novel mediators of cellular dysfunction. Mol Med 8:337–346, 2002[Medline]
16. Goldberg T, Cai W, Peppa M, Dardaine V, Uribarri J, Vlassara H: Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc 104:1287–1291, 2004[Medline]
17. 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 U S A 94:6474–6479, 1997[Abstract/Free Full Text]
18. Peppa M, He C, Hattori C, McEvoy R, Zheng F, Vlassara H: Fetal or neonatal low-glycotoxin environment prevents autoimmune diabetes in NOD mice. Diabetes 52:1441–1448, 2003[Abstract/Free Full Text]
19. Lin RY, Choudhury RP, Cai W, Lu M, Fallon JT, Fisher EA, Vlassara H: Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 168:213–220, 2003[Medline]
20. Lin RY, Reis ED, Dore AT, Lu M, Ghodsi N, Fallon JT, Fisher EA, Vlassara H: Lowering of dietary advanced glycation endproducts (AGE) reduces neointimal formation after arterial injury in genetically hypercholesterolemic mice. Atherosclerosis 163:303–311, 2002[Medline]
21. Zheng F, He C, Cai W, Hattori M, Steffes M, Vlassara H: Prevention of diabetic nephropathy in mice by a diet low in glycoxidation products. Diabetes Metab Res Rev 18:224–237, 2002[Medline]
22. Peppa M, Brem H, Ehrlich P, Zhang JG, Cai W, Li Z, Croitoru A, Thung S, Vlassara H: Adverse effects of dietary glycotoxins on wound healing in genetically diabetic mice. Diabetes 52:2805–2813, 2003[Abstract/Free Full Text]
23. Vlassara H, Cai W, Crandall J, Goldberg T, Oberstein R, Dardaine V, Peppa M, Rayfield EJ: Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci 99:15596–601, 2002[Abstract/Free Full Text]
24. Uribarri J, Peppa M, Cai W, Goldberg T, Lu M, He C, Vlassara H: Restriction of dietary glycotoxins markedly reduces AGE toxins in renal failure patients. J Am Soc Nephrol 14:728–731, 2003[Abstract/Free Full Text]
25. Storlien LH, James DE, Burleigh KM, Chisholm DJ, Kraegen EW: Fat feeding causes widespread insulin resistance, decreased energy expenditure and obesity in rats. Am J Physiol 295:E576–E583, 1987
26. Mitsuhashi T, Vlassara H, Founds HW, Li YM: Standardizing the immunological measurement of advanced glycation end product using normal human serum. J Immunol Methods 207:79–88, 1997[Medline]
27. Fu MX, Requena JR, Jenkins AJ, Lyons TJ, Baynes JW, Thorpe SR: The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. J Biol Chem 271:9982–9986, 1996[Abstract/Free Full Text]
28. Rongstad R: Glucose-6-phosphatase flux and the hepatic glucose balance model. Am J Physiol 271:E1037–E1043, 1996
29. Burcelin R, Thorens B: Evidence that extrapancreatic GLUT2-dependent glucose sensors control glucagon secretion. Diabetes 50:1282–1289, 2001[Abstract/Free Full Text]
30. Staprans I, Hardman DA, Pan XM, Feingold KR: Effect of oxidized lipids in the diet on oxidized lipid levels in postprandial serum chylomicrons of diabetic patients. Diabetes Care 200:300–306, 1999
31. Brownlee M, Cerami A, Vlassara H: Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318:1315–1321, 1988[Medline]
32. Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM, Brunzell JD, Shofer JB, Fish BE, Knopp RH, Kahn SE: Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. Diabetes 53:2087–2094, 2004[Abstract/Free Full Text]
33. Carr MC, Brunzell JD: Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrinol Metab 89:2601–2607, 2004[Abstract/Free Full Text]
34. Trayhurn P, Beattie JH: Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60:329–339, 2001[Medline]
35. 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 280:E685–E694, 2001
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 108:949–955, 2001[Medline]
37. Hotamisligil GS, Budavari A, Murray DL, Spiegelman BM: Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes: central role of tumor necrosis factor-alpha. J Clin Invest 94:1543–1549, 1994
38. Matsuoka T, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y, Fujitani Y, Kamada T, Kawamori R, Yamasaki Y: Glycation-dependant, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest 99:144–150, 1997[Medline]
39. Kaneto H, Fujii J, Myint T, Miyazawa N, Islam KN, Kawasaki Y, Suzuki K, Nakamura M, Tatsumi H, Yamasaki Y, Taniguchi N: Reducing sugars trigger oxidative modification and apoptosis in pancreatic beta-cells by provoking oxidative stress through the glycation reaction. Biochem J 320:855–863, 1996
40. Patrono C, FitzGerald GA: Isoprostanes: potential markers of oxidant stress in atherothrombotic disease. Arterioscler Thromb Vasc Biol 17:2309–2315, 1997[Abstract/Free Full Text]
41. Xydakis AM, Case CC, Jones PH, Hoogeveen RC, Liu MY, Smith EO, Nelson KW, Ballantyne CM: Adiponectin, inflammation, and the expression of the metabolic syndrome in obese individuals: the impact of rapid weight loss through caloric restriction. J Clin Endocrinol Metab 89:2697–2703, 2004[Abstract/Free Full Text]
42. Peppa M, Uribarri J, Cai W, Lu M, Vlassara H: Glycoxidation and inflammation in renal failure patients. Am J Kidney Dis 43:690–695, 2004[Medline]

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				W. Cai, J. C. He, L. Zhu, X. Chen, S. Wallenstein, G. E. Striker, and H. Vlassara Reduced Oxidant Stress and Extended Lifespan in Mice Exposed to a Low Glycotoxin Diet: Association with Increased AGER1 Expression Am. J. Pathol., June 1, 2007; 170(6): 1893 - 1902. [Abstract] [Full Text] [PDF]

				M. Negrean, A. Stirban, B. Stratmann, T. Gawlowski, T. Horstmann, C. Gotting, K. Kleesiek, M. Mueller-Roesel, T. Koschinsky, J. Uribarri, et al. Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus Am. J. Clinical Nutrition, May 1, 2007; 85(5): 1236 - 1243. [Abstract] [Full Text] [PDF]

				J. Uribarri, W. Cai, M. Peppa, S. Goodman, L. Ferrucci, G. Striker, and H. Vlassara Circulating Glycotoxins and Dietary Advanced Glycation Endproducts: Two Links to Inflammatory Response, Oxidative Stress, and Aging J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2007; 62(4): 427 - 433. [Abstract] [Full Text] [PDF]

				H. Liu, F. Zheng, Z. Li, J. Uribarri, B. Ren, R. Hutter, J. R. Tunstead, J. Badimon, G. E. Striker, and H. Vlassara Reduced Acute Vascular Injury and Atherosclerosis in Hyperlipidemic Mice Transgenic for Lysozyme Am. J. Pathol., July 1, 2006; 169(1): 303 - 313. [Abstract] [Full Text] [PDF]

				S. M. Sweitzer, S. A. Fann, T. K. Borg, J. W. Baynes, and M. J. Yost What is the future of diabetic wound care? The Diabetes Educator, March 1, 2006; 32(2): 197 - 210. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sandu, O. Articles by Vlassara, H. Search for Related Content PubMed PubMed Citation Articles by Sandu, O. Articles by Vlassara, H. Social Bookmarking                What's this?