Serum Levels of Advanced Glycation End Products (AGEs) are Independent Correlates of Insulin Resistance in Nondiabetic Subjects

Department of Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, Kurume, Japan.
Cardiovascular Therapeutics (Impact Factor: 2.36). 02/2012; 30(1):42-8. DOI: 10.1111/j.1755-5922.2010.00177.x
Source: PubMed


Advanced glycation end products (AGEs) evoke oxidative stress generation and inflammatory reactions, thus being involved in vascular complications in diabetes. Since oxidative stress and inflammation impair insulin actions as well, it is conceivable that AGEs may play some role in insulin resistance. However, there is no clinical study to examine the relationship between serum levels of AGEs and insulin resistance. This study investigated whether serum AGE levels were independent correlates of insulin resistance in humans.
Three hundred twenty-two nondiabetic Japanese subjects (216 male and 106 female; mean age 61.5 ± 9.1 years) underwent a complete history and physical examination, determinations of blood chemistries, anthropometric and metabolic variables, including AGEs. Serum AGE levels were examined with an enzyme-linked immunosorbent assay.
Mean serum AGE levels were 8.96 ± 2.57 U/mL. In univariate analysis, waist circumference, diastolic blood pressure (BP), mean BP, AGEs, low-density lipoprotein (LDL) cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol (inversely), hemoglobin A1c (GHb), creatinine clearance, uric acid, and high sensitivity C-reactive protein were significantly associated with insulin resistance evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) index. After performing multiple regression analysis, waist circumference (P < 0.001), GHb (P < 0.001), triglycerides (P < 0.001), and AGEs (P < 0.01) still remained significant independently. When age-adjusted HOMA-IR levels stratified by AGE tertiles were compared using ANCOVA, a significant trend was demonstrated in both males and females.
The present study demonstrated for the first time that serum AGE levels were one of the independent correlates of HOMA-IR index, thus suggesting that AGEs may play some pathological role in insulin resistance in humans.

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Available from: Nobuhiro Tahara, Oct 18, 2014
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    • "More recently, AGEs have been implicated in the pathogenesis of both type 1 and type 2 diabetes. Several studies have shown that AGEs are associated with insulin resistance [12,13], and can induce low-grade inflammation [14] and pancreatic beta cell dysfunction [15,16]. "
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    ABSTRACT: Background Advanced glycation endproducts (AGEs) contribute to the development of vascular complications of diabetes and have been recently implicated in the pathogenesis of diabetes. Since AGEs are generated within foodstuffs upon food processing, it is increasingly recognised that the modern diet is replete with AGEs. AGEs are thought to stimulate chronic low-grade inflammation and promote oxidative stress and have been linked to the development of insulin resistance. Simple therapeutic strategies targeted at attenuating the progression of chronic low-grade inflammation and insulin resistance are urgently required to prevent or slow the development of type 2 diabetes in susceptible individuals. Dietary modulation of the human colonic microbiota has been shown to confer a number of health benefits to the host, but its effect on advanced glycation is unknown. The aim of this article is to describe the methodology of a double-blind placebo-controlled randomised crossover trial designed to determine the effect of 12 week consumption of a prebiotic dietary supplement on the advanced glycation pathway, insulin sensitivity and chronic low-grade inflammation in adults with pre-diabetes. Methods/Design Thirty adults with pre-diabetes (Impaired Glucose Tolerance or Impaired Fasting Glucose) aged between 40–60 years will be randomly assigned to receive either 10 grams of prebiotic (inulin/oligofructose) daily or 10 grams placebo (maltodextrin) daily for 12 weeks. After a 2-week washout period, study subjects will crossover to receive the alternative dietary treatment for 12 weeks. The primary outcome is the difference in markers of the advanced glycation pathway carboxymethyllysine (CML) and methylglyoxal (MG) between experimental and control treatments. Secondary outcomes include HbA1c, insulin sensitivity, lipid levels, blood pressure, serum glutathione, adiponectin, IL-6, E-selectin, myeloperoxidase, C-reactive protein, Toll-like Receptor 4 (TLR4), soluble receptor for AGE (sRAGE), urinary 8-isoprostanes, faecal bacterial composition and short chain fatty acid profile. Anthropometric measures including BMI and waist circumference will be collected in addition to comprehensive dietary and lifestyle data. Discussion Prebiotics which selectively stimulate the growth of beneficial bacteria in the human colon might offer protection against AGE-related pathology in people at risk of developing type 2 diabetes. Trial registration Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12613000130763.
    BMC Endocrine Disorders 07/2014; 14(1):55. DOI:10.1186/1472-6823-14-55 · 1.71 Impact Factor
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    • "These results are difficult to compare with those from our study, since Tan et al. dealt with older subjects (mean of 47 years of age) and specific chemically-defined AGEs (non-fluorescent carboxymethyllysine and arginine-lysine-imidazole) were determined (Mancini et al. 2008). Moreover, Tahara et al. (2012) failed to show a difference in AGEs (carboxymethyllysine and glyceraldehyd-derived AGEs) levels in plasma between males and females, but in this cohort of older patients (mean of 62 years of age) smokers and those pharmacologically treated for different chronic degenerative diseases were also included. In contrast to AGEs, in our study young healthy non-smoking males displayed higher AOPP levels than their female counterparts. "
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    ABSTRACT: Background: Several studies showed there are sex differences in oxidative stress. An observational study analysing oxidative stress markers in young healthy men and women is lacking. Moreover, it is unclear whether the differences are related to sex hormones. Aim: The primary goal was to analyse differences in oxidative stress markers with regard to sex in plasma of young healthy subjects and whether differences are related to sex hormones. The secondary study compared oxidative stress markers in plasma with salivary samples. Methods: Plasma and saliva samples were analysed from 158 young healthy probands. Established spectro-photometric/fluorometric methods were used to quantify oxidative stress markers. Sex hormones were measured using ELISA kits. Results: In plasma, malondialdehyde and advanced glycation end products were significantly higher in women. Advanced oxidation protein products and the ferric reducing ability of plasma were higher in men. Sex hormones were not associated with oxidative stress markers. In saliva, analysed markers of antioxidant status were higher in men, but no sex differences were found in other markers. Conclusion: Observed parameters showed marker-specific sex differences in plasma, but these differences were not related to sex hormones. Plasma and saliva concentrations of biomarkers did not correlate, reflecting oral but not systemic conditions.
    Annals of Human Biology 01/2013; 40(2). DOI:10.3109/03014460.2012.754495 · 1.27 Impact Factor
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    • "Furthermore, the expression levels of AGEs and RAGE were increased in diabetic atherosclerotic lesions [29,30] Because AGEs are generated not only from Amadori products under hyperglycemic conditions, but also from dicarbonyl compounds derived from the Maillard reaction, the auto-oxidation of reducing sugars and other metabolic pathways of glucose [15]. They include heterogeneous molecules such as carboxymethyllysine, pentosidine, and glyceraldehyde-derived AGEs [23-25]. In the present study, we measured levels of glyceraldehyde-derived AGEs, which could reflect inflammatory oxidative stress conditions and/or hyperglycaemic states [23-25]. "
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    ABSTRACT: The Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS) trial demonstrated that early aggressive statin therapy in patients with ACS significantly reduces plaque volume (PV). Advanced glycation end products (AGEs) and the receptors of AGEs (RAGE) may lead to angiopathy in diabetes mellitus (DM) and may affect on the development of coronary PV. The present sub-study of JAPAN-ACS investigates the association between AGEs and RAGE, and PV. Intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) was undertaken, followed by the initiation of statin treatment (either 4 mg/day of pitavastatin or 20 mg/day of atorvastatin), in patients with ACS. In the 208 JAPAN-ACS subjects, PV using IVUS in non-culprit segment > 5 mm proximal or distal to the culprit lesion and, serum levels of AGEs and soluble RAGE (sRAGE) were measured at baseline and 8–12 months after PCI. At baseline, no differences in the levels of either AGEs or sRAGE were found between patients with DM and those without DM. The levels of AGEs decreased significantly with statin therapy from 8.6 ± 2.2 to 8.0 ± 2.1 U/ml (p < 0.001), whereas the levels of sRAGE did not change. There were no significant correlations between changes in PV and the changes in levels of AGEs as well as sRAGE. However, high baseline AGEs levels were significantly associated with plaque progression (odds ratio, 1.21; 95% confidence interval, 1.01 - 1.48; p = 0.044) even after adjusting for DM in multivariate logistic regression models. High baseline AGEs levels were associated with plaque progression in the JAPAN-ACS trial. This relationship was independent of DM. These findings suggest AGEs may be related to long-term glucose control and other oxidative stresses in ACS. Trial registration
    Cardiovascular Diabetology 01/2013; 12(1):5. DOI:10.1186/1475-2840-12-5 · 4.02 Impact Factor
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