Serum Levels of Advanced Glycation End Products (AGEs) are Independent Correlates of Insulin Resistance in Nondiabetic Subjects
Abstract
SUMMARY: Background: 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. Methods: 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. Results: 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. Conclusion: 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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High circulating AGE levels correlate with HOMA-IR in nondiabetic subjects.
“and correlate with HOMA-IR in nondiabetic subjects.[112]”
From The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction (2021) · cites this paper as [112]
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Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies
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“This finding is contrary to a previous study of 322 non-diabetic Japanese subjects, which found that serum AGE level was one of the independent correlates of insulin resistance [43].”
ResultTruong, C.-S., Seo, E., & Jun, H. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/4310319 · Cited by 30 · see citing works
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“Several studies have shown that AGEs are associated with insulin resistance [34, 35], and can induce low-grade inflammation [36] and pancreatic beta cell dysfunction [37].”
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“In humans, high intake of dietary MRPs is associated with decreased insulin sensitivity, and circulating AGE levels are directly related to insulin resistance [18–21].”
BackgroundMatsui, T., Joo, H. D., Lee, J. M., Ju, S. M., Tao, W. H., Higashimoto, Y., Fukami, K., & Yamagishi, S. (2015) · Immunology Letters · doi:10.1016/j.imlet.2015.08.008 · Cited by 26 · see citing works
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“In non-diabetic Japanese subjects, serum AGE levels were independently correlated with insulin resistance, which may gradually cause diabetes [15].”
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“This association extends to nondiabetic individuals after adjusting for BMI, waist circumference, and hemoglobin A1C, suggesting that AGEs may influence insulin resistance and overall metabolic health even in those without diabetes [114].”
Tóthová, Ľ., Ostatníková, D., Šebeková, K., Celec, P., & Hodosy, J. (2013) · Annals of Human Biology · doi:10.3109/03014460.2012.754495 · Cited by 21 · see citing works
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“For example, Tahara et al. 55 have reported independent correlation be-tween IR and AGEs levels in nondiabetic subjects.”
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Phosphatidylglycerol to Treat Chronic Skin Wounds in Diabetes
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“[31] independently conducted clinical studies of 207 (97 males, 110 females) non-obese, non-diabetic subjects and 322 (216 males, 106 females) nondiabetic Japanese subjects, respectively.”
Mi, J., Song, J. H., Zhao, Y., & Wu, X. (2020) · BMC Cardiovascular Disorders · doi:10.1186/s12872-020-01762-0 · Cited by 16 · see citing works
Advanced glycation end products and insulin resistance in diabetic nephropathy
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Plant Foods, Healthy Plant-Based Diets, and Type 2 Diabetes: A Review of the Evidence
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“…the formation of AGEs, while AGE-RAGE-evoked NADPH oxidase-mediated ROS generation further enhances RAGE expression in various tissues (Kaida et al. 2013; Yamagishi and Imaizumi 2005; Yamag-ishi and Matsui 2018; Ide et al. 2010; Tan et al. 2010; Tahara et al. 2010, 2012; Yoshida et al. 2006).”
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“The association between higher blood circulating AGEs levels and higher insulin resistance was observed [2,3], while other studies [4–6] showed the association between lower blood circulating AGEs levels and higher insulin resistance.”
ResultTajiri, E., Yoshimura, E., Tobina, T., Yamashita, T., Kume, K., Hatamoto, Y., & Shimoda, S. (2023) · Appetite · doi:10.1016/j.appet.2023.106998 · Cited by 16 · see citing works
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Mild Chronic Kidney Disease Associated with Greater Risk of Arterial Stiffness in Elderly Adults
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“Individuals with diabetes mellitus and prediabetes mellitus have greater insulin resistance,(23) which is positively correlated with the amount of advanced glycation end products.(24) In addition, hyperglycemia itself results in arterial stiffness through the effects of activated proinflammatory transcription factors…”
BackgroundLi, C., Lu, F.-H., Yang, Y., Wu, J., & Chang, C. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8050603 · Cited by 12 · see citing works
“Furthermore, the serum levels of AGEs are positive correlates of insulin resistance [27], which is related to the reduced production of nitric oxide and its related vasodilation [28], post-load hyperinsulinemia-induced oxidative stress [29], decreased endothelial progenitor cells with impaired vascular repair qualitie…”
BackgroundImpact of Androgen and Dietary Advanced Glycation End Products on Female Rat Liver
Palioura, E., Palimeri, S., Piperi, C., Sakellariou, S., Kandaraki, E., Sergentanis, T. Ν., Levidou, G., Agrogiannis, G. D., Papalois, A. E., Korkolopoulou, P. A., et al. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000430400 · Cited by 12 · see citing works
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Self-citationFrom diabetes to renal aging: the therapeutic potential of adiponectin
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“Several studies in humans showed that serum AGEs were associated with homeostasis model assessment index (HOMA-IR) in subjects with or without diabetes [17, 18].”
BackgroundNawaz, M., Afridi, M. N., Ullah, I., Khan, I. A., Ishaq, M. S., Su, Y., Rizwan, H. M., Cheng, K., Zhou, Q., & Wang, M. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.131869 · Cited by 8 · see citing works
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Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction
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Assessment of Total Sugar and Glucose Concentrations in Commonly Consumed Beverages in Japan
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“We recently indicated that serum levels of TAGE, but not those of hemoglobin A1c (HbA1c), glucose-derived AGEs (Glu-AGEs), or Nε(carboxymethyl)lysine (CML), a representative AGE compound found in food, may be used as a biomarker to predict the progression of lifestylerelated diseases [21-25].”
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“RAGE exists in two other forms: a soluble form that circulates in the blood and an alternatively spliced isoform known as endogenous secreted RAGE (esRAGE), which lacks the NF-κ B domain and acts as a decoy receptor rather than inducing inflammation [14,15].”
BackgroundAltered Inflammatory Mediators in Fibromyalgia
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26. Advanced glycation end products in infant formulas
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Gallstone disease associated with increased risk of arterial stiffness in a Taiwanese population
Wang, J.-Y., Lu, F.-H., Sun, Z.-J., Wu, J.-S., Yang, Y.-C., Lee, C. T., & Chang, C.-J. (2017) · Journal of Human Hypertension · doi:10.1038/jhh.2017.43 · Cited by 5 · see citing works
- Authors
- Tahara, N., Yamagishi, S., Matsui, T., Takeuchi, M., Nitta, Y., Kodama, N., Mizoguchi, M., & Imaizumi, T.
- Affiliations
- Kurume University (JP)
- Hokuriku University (JP)
- Corresponding author
- Tahara, Nobuhiro
- Venue
- Cardiovascular Therapeutics
- Publisher
- Wiley
- Published
- 2012-01-26
- Volume
- 30
- Issue
- 1
- Pages
- 42-48
- ISSN
- 1755-5914 (ISSN-L)
- 1755-5922
- OpenAlex
- W1509582521
- Cited by
- 116
- References
- 37
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 10 · 2020: 14 · 2019: 7 · 2018: 2 · 2017: 6 · 2016: 6 · 2015: 18 · 2014: 5 · 2013: 11 · 2012: 6
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cardiovascular Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23591072, 22300264)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- advanced glycation end products, insulin resistance, non-diabetic adults, HOMA-IR, waist circumference, HbA1c, triglycerides, oxidative stress, inflammation, C-reactive protein, uric acid, LDL cholesterol, HDL cholesterol, diastolic blood pressure, creatinine clearance
- MeSH terms
- Aged, Cross-Sectional Studies, Enzyme-Linked Immunosorbent Assay, Female, Humans, Insulin Resistance, Japan, Male, Middle Aged, Regression Analysis, Risk Factors, Biomarkers, Multivariate Analysis, Glycation End Products, Advanced, Risk Assessment
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