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  • Review Article
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AGE restriction in diabetes mellitus: a paradigm shift

Nature Reviews Endocrinology volume 7, pages 526–539 (2011)Cite this article

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Abstract

Persistently elevated oxidative stress and inflammation precede or occur during the development of type 1 or type 2 diabetes mellitus and precipitate devastating complications. Given the rapidly increasing incidence of diabetes mellitus and obesity in the space of a few decades, new genetic mutations are unlikely to be the cause, instead pointing to environmental initiators. A hallmark of contemporary culture is a preference for thermally processed foods, replete with pro-oxidant advanced glycation endproducts (AGEs). These molecules are appetite-increasing and, thus, efficient enhancers of overnutrition (which promotes obesity) and oxidant overload (which promotes inflammation). Studies of genetic and nongenetic animal models of diabetes mellitus suggest that suppression of host defenses, under sustained pressure from food-derived AGEs, may potentially shift homeostasis towards a higher basal level of oxidative stress, inflammation and injury of both insulin-producing and insulin-responsive cells. This sequence promotes both types of diabetes mellitus. Reducing basal oxidative stress by AGE restriction in mice, without energy or nutrient change, reinstates host defenses, alleviates inflammation, prevents diabetes mellitus, vascular and renal complications and extends normal lifespan. Studies in healthy humans and in those with diabetes mellitus show that consumption of high amounts of food-related AGEs is a determinant of insulin resistance and inflammation and that AGE restriction improves both. This Review focuses on AGEs as novel initiators of oxidative stress that precedes, rather than results from, diabetes mellitus. Therapeutic gains from AGE restriction constitute a paradigm shift.

Key Points

  • The current epidemics of diabetes mellitus and aging-related diseases may largely be due to environmental factors, as industrial and societal changes have led to the production and consumption of foods rich in advanced glycation endproducts (AGEs)

  • The sustained influx of AGEs leads to suppression of host defenses and a surplus of intracellular reactive oxygen species, which can shift basal oxidative stress and lead to inflammation and obesity

  • The combination of these processes can simultaneously cause β-cell dysfunction, impaired insulin secretion and insulin resistance, as well as diabetic complications

  • Restriction of food-related AGEs helps reduce basal oxidative stress, restore host defenses and prevents or improves type 1 and type 2 diabetes mellitus in mice, regardless of genetic susceptibility

  • AGE restriction in humans is emerging as a promising, cost-effective, broadly applicable intervention

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Figure 1: Detrimental effects of overnutrition.
Figure 2: Synergism between AGER1 and SIRT1.
Figure 3: Excessive AGEs impair insulin sensitivity in insulin-target tissues.
Figure 4: AGEs impair insulin secretion in pancreatic islet β cells.

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Acknowledgements

Work described in this Review was supported in part by MERIT grant AG-23,188, AG-09,453 and DK091231 (H. Vlassara) and RR-00071.

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  1. Division of Experimental Diabetes and Aging, Brookdale Department of Geriatrics, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1460, New York, 10029, NY, USA

    Helen Vlassara & Gary E. Striker

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Both authors researched the data for the article, provided a substantial contribution to discussions of the content, contributed equally to writing the article and reviewed and/or edited the manuscript before submission.

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Vlassara, H., Striker, G. AGE restriction in diabetes mellitus: a paradigm shift. Nat Rev Endocrinol 7, 526–539 (2011). https://doi.org/10.1038/nrendo.2011.74

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