Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy

doi:10.1073/pnas.242407999

Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy

^*Division of Experimental Diabetes and Aging, Department of Geriatrics, and ^‡Division of Endocrinology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029

Edited by Jan L. Breslow, The Rockefeller University, New York, NY, and approved October 7, 2002 (received for review July 8, 2002)

Abstract

Diet is a major environmental source of proinflammatory AGEs (heat-generated advanced glycation end products); its impact in humans remains unclear. We explored the effects of two equivalent diets, one regular (high AGE, H-AGE) and the other with 5-fold lower AGE (L-AGE) content on inflammatory mediators of 24 diabetic subjects: 11 in a 2-week crossover and 13 in a 6-week study. After 2 weeks on H-AGE, serum AGEs increased by 64.5% (P = 0.02) and on L-AGE decreased by 30% (P = 0.02). The mononuclear cell tumor necrosis factor-α/β-actin mRNA ratio was 1.4 ± 0.5 on H-AGE and 0.9 ± 0.5 on L-AGE (P = 0.05), whereas serum vascular adhesion molecule-1 was 1,108 ± 429 and 698 ± 347 ng/ml (P = 0.01) on L- and H-AGE, respectively. After 6 weeks, peripheral blood mononuclear cell tumor necrosis factor-α rose by 86.3% (P = 0.006) and declined by 20% (P, not significant) on H- or L-AGE diet, respectively; C-reactive protein increased by 35% on H-AGE and decreased by 20% on L-AGE (P = 0.014), and vascular adhesion molecule-1 declined by 20% on L-AGE (P < 0.01) and increased by 4% on H-AGE. Serum AGEs were increased by 28.2% on H-AGE (P = 0.06) and reduced by 40% on L-AGE (P = 0.02), whereas AGE low density lipoprotein was increased by 32% on H-AGE and reduced by 33% on L-AGE diet (P < 0.05). Thus in diabetes, environmental (dietary) AGEs promote inflammatory mediators, leading to tissue injury. Restriction of dietary AGEs suppresses these effects.

Footnotes

↵ † To whom correspondence should be addressed at: Mount Sinai School of Medicine, Box 1640, One Gustave Levy Place, New York, NY 10029. E-mail: helen.vlassara{at}mssm.edu.
This paper was submitted directly (Track II) to the PNAS office.
↵ § Lin, J., Alt, A., Liersch, J., Reinhard, G. B., Brownlee, M. A. & Hammes, H.-P. (2000) Diabetes 49,A143 (abstr.).
Abbreviations:
1. AGE, advanced glycation end product
2. MG, methylglyoxal
3. CML, ^∈ N-carboxymethyl-lysine
4. TNFα, tumor necrosis factor α
5. VCAM, vascular adhesion molecule
6. L-AGE, low AGE
7. sAGE, serum AGE
8. H-AGE, high AGE
9. CRP, C-reactive protein
10. LDL, low density lipoprotein