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Diabetes 52:2805-2813, 2003
© 2003 by the American Diabetes Association, Inc.

Adverse Effects of Dietary Glycotoxins on Wound Healing in Genetically Diabetic Mice

Melpomeni Peppa1, Harold Brem2, Paul Ehrlich3, Jian-Gang Zhang2, Weijing Cai1, Zhu Li1, Anca Croitoru4, Swan Thung4, and Helen Vlassara1

1 Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, New York
2 Angiogenesis and Wound Healing Laboratory, Department of Surgery, Mount Sinai School of Medicine, New York, New York
3 Division of Plastic Surgery, Hershey Medical Center, Hershey, Pennsylvania
4 Department of Pathology, Mount Sinai School of Medicine, New York, New York

Advanced glycoxidation end products (AGEs) are implicated in delayed diabetic wound healing. To test the role of diet-derived AGE on the rate of wound healing, we placed female db/db (+/+) (n = 55, 12 weeks old) and age-matched control db/db (+/-) mice (n = 45) on two diets that differed only in AGE content (high [H-AGE] versus low [L-AGE] ratio, 5:1) for 3 months. Full-thickness skin wounds (1 cm) were examined histologically and for wound closure. Serum 24-h urine and skin samples were monitored for N{epsilon}-carboxymethyl-lysine and methylglyoxal derivatives by enzyme-linked immunosorbent assays. L-AGE-fed mice displayed more rapid wound closure at days 7 and 14 (P < 0.005) and were closed completely by day 21 compared with H-AGE nonhealed wounds. Serum AGE levels increased by 53% in H-AGE mice and decreased by 7.8% in L-AGE mice (P < 0.04) from baseline. L-AGE mice wounds exhibited lower skin AGE deposits, increased epithelialization, angiogenesis, inflammation, granulation tissue deposition, and enhanced collagen organization up to day 21, compared with H-AGE mice. Reepithelialization was the dominant mode of wound closure in H-AGE mice compared with wound contraction that prevailed in L-AGE mice. Thus, increased diet-derived AGE intake may be a significant retardant of wound closure in diabetic mice; dietary AGE restriction may improve impaired diabetic wound healing.

Address correspondence and reprint requests to Helen Vlassara, Mount Sinai School of Medicine, Box 1640, New York, NY 10029. E-mail: helen.vlassara{at}mssm.edu


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