Fetal or neonatal low-glycotoxin environment prevents autoimmune diabetes in NOD mice.
Advanced glycation end products (AGEs) are implicated in beta-cell oxidant stress. Diet-derived AGE (dAGE) are shown to contribute to end-organ toxicity attributed to diabetes. To assess the role of dAGE on type 1 diabetes, NOD mice were exposed to a high-AGE diet (H-AGE) and to a nutritionally similar diet with approximate fivefold-lower levels of N(epsilon)-carboxymethyllysine (CML) and methylglyoxal-derivatives (MG) (L-AGE). Suppression of serum CML and MG in L-AGE-fed mice was marked by suppression of diabetes (H-AGE mice >94% vs. L-AGE mice 33% in founder [F](0), 14% in F(1), and 13% in F(2) offspring, P < 0.006) and by a delay in disease onset (4-month lag). Survival for L-AGE mice was 76 vs. 0% after 44 weeks of H-AGE mice. Reduced insulitis in L-AGE versus H-AGE mice (P < 0.01) was marked by GAD- and insulin-unresponsive pancreatic interleukin (IL)-4-positive CD4+ cells compared with the GAD- and insulin-responsive interferon (IFN)-gamma-positive T-cells from H-AGE mice (P < 0.005). Splenocytes from L-AGE mice consisted of GAD- and insulin-responsive IL-10-positive CD4+ cells compared with the IFN-gamma-positive T-cells from H-AGE mice (P < 0.005). Therefore, high AGE intake may provide excess antigenic stimulus for T-cell-mediated diabetes or direct beta-cell injury in NOD mice; both processes are ameliorated by maternal or neonatal exposure to L-AGE nutrition.
Peppa
Melpomeni
M
Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, Box 1640, New York, NY 10029, USA. moly.peppa@internet.gr
He
Cijiang
C
Hattori
Masakazu
M
McEvoy
Robert
R
Zheng
Feng
F
Vlassara
Helen
H
D000284:Administration, Oral; D000375:Aging; D000419:Albuminuria; D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D017127:Glycation End Products, Advanced / Q000008:administration & dosage / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000032:analysis; D008297:Male; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011765:Pyruvaldehyde / Q000032:analysis
D001786:Blood Glucose; D017127:Glycation End Products, Advanced; C048496:N(6)-carboxymethyllysine; D011765:Pyruvaldehyde; D003404:Creatinine; D008239:Lysine