Fetal or Neonatal Low-Glycotoxin Environment Prevents Autoimmune Diabetes in NOD Mice

Fetal or Neonatal Low-Glycotoxin Environment Prevents Autoimmune Diabetes in NOD Mice Melpomeni Peppa 1 , Cijiang He 1 , Masakazu Hattori 2 , Robert McEvoy 1 , Feng Zheng 1 and Helen Vlassara 1 1 Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, New York 2 Joslin Diabetes Center, Boston, Massachusetts Abstract Advanced glycation end products (AGEs) are implicated in β-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 ε -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)-γ-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-γ-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 β-cell injury in NOD mice; both processes are ameliorated by maternal or neonatal exposure to L-AGE nutrition. Footnotes Address correspondence and reprint requests to Melpomeni Peppa, MD, Mount Sinai School of Medicine, Box 1640, New York, NY, 10029. E-mail: moly.peppa{at}internet.gr . Received for publication 20 August 2001 and accepted in revised form 10 February 2003 CML, N ε -carboxymethyllysine; dAGE, diet-derived AGE; ELISA, enzyme-linked immunosorbent assay; GALT, gut-associated lymphoid tissue; H&E, hematoxylin and eosin; H-AGE, high-AGE diet; IFN, interferon; IGTT, intraperitoneal glucose tolerance test; IL, interleukin; L-AGE, low-AGE diet; MG, methylglyoxal; PI, proinsulin; pLy, pancreatic lymphocytes; ROS, reactive oxygen species; sAGE, serum AGE; SI, stimulation index; sLy, splenic lymphocytes; UA, urinary albumin. DIABETES