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Fetal or neonatal low-glycotoxin environment prevents autoimmune diabetes in NOD mice
Melpomeni Peppa1, Cijiang He, Masakazu Hattori
1Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, Box 1640, New York, NY 10029, USA. moly.peppa@internet.gr
Abstract:
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.
Insights
Reducing dietary advanced glycation end products (AGEs) significantly suppresses type 1 diabetes in NOD mice. Lower AGE intake ameliorates T-cell responses and beta-cell injury, preventing diabetes development.
Area of Science:
- Immunology
- Endocrinology
- Nutrition Science
Background:
- Advanced glycation end products (AGEs) are linked to beta-cell dysfunction and diabetes complications.
- Diet-derived AGEs (dAGEs) contribute to diabetic end-organ damage.
- The specific role of dAGEs in type 1 diabetes pathogenesis requires further investigation.
Observation:
- NOD mice were fed either a high-AGE diet (H-AGE) or a low-AGE diet (L-AGE) with reduced N(epsilon)-carboxymethyllysine (CML) and methylglyoxal (MG).
- Maternal and neonatal exposure to L-AGE nutrition was assessed for its impact on diabetes development and immune responses.
- Insulitis and specific T-cell populations (CD4+, IL-4+, IFN-gamma+, IL-10+) were analyzed in spleen and pancreatic lymph nodes.
Findings:
- L-AGE diet significantly suppressed diabetes incidence (33% vs. >94% in H-AGE mice) and delayed onset by 4 months.
- Survival rates were markedly higher in L-AGE fed mice (76% vs. 0% at 44 weeks).
- Reduced insulitis in L-AGE mice correlated with altered T-cell profiles, showing less pro-inflammatory IFN-gamma+ T-cells and more regulatory IL-4+ and IL-10+ CD4+ cells.
Implications:
- High dietary AGE intake may promote T-cell-mediated diabetes or direct beta-cell injury.
- Early life exposure to a low-AGE diet can protect against type 1 diabetes development in susceptible individuals.
- Dietary modification represents a potential strategy for preventing or mitigating type 1 diabetes.