Abstract
BackgroundThe current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases. Previous studies linked insulin resistance diseases to high fat diets or exposure to streptozotocin, a nitrosamine-related compound that causes T2DM, NASH, and AD-type neurodegeneration. We hypothesize that low-level exposure to nitrosamines that are widely present in processed foods, amplifies the deleterious effects of high fat intake in promoting T2DM, NASH, and neurodegeneration.MethodsLong Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. Injection, and upon weaning, they were fed with high fat (60%; HFD) or low fat (5%; LFD) chow for 6 weeks. Rats were evaluated for cognitive impairment, insulin resistance, and neurodegeneration using behavioral, biochemical, molecular, and histological methods.ResultsNDEA and HFD ± NDEA caused T2DM, NASH, deficits in spatial learning, and neurodegeneration with hepatic and brain insulin and/or IGF resistance, and reductions in tau and choline acetyltransferase levels in the temporal lobe. In addition, pro-ceramide genes, which promote insulin resistance, were increased in livers and brains of rats exposed to NDEA, HFD, or both. In nearly all assays, the adverse effects of HFD+NDEA were worse than either treatment alone.ConclusionsEnvironmental and food contaminant exposures to low, sub-mutagenic levels of nitrosamines, together with chronic HFD feeding, function synergistically to promote major insulin resistance diseases including T2DM, NASH, and AD-type neurodegeneration. Steps to minimize human exposure to nitrosamines and consumption of high-fat content foods are needed to quell these costly and devastating epidemics.
Highlights
The current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases
Effects of NDEA and high fat diet (HFD) on Serum Biomarkers of T2DM, Dyslipidemia, Body Weight, and Brain Weight Fasting blood glucose and serum insulin concentrations were significantly higher in NDEA-treated rats, with or without HFD-feeding, relative to LFD fed, vehicle treated controls, and the highest mean blood glucose and serum insulin levels were detected in the HFD+NDEA group (Figs 1A-B)
Neither the NDEA exposure nor the chronic HFD feeding caused hyperlipidemia, indicating that seemingly favorable serum lipid profiles can exist in the context of peripheral insulin resistance or T2DM
Summary
The current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases. Previous studies linked insulin resistance diseases to high fat diets or exposure to streptozotocin, a nitrosamine-related compound that causes T2DM, NASH, and AD-type neurodegeneration. We have noted striking increases in age-specific AD mortality rates over the same time interval, and correlated these findings with sharply increased consumption of processed foods, use of preservatives, and demand for nitrogen-containing fertilizers [7]. Such rapid shifts in age-adjusted AD morbidity and mortality are more consistent with exposure-related rather than genetic etiologies. Better characterization of the non-neoplastic and degenerative effects of nitrosamines is warranted
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