Nitrosamine exposure causes insulin resistance diseases: relevance to type 2 diabetes mellitus, non-alcoholic steatohepatitis, and Alzheimer's disease.
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 showed that streptozotocin, a nitrosamine-related com-pound, causes insulin resistance diseases including, T2DM, NASH, and AD-type neurodegeneration. We hypothesize that chronic human exposure to nitrosamine compounds, which are widely present in processed foods, contributes to the pathogenesis of T2DM, NASH, and AD. Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. (x3) or i.c. (x1) injection, and 2-4 weeks later, they were evaluated for cognitive-motor dysfunction, insulin resistance, and neurodegeneration using behavioral, biochemical, and molecular approaches. NDEA treatment caused T2DM, NASH, deficits in motor function and spatial learning, and neurodegeneration characterized by insulin resistance and deficiency, lipid peroxidation, cell loss, increased levels of amyloid-beta protein precursor/amyloid-beta, phospho-tau, and ubiquitin immunoreactivities, and upregulated expression of pro-inflammatory cytokine and pro-ceramide genes, which together promote insulin resistance. In conclusion, environmental and food contaminant exposures to nitrosamines play critical roles in the pathogenesis of major insulin resistance diseases including T2DM, NASH, and AD. Improved detection and prevention of human exposures to nitrosamines will lead to earlier treatments and eventual quelling of these costly and devastating epidemics.
Tong
Ming
M
Department of Pathology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Neusner
Alexander
A
Longato
Lisa
L
Lawton
Margot
M
Wands
Jack R
JR
de la Monte
Suzanne M
SM
D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002518:Ceramides / Q000235:genetics / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000378:metabolism*; D004052:Diethylnitrosamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007333:Insulin Resistance; D015227:Lipid Peroxidation; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D013028:Space Perception / Q000187:drug effects; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002518:Ceramides; D016207:Cytokines; D025801:Ubiquitin; D016875:tau Proteins; D004052:Diethylnitrosamine
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