Nitrosamine Exposure Causes Insulin Resistance Diseases: Relevance to Type 2 Diabetes Mellitus, Non-Alcoholic Steatohepatitis, and Alzheimer's Disease

Article type: Research Article

Authors: Tong, Ming | Neusner, Alexander | Longato, Lisa | Lawton, Margot | Wands, Jack R. | de la Monte, Suzanne M.^{; *}

Affiliations: Departments of Pathology (Neuropathology), Clinical Neuroscience, and Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA

Correspondence: [*] Corresponding author: Dr. Suzanne M. de la Monte, MD, MPH, Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903, USA. Tel.: +1 401 444 7364; Fax: +1 401 444 2939; E-mail: Suzanne_DeLaMonte_MD@Brown.edu.

Note: [] Communicated by Paula Moreira

Abstract: 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 compound, 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-β protein precursor/amyloid-β, 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.

Keywords: Alzheimer's disease, diabetes, environmental toxin, neurodegeneration, nitrosamine, obesity

DOI: 10.3233/JAD-2009-1155

Journal: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 827-844, 2009