Cycad toxin-induced damage of rodent and human pancreatic beta-cells.

1995

Environmental toxins may be risk factors for some forms of diabetes mellitus and neurodegenerative diseases. The medicinal and food use of seed from the cycad plant (Cycas spp.), which contains the genotoxin cycasin, is a proposed etiological factor for amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), a prototypical neurodegenerative disease found in the western Pacific. Patients with ALS/PDC have a very high prevalence of glucose intolerance and diabetes mellitus (in the range of 50-80%). We investigated whether the cycad plant toxin cycasin (methylazoxymethanol (MAM) beta-D-glucoside) or the aglycone MAM are toxic in vitro to mouse or human pancreatic islets of Langerhans. Mouse pancreatic islets treated for 6 days with cycasin impaired the beta-cell insulin response to glucose, but this effect was reversible after a further 4 days in culture without the toxin. When mouse islets were exposed for 24 hr to MAM/MAM acetate (MAMOAc; 0.1-1.0 mM), there was a dose-dependent impairment in insulin release and glucose metabolism, and a significant decrease in islet insulin and DNA content. At higher MAM/MAMOAc concentrations (1.0 mM), widespread islet cell destruction was observed. Glucose-induced insulin release remained impaired even after removal of MAM and a further culturing for 4 days without the toxin. MAM damages islets by two possible mechanisms: (a) nitric oxide generation, as judged by increased medium nitrite accumulation; and (b) DNA alkylation, as judged by increased levels of O6-methyldeoxyguanosine in cellular DNA. Incubation of mouse islets with hemin (10 or 100 microM), a nitric oxide scavenger, or nicotinamide (5-20 mM) protected beta-cells from a decrease in glucose oxidation by MAM. In separate studies, a 24 hr treatment of human beta-islet cells with MAMOAc (1.0 mM) produced a significant decrease in both insulin content and release in response to glucose. In conclusion, the present data indicate that cycasin and its aglycone MAM
In Vitro
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
info:eu-repo/semantics/published

Sciences bio-médicales et agricoles; Alkylating Agents -- toxicity; Amino Acids, Diamino -- toxicity; Animals; Cycasin -- toxicity; DNA -- analysis; Diabetes Mellitus -- chemically induced; Environmental Exposure; Glucose -- metabolism; Glucose -- pharmacology; Humans; Insulin -- analysis; Insulin -- secretion; Insulin Resistance; Islets of Langerhans -- drug effects; Islets of Langerhans -- metabolism; Islets of Langerhans -- pathology; Methylazoxymethanol Acetate -- analogs & derivatives; Methylazoxymethanol Acetate -- toxicity; Mice; info:eu-repo/semantics/article; info:ulb-repo/semantics/articlePeerReview; info:ulb-repo/semantics/openurl/article

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EQY oai:dipot.ulb.ac.be:2013/56019
uri/info:pii/0006-2952(95)00150-X
uri/info:pmid/7646537
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