CYCAD TOXIN-INDUCED DAMAGE OF RODENT AND HUMAN PANCREATIC BETA-CELLS

Environmental toxins may be risk factors for some forms of diabetes me llitus and neurodegenerative diseases. The medicinal and food use of s eed from the cycad plant (Cycas spp.), which contains the genotoxin cy casin, is a proposed etiological factor for amyotrophic lateral sclero sis/Parkinsonism-dementia complex (ALS/PDC), a prototypical neurodegen erative disease found in the western Pacific. Patients with ALS/PDC ha ve a very high prevalence of glucose intolerance and diabetes mellitus (in the range of 50-80%). We investigated whether the cycad plant tox in cycasin (methylazoxymethanol (MAM) beta-D-glucoside) or the aglycon e MAM are toxic in vitro to mouse or human pancreatic islets of Langer hans. Mouse pancreatic islets treated for 6 days with cycasin impaired the beta-cell insulin response to glucose, but this effect was revers ible after a further 4 days in culture without the toxin. When mouse i slets 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 m etabolism, 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 imp aired even after removal of MAM and a further culturing for 4 days wit hout the toxin. MAM damages islets by two possible mechanisms: (a) nit ric oxide generation, as judged by increased medium nitrite accumulati on; and (b) DNA alkylation, as judged by increased levels of O-6-methy ldeoxyguanosine in cellular DNA. Incubation of mouse islets with hemin (10 or 100 mu M), 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 MAM OAc (1.0 mM) produced a significant decrease in both insulin content a nd release in response to glucose. In conclusion, the present data ind icate that cycasin and its aglycone MAM impair both rodent and human b eta-cell function which may lead to the death of pancreatic islet cell s. These data suggest that a ''slow toxin'' may be a common aetiologic al factor for both diabetes mellitus and neurodegenerative disease.