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 impair both rodent and human beta-cell function which may lead to the death of pancreatic islet cells. These data suggest that a "slow toxin" may be a common aetiological factor for both
diabetes mellitus and
neurodegenerative disease.