Cycad toxin-induced damage of rodent and human pancreatic β-cells

Abstract

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) β- 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 β-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 O 6-methyldeoxyguanosine in cellular DNA. Incubation of mouse islets with hemin (10 or 100 μM), a nitric oxide scavenger, or nicotinamide (5–20 mM) protected β-cells from a decrease in glucose oxidation by MAM. In separate studies, a 24 hr treatment of human β-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 β-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.