Abstract
Aims/HypothesisTo study the effects of cereulide, a food toxin often found at low concentrations in take-away meals, on beta-cell survival and function.MethodsCell death was quantified by Hoechst/Propidium Iodide in mouse (MIN6) and rat (INS-1E) beta-cell lines, whole mouse islets and control cell lines (HepG2 and COS-1). Beta-cell function was studied by glucose-stimulated insulin secretion (GSIS). Mechanisms of toxicity were evaluated in MIN6 cells by mRNA profiling, electron microscopy and mitochondrial function tests.Results24 h exposure to 5 ng/ml cereulide rendered almost all MIN6, INS-1E and pancreatic islets apoptotic, whereas cell death did not increase in the control cell lines. In MIN6 cells and murine islets, GSIS capacity was lost following 24 h exposure to 0.5 ng/ml cereulide (P<0.05). Cereulide exposure induced markers of mitochondrial stress including Puma (p53 up-regulated modulator of apoptosis, P<0.05) and general pro-apoptotic signals as Chop (CCAAT/-enhancer-binding protein homologous protein). Mitochondria appeared swollen upon transmission electron microscopy, basal respiration rate was reduced by 52% (P<0.05) and reactive oxygen species increased by more than twofold (P<0.05) following 24 h exposure to 0.25 and 0.50 ng/ml cereulide, respectively.Conclusions/InterpretationCereulide causes apoptotic beta-cell death at low concentrations and impairs beta-cell function at even lower concentrations, with mitochondrial dysfunction underlying these defects. Thus, exposure to cereulide even at concentrations too low to cause systemic effects appears deleterious to the beta-cell.
Highlights
The prevalence of type 1 and type 2 diabetes is rising and this increase is believed to be related to environmental factors
31.6% of MIN6 cells were apoptotic when exposed to a concentration of 0.25 ng/ml for 24 h (P,0.01) and no cells survived exposure to 5 ng/ml (P,0.001 vs control, figure 1A). 72 h incubation with 0.15 ng/ml cereulide caused 47.5% apoptotic cell death versus 2.7% in non-exposed cells, while there were no viable MIN6 cells when exposed to 0.5 ng/ml for 72 h
Whole mouse islets were sensitive as the murine MIN6 cell line, with 0.5 ng/ml cereulide causing 42% cell death and no surviving islets at 0.5 ng/ml exposure for 24 h (P,0.001, figure 1B)
Summary
The prevalence of type 1 and type 2 diabetes is rising and this increase is believed to be related to environmental factors. To sedentary lifestyle and western style diet, it is known that certain environmental polluents, such as polychlorinated biphenyls, xenoestrogens or cadmium can cause beta-cell dysfunction and cell death, both key traits of the pathophysiology of diabetes [1,2]. We propose cereulide, a toxin produced by certain strains of Bacillus cereus, as a putative culprit. It is a cyclic dodecadepsipeptide (1.2 kDa), that acts as a potassium ionophore, and is structurally very similar to the well-known valinomycin. Exposure of porcine pancreatic islets to 1 ng/ml of cereulide, decreased insulin content and increased necrotic cell death within 2 days [7]
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