A short exposure to a high‐glucose milieu stabilizes the acidic vacuolar apparatus of insulinoma cells in culture to ensuing oxidative stress

Abstract

U. T. A short exposure to a high-glucose milieu stabilizes the acidic vacuolar apparatus of insulinoma cells in culture to ensuing oxidative stress. APMIS 105:It was recently suggested that extracellular hydrogen peroxide, after diffusing into and throughout adjacent cellswhich may be the case if they have only a weak capacity to degrade hydrogen peroxidelabilizes their lysosomal compartment due to its content of low-molecular-weight iron in redox-active form. The iron would be present as a consequence of normal autophagocytotic degradation of various iron-containing metalloproteins. Beta-and insulinoma cells are especially vulnerable to oxidative stress, since they possess only low capacity to degrade hydrogen peroxide, and, perhaps, since they normally have a certain degree of autophagocytotic degradation of secretory granules with some iron contentcrinophagy. The toxicity to beta cells of oxidative stress, such as an exposure to alloxan, that results in extracellular formation of hydrogen peroxide, is considerably reduced if animals are initially given an intravenous bolus dose of glucose, temporarily bringing up the blood level to about 20 mM. In this study it was demonstrated that already as short an exposure as 30 min to 20 mM D-glucose reduces the sensitivity of HIT and NIT insulinoma cells in culture to a subsequent exposure to hydrogen peroxide. In parallel, exposure to such a high-glucose medium also reduces their desferrioxamine-available amount of iron and, moreover, stabilizes their lysosomal membranes against oxidative stressthus preventing diffusion to the cytosol of damaging lysosomal contents following iron-catalyzed, Fenton-type, intralysosomal reactions. We suggest that both general autophagocytotic turnover and, in particular, crinophagy of secretory granules are decreased by an increased glucose concentration of the surrounding milieu, with attendant reduced amounts of intralysosomal lowmolecular-weight iron and, thus, diminished sensitivity to oxidative stress.

Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture

“…The finding that exposure to two structurally unrelated metal chelators preserved lysosomal stability both under and after the steady-state oxidative stress, and prevented apoptosis as well, is consistent with our previous observations when H # O # was used in large bolus doses [3,4]. The protection by pre-exposure to desferrioxamine, which is taken up only by endocytosis and stored intralysosomally [21][22][23], confirms that lysosomal vul-…”

“…Desferrioxamine is taken up into cells by endocytosis [21][22][23] and, consequently, binds lysosomal low-molecular-mass redoxactive transition metals. 2,2h-Dipyridyl is a lipophilic compound that transverses membranes freely [24] ; hence, a broader cellular range of effects may be expected with 2,2h-dipyridyl.…”

Adenoviral infection or deferoxamine? Two approaches to overexpress VEGF in β-cell lines

“…However, several data have demonstrated that iron could play a crucial role in the inhibition of insulin expression in -cell (Guillygomarc'h et al, 2001;Fernández-Real, López-Bermejo, & Ricart, 2002). We therefore suggest that the DFO-induced increase in insulin expression may be mediated by iron chelation, which may also explain at least in part the reported protection against oxidative stress by Olejnicka et al (1997Olejnicka et al ( , 1999 in -cells. At the optimal concentration of 10 µmol/L DFO, an inhibition of cell apoptosis was observed with a decrease in Bax expression, a regulating protein involved in the activation of apoptosis (Messaris et al, 2004).…”

“…DFO removes both free and bound iron from hemosiderin and ferritin but not from hemoglobin, transferrin, or cytochromes. Moreover, DFO protects myocytes against peroxide-induced damages (Le et al, 1994), and by stimulating VEGF expression in cells (Agani & Semenza, 1998) it protects them against oxidative stress (Olejnicka, Ollinger, & Brunk, 1997;Olejnicka et al, 1999) and macrophagic activation (Mendola, Wright, & Lacy, 1989;Olejnicka et al, 1999).…”

Beneficial Effects of Desferrioxamine on Encapsulated Human Islets—In Vitro and In Vivo Study

“…We hypothesized that a combination of the above strategies, particularly ischemic preconditioning and enhanced VEGF expression would be beneficial. (17)(18)(19). Preconditioning with DFO stabilizes HIF-1a and protects neuronal cells against cytokine mediated cell death (20).…”