Interference of H₂O₂ with stimulus‐secretion coupling in mouse pancreatic β‐cells

Abstract

Several studies have shown that the infiltration of macrophages into the islets of Langerhans during the early stages of insulitis is one of the first steps in the development of insulin-dependent diabetes mellitus (Kolb-Bachofen et al. 1988;Lee et al. 1988; Hanenberg et al. 1989). It is generally believed that macrophages produce large amounts of reactive oxygen species such as hydrogen peroxide (HµOµ), resulting in an undesired cytotoxic attack against â_cells. Alloxan and streptocotocin, two agents widely used to induce diabetes in animals, also lead to the formation of HµOµ, which may thus contribute to the manifestation of diabetes (Takasu et al. 1991). Pancreatic â_cells are extremely sensitive to oxidative stress because of the low expression and activity of the enzymes defending cells against an assault by oxidants (Malaisse et al. 1982;Lenzen et al. 1996). Moreover, the GSHÏGSSG (reduced/oxidized glutathione) ratio in islets is low compared with other tissues (Ammon et al. 1983). It is well known that reactive oxygen 8593

Activation of ATP-sensitive K+(KATP) channels by H2O2underlies glutamate-dependent inhibition of striatal dopamine release

“…Consistent with this hypothesis, Krippeit-Drews et al (46) have shown that exogenous H 2 O 2 can lead to the opening of tolbutamide-sensitive K ATP channels in pancreatic beta cells and thereby inhibit insulin release. On the other hand, it has been reported that tolbutamide can also inhibit K ϩ channels linked to dopaminergic D 2 receptors in both DA and non-DA cells (22,(47)(48)(49).…”

“…In various cell types, including neurons and pancreatic beta cells, exogenous H 2 O 2 causes activation of a K ϩ channel that results in membrane hyperpolarization that can be prevented by the nonspecific K ϩ channel blocker, barium (Ba 2ϩ ), or the sulfonylurea, tolbutamide (46,56). In pilot studies, Ba 2ϩ (100 M) prevented the suppression of evoked DA release (10 Hz, 30 pulses) by exogenous H 2 O 2 (1.5 mM) and by MCS (1 mM) applied sequentially in a given slice (n ϭ 3; data not shown).…”

“…However, the data indicate that the K ATP channels targeted by AMPA-receptordependent H 2 O 2 in striatum contain SUR1 subunits. The question of whether the effect of H 2 O 2 is direct or mediated by additional pathways [e.g., by altering ATP levels as exogenous H 2 O 2 does in pancreatic beta cells (46)] remains open. The most logical location for H 2 O 2 -sensitive K ATP channels to modulate striatal DA release is on the presynaptic membrane of DA release sites.…”

Transient Oxidative Stress Damages Mitochondrial Machinery Inducing Persistent β-Cell Dysfunction

“…These data suggest adaptive effects at mitochondrial level induced by oxidative stress. Previous studies typically analyzed cell function during and immediately following oxidative attacks (12,25,33). Here, we observed persistent alterations of ␤-cell function resulting in elevated basal insulin release and severely impaired glucosestimulated insulin secretion.…”

“…In vitro, oxidative stress applied to ␤-cells rapidly interrupts the transduction of signals normally coupling glucose metabolism to insulin secretion (12,25). Specifically, we reported that INS-1E ␤-cells and rat islets subjected to a 10-min H 2 O 2 exposure exhibit impaired secretory response associated with mitochondrial dysfunction appearing already during the first minutes of oxidative stress (12).…”