Biomedical subjects

Monique C Saleh

Publications and source records attributed to Monique C Saleh.

4 recordsLinked to original sources

PubMed2004

Free fatty acid-induced beta-cell defects are dependent on uncoupling protein 2 expression.

Chronic exposure to elevated free fatty acids (lipotoxicity) induces uncoupling protein (UCP2) in the pancreatic beta-cell, and therefore a causal link between UCP2 and beta-cell defects associated with obesity may exist. Recently, we showed that lipid treatment in vivo and in vitro in UCP2(-/-) mice/islets does not result in any loss in beta-cell glucose sensitivity. We have now assessed the mechanism of maintained beta-cell function in UCP2(-/-) mice by exposing islets to 0.4 mM palmitate for 48 h. Palmitate treatment increased triglyceride concentrations in wild type (WT) but not UCP2(-/-) islets because of higher palmitate oxidation rates in the UCP2(-/-) islets. Dispersed beta-cells from the palmitate-exposed WT islets had reduced glucose-stimulated hyperpolarization of the mitochondrial membrane potential compared with both control WT and palmitate-exposed UCP2(-/-) beta-cells. The glucose-stimulated increases in the ATP/ADP ratio and cytosolic Ca2+ are attenuated in palmitate-treated WT but not UCP2(-/-) beta-cells. Exposure to palmitate reduced glucose-stimulated insulin secretion (GSIS) in WT islets, whereas UCP2(-/-) islets had enhanced GSIS. Overexpression of recombinant UCP2 but not enhanced green fluorescent protein in beta-cells resulted in a loss of glucose-stimulated hyperpolarization of the mitochondrial membrane potential and GSIS similar to that seen in WT islets exposed to palmitate. Reactive oxygen species (ROS) are known to increase the activity of UCP2. We showed that ROS levels were elevated in control UCP2(-/-) islets as compared with WT and UCP2(-/-) islets overexpressing UCP2 and that palmitate increased ROS in WT and UCP2(-/-) islets overexpressing UCP2 but not in UCP2(-/-) islets. Thus, UCP2(-/-) islets resisted the toxic effects of palmitate by maintaining glucose-dependent metabolism-secretion coupling. We propose that higher free fatty acid oxidation rates prevent accumulation of triglyceride in UCP2(-/-) islets, such accumulation being a phenomenon associated with lipotoxicity.

Adenosine Diphosphate↗

PubMed2004

Uncoupling protein 2 and islet function.

Stressors such as chronic hyperglycemia or hyperlipidemia may lead to insufficient insulin secretion in susceptible individuals, contributing to type 2 diabetes. The molecules mediating this effect are just beginning to be identified. Uncoupling protein (UCP)-2 may be one such negative modulator of insulin secretion. Accumulating evidence shows that beta-cell UCP2 expression is upregulated by glucolipotoxic conditions and that increased activity of UCP2 decreases insulin secretion. Mitochondrial superoxide has been identified as a posttranslational regulator of UCP2 activity in islets; thus, UCP2 may provide protection to beta-cells at one level while simultaneously having detrimental effects on insulin secretion. Interestingly, the latter appears to be the dominant outcome, because UCP2 knockout mice display an increased beta-cell mass and retained insulin secretion capacity in the face of glucolipotoxicity.

Animals↗

PubMed2002

Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic beta-cells enhances glucose-dependent insulin secretion.

Voltage-dependent (Kv) outward K(+) currents repolarize beta-cell action potentials during a glucose stimulus to limit Ca(2+) entry and insulin secretion. Dominant-negative "knockout" of Kv2 family channels enhances glucose-stimulated insulin secretion. Here we show that a putative Kv2.1 antagonist (C-1) stimulates insulin secretion from MIN6 insulinoma cells in a glucose- and dose-dependent manner while blocking voltage-dependent outward K(+) currents. C-1-blocked recombinant Kv2.1-mediated currents more specifically than currents mediated by Kv1, -3, and -4 family channels (Kv1.4, 3.1, 4.2). Additionally, C-1 had little effect on currents recorded from MIN6 cells expressing a dominant-negative Kv2.1 alpha-subunit. The insulinotropic effect of acute Kv2.1 inhibition resulted from enhanced membrane depolarization and augmented intracellular Ca(2+) responses to glucose. Immunohistochemical staining of mouse pancreas sections showed that expression of Kv2.1 correlated highly with insulin-containing beta-cells, consistent with the ability of C-1 to block voltage-dependent outward K(+) currents in isolated mouse beta-cells. Antagonism of Kv2.1 in an ex vivo perfused mouse pancreas model enhanced first- and second-phase insulin secretion, whereas glucagon secretion was unaffected. The present study demonstrates that Kv2.1 is an important component of beta-cell stimulus-secretion coupling, and a compound that enhances, but does not initiate, beta-cell electrical activity by acting on Kv2.1 would be a useful antidiabetic agent.

Animals↗

PubMed2002

17beta-Estradiol release in the parabrachial nucleus of the rat evoked by visceral afferent activation.

In the present investigation, in vivo microdialysis was used to measure the concentration of estrogen in the parabrachial nucleus (PBN) and plasma of male and ovariectomized female Sprague-Dawley rats supplemented with either estrogen (OVX-E(2)) or saline (OVX-S) following visceral afferent activation. Analysis of dialysate samples prior to vagal stimulation and in non-stimulated controls revealed a continuous concentration of estrogen in the PBN for all treatment groups (male, 38 +/-4 pg ml(-1); OVX-E(2), 38+/-5 pg ml(-1); OVX-S, 33 +/- 4 pg ml(-1)). This concentration of estrogen in the PBN was significantly increased during vagal stimulation in all groups (male, 64+/-4 pg ml(-1); OVX-E(2), 104+/-9 pg ml(-1); OVX-S, 80+/-6 pg ml(-1); P<0.05) and returned to pre-stimulation values within 2 h following termination of the stimulation. Immunohistochemical analysis revealed that estrogen receptor (ERalpha and ERbeta) density in males and ovariectomized saline-replaced female rats was significantly lower than that of estrogen-replaced female rats. These results suggest that estrogen is released into the PBN by an increase in visceral afferent traffic, however, alterations in estrogen receptor populations in the PBN may contribute to an attenuated physiological role of estrogen in the PBN of male and saline-replaced ovariectomized female rats.

Animals↗