Thiols and pancreatic β‐cell function: A review

Ammon, H. P. T.; Mark, Melanie D.

doi:10.1002/cbf.290030302

Cited by 65 publications

(36 citation statements)

References 85 publications

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“…Asterisks denote probability level of random difference: *P Ͻ 0.05; ***P Ͻ 0.001. targets for neuronally generated NO through S-nitrosylation processes (18). In contrast with the negative impact exerted by NO on glucose-stimulated insulin release, this gaseous messenger seems to have no appreciable effect on insulin secretory mechanisms elicited by secretagogues directly activating the cyclic AMP system (2,3,(33)(34)(35), since such secretagogues apparently act independently of regulating thiol groups (3). In fact, NO may even amplify cyclic AMP-induced insulin release (2).…”

Section: Discussionmentioning

confidence: 99%

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Qader

Jimenez-Feltström²,

Ekelund³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Qader SS, Jimenez-Feltström J, Ekelund M, Lundquist I, Salehi A. Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27. Am J Physiol Endocrinol Metab 292: E1447-E1455, 2007. First published January 30, 2007; doi:10.1152/ajpendo.00172.2006.-Chronic exposure of pancreatic islets to elevated plasma lipids (lipotoxicity) can lead to ␤-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase (iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to ␤-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive (nc)NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP-and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in ␤-cells. pancreatic islets; insulin secretion; isoforms of nitric oxide synthase; pituitary adenylate cyclase-activating polypeptide 27 THE SOLUTION USED for total parenteral nutrition (TPN) contains a high amount of lipids, which results in increased plasma levels of free fatty acid (FFA), triglycerides, and cholesterol (8,31,34,36). FFA has complex effects on pancreatic ␤-cells and insulin secretion (8,9,25,31,32,34,36,45,51). Hence, FFA acutely stimulates insulin secretion from isolated pancreatic islets (9), whereas long-term incubation (24 h) of islets in the presence of FFAs negatively modulates ␤-cell function and results in a markedly decreased glucose-stimulated release of insulin (51). Indeed, it has been known for a long time that chronic elevation of plasma FFA impairs the insulin-secreting response to glucose in both humans and animals (8,31,32,34,36,45,51), and this hyperlipidemia has been suggest...

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Section: Discussionmentioning

confidence: 99%

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Qader

Jimenez-Feltström²,

Ekelund³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Indeed earlier reports, using primary rat islets, described the importance of redox enzymes to the regulation of beta cell metabolism, including a study describing the inhibition of glutathione reductase (a GSSG-reducing enzyme), which impaired glucose metabolism and insulin secretion [58]. GSIS was reported to be dependent on the level of intracellular reduced glutathione [59]. Using a patch-clamp technique, investigators reported a reduction in ATP-sensitive K + channel activity, suppression of plasma membrane electrical excitability and inhibition of metabolism after H 2 O 2 addition [60][61][62].…”

Section: Beta Cell Redox Regulation Metabolism and Insulin Secretionmentioning

confidence: 99%

Insights into the critical role of NADPH oxidase(s) in the normal and dysregulated pancreatic beta cell

et al. 2009

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It is now widely accepted that reactive oxygen species (ROS) contribute to cell and tissue dysfunction and damage in diabetes. The source of ROS in the insulin secreting pancreatic beta cells has traditionally been considered to be the mitochondrial electron transport chain. While this source is undoubtedly important, we fully describe in this article recent information and evidence of NADPH oxidase-dependent generation of ROS in pancreatic beta cells and identify the various isoforms that contribute to O 2•− and H 2 O 2 production in various conditions. While glucose-stimulated ROS generation may be important for acute regulation of insulin secretion, at higher levels ROS may disrupt mitochondrial energy metabolism. However, ROS may alter other cellular processes such as signal transduction, ion fluxes and/or cell proliferation/death. The various beta cell isoforms of NADPH oxidase (described in this review) may, via differences in the kinetics and species of ROS generated, positively and negatively regulate insulin secretion and cell survival. Regulation of insulin secretionThe combination of glucose transport and phosphorylation at the glucokinase step determines a major part of metabolic flux through glycolysis in the beta cell. Glucose may be further metabolised by pyruvate dehydrogenase and pyruvate carboxylase, resulting in enhanced tricarboxylic acid cycle activity and subsequent ATP generation [1]. This results in closure of the ATP-sensitive K + channels, decreasing the hyperpolarising outward K + flux, depolarising the plasma membrane and opening voltage-gated Ca 2+ channels to increase the influx of extracellular Ca 2+ , which is a primary driver of the mechanism of glucose-stimulated P. Newsholme (*)

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“…However, most previous data suggest that an NO-induced inhibition of Ca 2+ influx is not the most important signalling mechanism(s) underlying the NOmediated inhibition of glucose-induced insulin release. We have previously proposed (Panagiotidis et al 1992a, 1994, Salehi et al 1996 that the inhibitory action of NO on nutrient-induced insulin release might be exerted through the formation of S-nitrosothiols (Stamler et al 1992), thereby impairing thiol groups essential for the nutrient-induced insulin secretory process (Hellman et al 1974, Ammon & Mark 1985. Moreover, since we have shown here that the potentiating effect of L-NAME on glucose-induced insulin release seems to be exerted mainly independently of membrane depolarization events and in the presence of the K + ATP channel opener, diazoxide, it seems very likely that the major effect of NO is exerted at distal events in the stimulus-secretion coupling i.e.…”

Section: Insulin Secretionmentioning

confidence: 99%

Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice

Åkesson¹,

Henningsson²,

Salehi³

et al. 1999

Journal of Endocrinology

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We have studied, by a combined in vitro and in vivo approach, the relation between the inhibitory action of N G -nitro--arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide synthase (NOS), on the activity of islet constitutive NOS (cNOS) and glucose regulation of islet hormone release in mice. The cNOS activity in islets incubated in vitro at 20 mM glucose was not appreciably affected by 0·05 or 0·5 mM L-NAME, but was greatly suppressed (-60%) by 5 mM L-NAME. Similarly, glucosestimulated insulin release was unaffected by the lower concentrations of L-NAME but greatly enhanced in the presence of 5 mM of the NOS inhibitor. In incubated islets inhibition of cNOS activity resulted in a modestly enhanced insulin release in the absence of glucose, did not display any effect at physiological or subphysiological glucose concentrations, but resulted in a markedly potentiated insulin release at hyperglycaemic glucose concentrations. In the absence of glucose, glucagon secretion was suppressed by L-NAME. The dynamics of glucoseinduced insulin release and 45 Ca 2+ efflux from perifused islets revealed that L-NAME caused an immediate potentiation of insulin release, and a slight increase in 45 Ca 2+ efflux. In islets depolarized with 30 mM K + in the presence of the K + ATP channel opener, diazoxide, L-NAME still greatly potentiated glucose-induced insulin release. Finally, an i.v. injection of glucose to mice pretreated with L-NAME was followed by a markedly potentiated insulin response, and an improved glucose tolerance. In accordance, islets isolated directly ex vivo after L-NAME injection displayed a markedly reduced cNOS activity. In conclusion, we have shown here, for the first time, that biochemically verified suppression of islet cNOS activity, induced by the NOS inhibitor L-NAME, is accompanied by a marked potentiation of glucosestimulated insulin release both in vitro and in vivo. The major action of NO to inhibit glucose-induced insulin release is probably not primarily linked to changes in Ca 2+ fluxes and is exerted mainly independently of membrane depolarization events.

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Thiols and pancreatic β‐cell function: A review

Cited by 65 publications

References 85 publications

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Insights into the critical role of NADPH oxidase(s) in the normal and dysregulated pancreatic beta cell

Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice

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