Is there a role for neuronal nitric oxide synthase (nNOS) in cytokine toxicity to pancreatic beta cells?

Gurgul-Convey, Ewa; Hanzelka, Katarzyna; Lenzen, Sigurd

doi:10.1016/j.niox.2012.08.075

Cited by 11 publications

(6 citation statements)

References 41 publications

(82 reference statements)

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“…Additional work also revealed that ␤-cells respond to cytokine challenge by changing the expression status of RNS-generating enzymes such as the various isoforms of NOS. The constitutive form of NOS in ␤-cells, neuronal NOS (nNOS), is mainly expressed within insulin vesicles (66,94) and catalyzes the conversion of L-arginine to • NO and L-citrulline, using molecular oxygen and NADPH as substrates (120). However, when challenged with cytokines, nNOS expression decreased in ␤-cells as a compensatory mechanism to offset a cytokine-mediated rise in iNOS activity (66).…”

Section: Other Ros Species and Their Sourcesmentioning

confidence: 99%

Oxidative stress pathways in pancreatic β-cells and insulin-sensitive cells and tissues: importance to cell metabolism, function, and dysfunction

Newsholme

Keane

Carlessi

et al. 2019

American Journal of Physiology-Cell Physiology

133

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It is now accepted that nutrient abundance in the blood, especially glucose, leads to the generation of reactive oxygen species (ROS), ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensatory response from antioxidant mechanisms, the cell, or indeed the tissue, becomes overwhelmed by oxidative stress, leading to the activation of intracellular stress-associated pathways. Activation of the same or similar pathways also appears to play a role in mediating insulin resistance, impaired insulin secretion, and late diabetic complications. The ability of antioxidants to protect against the oxidative stress induced by hyperglycemia and elevated free fatty acid (FFA) levels in vitro suggests a causative role of oxidative stress in mediating the latter clinical conditions. In this review, we describe common biochemical processes associated with oxidative stress driven by hyperglycemia and/or elevated FFA and the resulting clinical outcomes: β-cell dysfunction and peripheral tissue insulin resistance.

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Section: Other Ros Species and Their Sourcesmentioning

confidence: 99%

Oxidative stress pathways in pancreatic β-cells and insulin-sensitive cells and tissues: importance to cell metabolism, function, and dysfunction

Newsholme

Keane

Carlessi

et al. 2019

American Journal of Physiology-Cell Physiology

133

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“…It exhibits cytochrome C reductase activity in addition to NO production activity, and a balance between both functions is essential for a normal insulin secretion in response to glucose stimulation. In contrast, eNOS expression has not been found in rat islets under basal conditions [2, 3]. …”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Is a Mediator of Antiproliferative Effects Induced by Proinflammatory Cytokines on Pancreatic Beta Cells

Quintana-Lopez

Blandino-Rosano

Pérez-Arana

et al. 2013

Mediators of Inflammation

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Nitric oxide (NO) is involved in several biological processes. In type 1 diabetes mellitus (T1DM), proinflammatory cytokines activate an inducible isoform of NOS (iNOS) in β cells, thus increasing NO levels and inducing apoptosis. The aim of the current study is to determine the role of NO (1) in the antiproliferative effect of proinflammatory cytokines IL-1β, IFN-γ, and TNF-α on cultured islet β cells and (2) during the insulitis stage prior to diabetes onset using the Biobreeding (BB) rat strain as T1DM model. Our results indicate that NO donors exert an antiproliferative effect on β cell obtained from cultured pancreatic islets, similar to that induced by proinflammatory cytokines. This cytokine-induced antiproliferative effect can be reversed by L-NMMA, a general NOS inhibitor, and is independent of guanylate cyclase pathway. Assays using NOS isoform specific inhibitors suggest that the NO implicated in the antiproliferative effect of proinflammatory cytokines is produced by inducible NOS, although not in an exclusive way. In BB rats, early treatment with L-NMMA improves the initial stage of insulitis. We conclude that NO is an important mediator of antiproliferative effect induced by proinflammatory cytokines on cultured β cell and is implicated in β-cell proliferation impairment observed early from initial stage of insulitis.

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“…Also, the expression of inducible NOS (iNOS) is undetectable upon HC or Cys exposure (Gurgul-Convey, unpublished). As we have shown the weak expression of nNOS is incapable of generating substantial, detectable amounts of NO inside insulin-producing cells [53]. Therefore in insulin-producing cells the HC-derived H 2 O 2 can undergo only the classical Fenton reaction in the presence of trace metals, but cannot be a partner in a more powerful and faster reaction with NO, leading to generation of hydroxyl radicals in higher concentrations [25].…”

Section: Discussionmentioning

confidence: 90%

“…One of possible explanation for this difference could be the lack of a strong endogenous NO synthase expression in insulinproducing cells [53]. While endothelial cells strongly express eNOS and neurons nNOS, insulin-producing cells lack eNOS and express only weakly nNOS [53]. Also, the expression of inducible NOS (iNOS) is undetectable upon HC or Cys exposure (Gurgul-Convey, unpublished).…”

Section: Discussionmentioning

confidence: 99%

Improved antioxidative defence protects insulin-producing cells against homocysteine toxicity

Scullion

Hahn

Tyka

et al. 2016

Chemico-Biological Interactions

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Homocysteine (HC) is considered to play an important role in the development of metabolic syndrome complications. Insulin-producing cells are prone to HC toxicity and this has been linked to oxidative stress. However, the exact mechanisms remain unknown. Therefore it was the aim of this study to determine the nature of reactive oxygen species responsible for HC toxicity. Chronic exposure of RINm5F and INS1E insulin-producing cells to HC decreased cell viability and glucose-induced insulin secretion in a concentration-dependent manner and led to a significant induction of hydrogen peroxide generation in the cytosolic, but not the mitochondrial compartment of the cell. Cytosolic overexpression of catalase, a hydrogen peroxide detoxifying enzyme, provided a significant protection against viability loss and hydrogen peroxide generation, while mitochondrial overexpression of catalase did not protect against HC toxicity. Overexpression of CuZnSOD, a cytosolic superoxide dismutating enzyme, also protected against HC toxicity. However, the best protection was achieved in the case of a combined overexpression of CuZnSOD and catalase. Incubation of cells in combination with alloxan resulted in a significant increase of HC toxicity and an increase of hydrogen peroxide generation. Overexpression of CuZnSOD or catalase protected against the toxicity of HC plus alloxan, with a superior protection achieved again by combined overexpression. The results indicate that HC induces oxidative stress in insulin-producing cells by stimulation of superoxide radical and hydrogen peroxide generation in the cytoplasm. The low antioxidative defence status makes the insulin-producing cells very vulnerable to HC toxicity.

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Is there a role for neuronal nitric oxide synthase (nNOS) in cytokine toxicity to pancreatic beta cells?

Cited by 11 publications

References 41 publications

Oxidative stress pathways in pancreatic β-cells and insulin-sensitive cells and tissues: importance to cell metabolism, function, and dysfunction

Oxidative stress pathways in pancreatic β-cells and insulin-sensitive cells and tissues: importance to cell metabolism, function, and dysfunction

Nitric Oxide Is a Mediator of Antiproliferative Effects Induced by Proinflammatory Cytokines on Pancreatic Beta Cells

Improved antioxidative defence protects insulin-producing cells against homocysteine toxicity

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