Cell oxidant stress delivery and cell dysfunction onset in type 2 diabetes

doi:10.1016/j.biochi.2012.01.020

Biochimie

Volume 94, Issue 9, September 2012, Pages 1837-1848

https://doi.org/10.1016/j.biochi.2012.01.020 Get rights and content

Abstract

Most known pathways of diabetic complications involve oxidative stress. The mitochondria electron transport chain is a significant source of reactive oxygen species (ROS) in insulin secretory cells, insulin peripheral sensitive cells and endothelial cells. Elevated intracellular glucose level induces tricarboxylic acid cycle electron donor overproduction and mitochondrial proton gradient increase leading to an increase in electron transporter lifetime. Subsequently, the electrons leaked combine with respiratory oxygen (O₂) resulting in superoxide anion (^•O₂⁻) production. Advanced glycation end products derive ROS via interaction with their receptors. Elevated diacylglycerol and ROS activate the protein kinase C pathway which, in turn, activates NADPH oxidases. A vicious circle of pathway derived ROS installs. Pathologic pathways induced ROS are activated and persistent though glycemia returns to normal due to hyperglycemia memory. Endothelial nitric oxide synthase may produce both superoxide anion (^•O₂⁻) and nitric oxide (NO) leading to peroxynitrite (^•ONOO⁻) generation. Homocysteine is also implicated in oxidative stress pathogenesis. In this paper we have highlighted the pathologic mechanisms of ROS on atherosclerosis, renal dysfunction, retina dysfunction and nerve dysfunction in type 2 diabetes. Cell oxidant stress delivery have pivotal role in cell dysfunction onset and progression of angiopathies but an early introduction of good glycemic control may protect cells more efficiently than antioxidants.

Highlights

► In type 2 diabetes tricarboxylic acid cycle electron donor are overproduced. ► Mitochondrial proton gradient increases. ► Mitochondrial electron transporter lifetime increases. ► Leaked electrons combine with respiratory oxygen resulting in superoxide anion production. ► A vicious circle of pathway derived ROS installs activating pathologic pathways.

Introduction

In type 2 diabetes, intricate physiopathologic pathways are activated mediating reactive oxygen species (ROS) production. A unifying hypothesis suggests that the initiator of hyperglycemia-induced damage in type 2 diabetes is excess generation of mitochondrial superoxide anion (^•O₂⁻) [1], which then leads to activation of several hyperglycemia-induced oxidant events, including increased advanced glycation end products formation [2], activation of protein kinase C (PKC) isoforms [3], activation of NAD(P)H oxidase [4], nitric oxide synthase (NOS) uncoupling and increased flux through the polyol and hexosamine pathways [5]. Each of these pathways contributes to type 2 diabetes pathogenesis through cellular as ROS generation[6]. Other enzymatic pathways are considered as ROS sources when excessively activated such as in the case of fatty acid peroxisomal beta oxidation [7], xanthine oxidase, arachidonic acid metabolism [5], microsomal P-450 enzymes [8] and myeloperoxidase [9].

In this paper, we have provided panorama information for mitochondrial ROS formation in type 2 diabetes and its effect on both pancreatic beta cells and insulin sensitive cells. We underlined the pathogenic mechanisms linking mitochondria beta cell dysfunction (impaired insulin release and insulin sensitivity) and endothelial cell impairment with oxidant stress. Cell oxidant stress delivery have pivotal role in cell dysfunction onset and progression of angiopathies but an early introduction of good glycemic control may protect cells more efficiently than antioxidants.

Section snippets

Mitochondrial ROS generation under physiological conditions

Following glucose cell entry via glucose transporters family 1–5 translocation, it is firstly phosphorylated and then converted to fructose-6-phosphate and next to glyceraldehyde 3-phosphate. The fructose-6-phosphate is also converted to glucosamine-6-phosphate by glutamine:fructose-6-phosphate-aminotransferase. Through the effect of various transferases and phosphatases, glyceraldehyde 3-phosphate is transformed into glycerol phosphate, a precursor of diacylglycerol, which is a signaling

ROS generation mechanisms in type 2 diabetes

When the cell is exposed to chronic hyperglycemia, many pathogenic pathways are activated ensuing in ROS generation. The major ROS source in type 2 diabetes is recently believed to be the mitochondria [1]. Other metabolic pathways such as increased protein glycation, increased sorbitol production, increased hexosamine production, ketoglycerate auto-oxidation, PKC activation, NAD(P)H oxidase activation and nitric oxide synthase (NOS) uncoupling are also involved in ROS generation [5]. Fig. 2

ROS associated cell damage in type 2 diabetes

Though cells have a number of antioxidant mechanisms available, elevated ROS in type 2 diabetes evade antioxidant defense mechanisms, resulting in a slow accumulation of chronic damage. Both the mitochondrion and nucleus contain a variety of DNA repair enzymes to correct oxidant-induced modifications [80], but damage most likely occurs when the endogenous antioxidant network and repair systems are overwhelmed. Oxidative damage to islet beta cells has been observed in human type 2 diabetes by

ROS derived pathogenesis in type 2 diabetes

Arguably, when cells are exposed to chronic hyperglycemia, they react differently to diminish glucose overload. Cells are able to decrease the transport of glucose across the plasma membrane into the cytosol when exposed to hyperglycemia in order to maintain intracellular glucose homeostasis. Consequently ROS generation rate varies within cell types and inter-individually. Thus the most important factor in the excessive intracellular generation of ROS by hyperglycemia is the ability of

Conclusion

The mitochondria electron transport chain represents an important source of ROS in insulin secretory cells, insulin peripheral sensitive cells and endothelial cells. In type 2 diabetes, increased intracellular glucose induces an overproduction of electron donors from the tricarboxylic acid cycle, the mitochondrial proton gradient increases, leading to an increase of the lifetime of electron transporters. Subsequently, electrons leak combine to molecular oxygen (O₂) resulting in superoxide anion

References (124)

A.R. Cross et al.
Enzymic mechanisms of superoxide production
Biochim. Biophys. Acta
(1991)
J. St-Pierre et al.
Topology of superoxide production from different sites in the mitochondrial electron transport chain
J. Biol. Chem.
(2002)
C. Affourtit et al.
Uncoupling protein-2 attenuates glucose-stimulated insulin secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species
Free Radic. Biol. Med.
(2011)
F. Criscuolo et al.
UCP2, UCP3, avUCP, what do they do when proton transport is not stimulated? Possible relevance to pyruvate and glutamine metabolism
Biochim. Biophys. Acta
(2006)
M. Klingenberg
Wanderings in bioenergetics and biomembranes
Biochim. Biophys. Acta
(2010)
P.B. Pun et al.
Gases in the mitochondria
Mitochondrion
(2010)
C. Affourtit et al.
On the role of uncoupling protein-2 in pancreatic beta cells
Biochim. Biophys. Acta
(2008)
A. Wiederkehr et al.
Impact of mitochondrial calcium on the coupling of metabolism to insulin secretion in the pancreatic beta-cell
Cell Calcium
(2008)
J.W. Lee et al.
ER stress is implicated in mitochondrial dysfunction-induced apoptosis of pancreatic beta cells
Mol. Cells
(2010)
A.l. Tan et al.
AGE, RAGE and ROS in diabetic nephropathy
Semin. Nephrol.
(2007)

B.M. Babior

NADPH oxidase

Curr. Opin. Immunol.

(2004)

G.C. Brown et al.

Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols

Biochim. Biophys. Acta

(2004)

J.R. Koo et al.

Effects of diabetes, insulin and antioxidants on NO synthase abundance and NO interaction with reactive oxygen species

Kidney Int.

(2003)

M.J. MacDonald et al.

Stimulation of insulin release by glyceraldehyde may not be similar to glucose

Arch. Biochem. Biophys.

(2006)

J.E. Hodge

The Amadori rearrangement

Adv.Carbohydr.Chem.

(1955)

H.J. Goldberg et al.

The hexosamine pathway regulates the plasminogen activator inhibitor-1 gene promoter and Sp1 transcriptional activation through protein kinase C-beta I and –delta

J. Biol. Chem.

(2002)

J. Dai et al.

Role of redox factor-1 in hyperhomocysteinemia-accelerated atherosclerosis

Free Radic. Biol. Med.

(2006)

Y.F. Chou et al.

Changes in mitochondrial DNA deletion, content, and biogenesis in folate-deficient tissues of young rats depend on mitochondrial folate and oxidative DNA injuries

J. Nutr.

(2007)

S. Shastry et al.

Homocysteine induces mesangial cell apoptosis via activation of p38-mitogen-activated protein kinase

Kidney Int.

(2007)

P.S. Chan et al.

Resistance of retinal inflammatory mediators to suppress after re-institution of good glycemic control: novel mechanism for metabolic memory

J. Diabetes Complications

(2010)

A. Piwowar et al.

AOPP and its relations with selected markers of oxidative/antioxidative system in type 2 diabetes mellitus

Diabetes Res. Clin. Pract.

(2007)

W.H. Kim et al.

Synergistic activation of JNK/SAPK induced by TNF-alpha and IFN-gamma: apoptosis of pancreatic beta-cells via the p53 and ROS pathway

Cell Signal.

(2005)

M.L. Onozato et al.

Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB

Kidney Int.

(2002)

T. Matoba et al.

Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries

Biochem. Biophys. Res. Commun.

(2002)

N. Quan et al.

Endothelial activation is an intermediate step for peripheral lipopolysaccharide induced activation of paraventricular nucleus

Brain Res. Bull.

(2003)

R. Ginnan et al.

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

Free Radic. Biol. Med.

(2008)

M. Neeper et al.

Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins

J. Biol. Chem.

(1992)

W.I. Sivitz et al.

Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities

Antioxid. Redox Signal.

(2010)

A. Soro-Paavonen et al.

Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase

J. Hypertens.

(2010)

A. Shahab

Why does diabetes mellitus increase the risk of cardiovascular disease?

Acta Med. Indones

(2006)

S. Serpillon et al.

Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH

Am. J. Physiol. Heart Circ. Physiol.

(2009)

F. Giacco et al.

Oxidative stress and diabetic complications

Circ. Res.

(2010)

A. Lapollaa et al.

Glyco-oxidation in diabetes and related diseases

Clin. Chim. Acta

(2005)

M. Elsner et al.

Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells

Diabetes

(2011)

R.M. Reznick et al.

The role of AMP-activated protein kinase in mitochondrial biogenesis

J. Physiol.

(2006)

S.L. Aronoff et al.

Glucose metabolism and regulation: beyond insulin and glucagons

Diabetes Spectr.

(2004)

J.L. Evans et al.

Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction?

Diabetes

(2003)

S. Raha et al.

Mitochondria, oxygen free radicals, disease and ageing

Trends Biochem. Sci.

(2000)

V. Adam-Vizi

Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources

Antioxid. Redox Signal.

(2005)

J. Vasquez-Vivar et al.

Mitochondrial aconitase is a source of hydroxyl radical: an electron spin resonance investigation

J. Biol. Chem.

(2000)

M. Pellegrini et al.

p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

Cell Death Differ.

(2007)

S. Krauss et al.

The mitochondrial uncoupling-protein homologues

Nat. Rev. Mol. Cell Biol.

(2005)

X. Wu et al.

Hyperglycemia potentiates H(2)O(2) production in adipocytes and enhances insulin signal transduction: potential role for oxidative inhibition of thiol-sensitive protein-tyrosine phosphatases

Antioxid. Redox Signal.

(2005)

D. Morgan et al.

Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line

Diabetologia

(2007)

G.C. Brown et al.

Nitric oxide, mitochondria and cell death

IUBMB Life

(2001)

F. Foury et al.

Mitochondrial DNA mutators

Cell Mol. Life Sci.

(2004)

A. Bast et al.

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

Diabetologia

(2002)

H. Sakuraba et al.

Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients

Diabetologia

(2002)

V. Poitout et al.

Glucolipotoxicity: fuel excess and beta-cell dysfunction

Endocr. Rev.

(2008)

N. Bashan et al.

Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species

Physiol. Rev.

(2009)

Cited by (52)

Rational design of a ratiometric fluorescent nanoprobe for real-time imaging of hydroxyl radical and its therapeutic evaluation of diabetes
2024, Biosensors and Bioelectronics
Hydroxyl radical (•OH), one of the most reactive and deleterious substances in organisms, belongs to a class of reactive oxygen species (ROS), and it has been verified to play an essential role in numerous pathophysiological scenarios. However, due to its extremely high reactivity and short lifetime, the development of a reliable and robust method for tracking endogenous •OH remains an ongoing challenge. In this work, we presented the first ratiometric fluorescent nanoprobe NanoDCQ-3 for •OH sensing based on oxidative C–H abstraction of dihydroquinoline to quinoline. The study mainly focused on how to modulate the electronic effects to achieve an ideal ratiometric detection of •OH, as well as solving the inherent problem of hydrophilicity of the probe, so that it was more conducive to monitoring •OH in living organisms. The screened-out probe NanoDCQ-3 exhibited an exceptional ratiometric sensing capability, better biocompatibility, good cellular uptake, and appropriate in vivo retention, which has been reliably used for detecting exogenous •OH concentration fluctuation in living cells and zebrafish models. More importantly, NanoDCQ-3 facilitated visualization of •OH and evaluation of drug treatment efficacy in diabetic mice. These findings afforded a promising strategy for designing ratiometric fluorescent probes for •OH. NanoDCQ-3 emerged as a valuable tool for the detection of •OH in vivo and held potential for drug screening for inflammation-related diseases.
The favorable impacts of cardamom on related complications of diabetes: A comprehensive literature systematic review
2024, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Complementary and alternative medicine plays an increasing role in preventing, and regulatory, complications associated with diabetes. There are plenty of polyphenolic compounds found in Elettaria cardamomum (Cardamom) such as luteolin, limonene, pelargonidin, caffeic acid, kaempferol, gallic acid, and quercetin which can be used in many metabolic diseases.
The objective of this systematic review was to appraise evidence from clinical and in vivo studies on the effects of cardamom on inflammation, blood glucose, oxidative stress and dyslipidemia of diabetes mellitus. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements, the present study was carried out. Studies were conducted by searching databases such as EMBASE, Scopus, PubMed, Google Scholar, web of sciences, and Cochrane Library from the commencement until April 2022.
All available human and animal studies examining the effects of cardamom on diabetes were published in the form of English articles. Finally, only 14 of the 241 articles met the criteria for analysis. Of the 14 articles, 8 were in vivo studies, and 6 were clinical trial studies. Most studies have indicated the beneficial effects of cardamom on insulin resistance, oxidative stress and inflammation. Cardamom also improved dyslipidemia, but had no substantial effect on weight loss.
According to most studies, cardamom supplementation enhanced antioxidant enzyme production and activity in diabetes mellitus and decreased oxidative stress and inflammatory factors. Despite this, the exact mechanism of the disease needs to be identified through more clinical trials.
Research progress on 2,4-thiazolidinedione and 2-thioxo-4-thiazolidinone analogues as aldose reductase inhibitors
2022, Journal of Molecular Structure
Citation Excerpt :
Overactivation of PKC is linked to changes in blood flow, increased vascular permeability, excessive apoptosis, and altered basement thickening, and plays an additional role in the pathogenesis of long-term diabetic complications [29–31]. Increased polyol pathway activation results in the formation of excess sorbitol, which is not able to pass through biological membranes and deposits inside cells, and causes osmotic stress, which leads to chronic problems in diabetics [19,32–35]. Reduced NADPH and oxidized NAD+ are essential co-factors in redox reactions throughout the body, and they are not interchangeable under normal conditions [36,37].
Diabetes-associated complications are a major global health concern. In diabetics, the increased accumulation of sorbitol, produced via over activated polyol pathway, from glucose by the action of aldose reductase (AR, ALR2, or AKR1B1), has been associated with life-threatening co-morbidities. Aldose reductase is crucial in detoxifying certain hazardous aldehydes. However, aldose reductase overexpression in the hyperglycemic state results in microvascular and macrovascular diabetic complications through the consequences of the activated polyol pathway. Accordingly, aldose reductase inhibition has been identified as a viable strategy for dealing with diabetes-associated complications, and it has been put under investigation by various researchers around the world. 2,4-Thiazolidinedione (TZD) and its bio-isosteric analog 2-thioxo-4-thiazolidinone (rhodanine) have been explored as potential inhibitors of aldose reductase to find new molecules. The current review provides a comprehensive insight into the development and medicinal chemistry of TZD and rhodanine derivatives as aldose reductase inhibitors during the last twenty years (2002–2021). Here, the synthetic strategies, SAR, and binding mode of various compounds, Quantitative structure activity relationship (QSARs) are discussed with an emphasis on structural changes to the both moieties for optimizing/designing potent target-specific inhibitors, which is expected to be beneficial for the further design and discovery of newer agents for the treatment of diabetic complications. In addition, the patents on TZDs and rhodanine derivatives as aldose reductase inhibitors are summarized to illustrate the current status.
A trisaccharide phenylethanoid glycoside from Scrophularia flava Grau with potential anti-type 2 diabetic properties by inhibiting α-glucosidase enzyme and decreasing oxidative stress
2020, Bioorganic Chemistry
The Scrophularia genus is a rich source of phenylethanoid glycosides, with diverse biological activities including anti-diabetic properties. This study investigated anti-type 2 diabetic potential and active component of Scrophularia flava Grau.
A new phenylethanoid glycoside was isolated from aerial parts of the plant and identified as 2-(4-hydroxy-3-methoxyphenyl) ethyl 6-deoxy-3-O-[(2E)-3-(3 hydroxy-4-methoxyphenyl) prop-2-enoyl]-α-rhamnopyranosyl-(1 → 3)-[α-rhamnopyranosyl-(1 → 6)]-4-O-[(2E)-3-(4-hydroxy-3-methoxyphenyl) prop-2-enoyl]-β-glucopyranoside. It was named flavaioside. The structure of flavaioside was identified based on ¹H NMR, ¹³C NMR, DEPT-HSQC, COSY, HMBC, NOESY and LC-ESI-MS-MS.
Total methanol extract, fractions (A-F) and specific main phenylethanoid glycoside (flavaioside), were assessed for inhibitory effects against the α-glucosidase enzyme (in vitro anti-type 2 diabetic assay).
The antioxidant activities of methanol extracts, all fractions and isolated flavaioside were identified based on 2, 2′-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging activity, 2, 2′-azino-bis (3-ethylbenzothiazoline)-6-sulphonic acid radical cation (ABTS⁺) scavenging activity, phosphomolybdenum method, and metal chelating activity.
In comparison to the other fractions, the best antioxidant result was observed in fraction E and its main compound, flavaioside, in DPPH (IC₅₀ = 4.26, 2.57 µg/mL) and ABTS⁺ (EC₅₀ = 55.45, 6.34 µg/mL) scavenging activities. Flavaioside showed significantly stronger activities than α-tocopherol and ascorbic acid in DPPH and ABTS⁺ assays.
Furthermore, flavaioside showed a potent inhibitory activity on the α-glucosidase enzyme which was comparable with the known anti-type 2 diabetic drug, acarbose (91.85%, and 92.87%, respectively). Fraction E and flavaioside showed α-glucosidase inhibitory activities with IC₅₀ values, 65.05 and 6.50 µg/mL. The plant and its isolated flavaioside can possess acceptable anti-type 2 diabetic potential and anti-oxidant activity.
Mitochondria as signaling platforms
2019, Mitochondria in Obesity and Type 2 Diabetes: Comprehensive Review on Mitochondrial Functioning and Involvement in Metabolic Diseases
This chapter provides an overview of the roles of mitochondria as whole players in signaling pathways. This includes both the signaling of processes that directly involve mitochondria, such as mitophagy, and processes in which mitochondria are not involved directly but contribute as a major modulator, such as Ca^2 +-signaling, or as a main player, such as cell death. Also, recent discoveries pointing at the signaling function of metabolites originating from mitochondria, such as tricarboxylic acid cycle products and reactive oxygen species, and at the role of mitochondria in general physiological functions, such as protein quality control and innate immunity response, are presented.
Redox imbalance and mitochondrial abnormalities in the diabetic lung
2017, Redox Biology
Although the lung is one of the least studied organs in diabetes, increasing evidence indicates that it is an inevitable target of diabetic complications. Nevertheless, the underlying biochemical mechanisms of lung injury in diabetes remain largely unexplored. Given that redox imbalance, oxidative stress, and mitochondrial dysfunction have been implicated in diabetic tissue injury, we set out to investigate mechanisms of lung injury in diabetes. The objective of this study was to evaluate NADH/NAD⁺ redox status, oxidative stress, and mitochondrial abnormalities in the diabetic lung. Using STZ induced diabetes in rat as a model, we measured redox-imbalance related parameters including aldose reductase activity, level of poly ADP ribose polymerase (PAPR-1), NAD⁺ content, NADPH content, reduced form of glutathione (GSH), and glucose 6-phophate dehydrogenase (G6PD) activity. For assessment of mitochondrial abnormalities in the diabetic lung, we measured the activities of mitochondrial electron transport chain complexes I to IV and complex V as well as dihydrolipoamide dehydrogenase (DLDH) content and activity. We also measured the protein content of NAD⁺ dependent enzymes such as sirtuin3 (sirt3) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Our results demonstrate that NADH/NAD⁺ redox imbalance occurs in the diabetic lung. This redox imbalance upregulates the activities of complexes I to IV, but not complex V; and this upregulation is likely the source of increased mitochondrial ROS production, oxidative stress, and cell death in the diabetic lung. These results, together with the findings that the protein contents of DLDH, sirt3, and NQO1 all are decreased in the diabetic lung, demonstrate that redox imbalance, mitochondrial abnormality, and oxidative stress contribute to lung injury in diabetes.

View all citing articles on Scopus

View full text

ReviewCell oxidant stress delivery and cell dysfunction onset in type 2 diabetes

Abstract

Highlights

Introduction

Section snippets

Mitochondrial ROS generation under physiological conditions

ROS generation mechanisms in type 2 diabetes

ROS associated cell damage in type 2 diabetes

ROS derived pathogenesis in type 2 diabetes

Conclusion

Biochim. Biophys. Acta

J. Biol. Chem.

Free Radic. Biol. Med.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Mitochondrion

Biochim. Biophys. Acta

Cell Calcium

Mol. Cells

Semin. Nephrol.

Curr. Opin. Immunol.

Biochim. Biophys. Acta

Kidney Int.

Arch. Biochem. Biophys.

Adv.Carbohydr.Chem.

J. Biol. Chem.

Free Radic. Biol. Med.

J. Nutr.

Kidney Int.

J. Diabetes Complications

Diabetes Res. Clin. Pract.

Cell Signal.

Kidney Int.

Biochem. Biophys. Res. Commun.

Brain Res. Bull.

Free Radic. Biol. Med.

J. Biol. Chem.

Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities

Antioxid. Redox Signal.

Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase

J. Hypertens.

Why does diabetes mellitus increase the risk of cardiovascular disease?

Acta Med. Indones

Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH

Am. J. Physiol. Heart Circ. Physiol.

Oxidative stress and diabetic complications

Circ. Res.

Glyco-oxidation in diabetes and related diseases

Clin. Chim. Acta

Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells

Diabetes

The role of AMP-activated protein kinase in mitochondrial biogenesis

J. Physiol.

Glucose metabolism and regulation: beyond insulin and glucagons

Diabetes Spectr.

Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction?

Diabetes

Mitochondria, oxygen free radicals, disease and ageing

Trends Biochem. Sci.

Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources

Antioxid. Redox Signal.

Mitochondrial aconitase is a source of hydroxyl radical: an electron spin resonance investigation

J. Biol. Chem.

p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

Cell Death Differ.

The mitochondrial uncoupling-protein homologues

Nat. Rev. Mol. Cell Biol.

Hyperglycemia potentiates H(2)O(2) production in adipocytes and enhances insulin signal transduction: potential role for oxidative inhibition of thiol-sensitive protein-tyrosine phosphatases

Antioxid. Redox Signal.

Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line

Diabetologia

Nitric oxide, mitochondria and cell death

IUBMB Life

Mitochondrial DNA mutators

Cell Mol. Life Sci.

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

Diabetologia

Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients

Diabetologia

Glucolipotoxicity: fuel excess and beta-cell dysfunction

Review
Cell oxidant stress delivery and cell dysfunction onset in type 2 diabetes