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PMID	17584843 ( )
Title	Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity.
Abstract	It is now widely accepted, given the current weight of experimental evidence, that reactive oxygen species (ROS) contribute to cell and tissue dysfunction and damage caused by glucolipotoxicity in diabetes. The source of ROS in the insulin secreting pancreatic beta-cells and in the cells which are targets for insulin action has been considered to be the mitochondrial electron transport chain. While this source is undoubtably important, we provide additional information and evidence for NADPH oxidase-dependent generation of ROS both in pancreatic beta-cells and in insulin sensitive cells. While mitochondrial ROS generation may be important for regulation of mitochondrial uncoupling protein (UCP) activity and thus disruption of cellular energy metabolism, the NADPH oxidase associated ROS may alter parameters of signal transduction, insulin secretion, insulin action and cell proliferation or cell death. Thus NADPH oxidase may be a useful target for intervention strategies based on reversing the negative impact of glucolipotoxicity in diabetes. Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. philip.newsholme@ucd.ie

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Targets by SciMiner Summary

HUGO ID	Symbol	Target Name	#Occur	ActualStr
6081	INS	insulin	70	insulin \|
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	32	nadph oxidase \|
6125	IRS1	insulin receptor substrate 1	21	IRS-1 \| IRS1 \| insulin receptor substrate 1 \|
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	20	Rac \| Akt \| PKB \| protein kinase b \|
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	12	UCPs \| UCP1 \| UCP \|
6881	MAPK8	mitogen-activated protein kinase 8	12	JNK \| JNK1 \| JNK-mediated \|
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	12	p110 \| phosphatidylinositol 3 kinase \| PI3K \|
6107	PDX1	pancreatic and duodenal homeobox 1	11	PDX-1 \| pdx 1 \|
6871	MAPK1	mitogen-activated protein kinase 1	9	p40 \| MAPK \| p38 \|
12518	UCP2	uncoupling protein 2 (mitochondrial, proton carrier)	9	UCP2 \|
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	8	iNOS \| nitric oxide synthase \|
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	8	p47 \| p47phox \|
6091	INSR	insulin receptor	7	insulin receptor \|
7889	NOX1	NADPH oxidase 1	7	NOX1 \| NOX \|
6126	IRS2	insulin receptor substrate 2	6	IRS2 \| IRS-2 \|
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	4	NOX2 \| gp91phox \|
6204	JUN	jun oncogene	4	c jun \| c-Jun \|
12519	UCP3	uncoupling protein 3 (mitochondrial, proton carrier)	4	UCP3 \|
2577	CYBA	cytochrome b-245, alpha polypeptide	4	p22phox \| p22 \|
4195	GCK	glucokinase (hexokinase 4)	3	glucokinase \|
5960	IKBKB	inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta	3	ikk beta \|
11006	SLC2A2	solute carrier family 2 (facilitated glucose transporter), member 2	3	GLUT-2 \| GLUT2 \|
9393	PRKCA	protein kinase C, alpha	3	protein kinase c \|
1516	CAT	catalase	3	catalase \|
6886	MAPK9	mitogen-activated protein kinase 9	3	SAPK \| JNK2 \|
7891	NOX4	NADPH oxidase 4	3	NOX4 \|
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	3	SOD \| superoxide dismutase \|
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	2	p67phox \| p67 \|
11180	SOD2	superoxide dismutase 2, mitochondrial	2	manganese superoxide dismutase \| MnSOD \|
8979	PIK3R1	phosphoinositide-3-kinase, regulatory subunit 1 (alpha)	2	p85 \|
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	2	TNF-alpha \| tnf alpha \|
7794	NFKB1	nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105)	2	NF-kB \|
990	BCL2	B-cell CLL/lymphoma 2	2	Bcl-2 \| bcl 2 \|
6872	MAPK10	mitogen-activated protein kinase 10	2	JNK3 \|
10436	RPS6KB1	ribosomal protein S6 kinase, 70kDa, polypeptide 1	2	p70 \| p70 s6 kinase \|
19404	NOXO1	NADPH oxidase organizer 1	1	Noxo1 \|
9232	PPARA	peroxisome proliferator-activated receptor alpha	1	PPAR \|
7664	NCK1	NCK adaptor protein 1	1	Nck \|
8800	PDGFB	platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)	1	platelet derived growth factor \|
11277	SPTLC1	serine palmitoyltransferase, long chain base subunit 1	1	serine palmitoyltransferase \|
4623	GSR	glutathione reductase	1	glutathione reductase \|
10668	NOXA1	NADPH oxidase activator 1	1	Noxa1 \|
11184	SORD	sorbitol dehydrogenase	1	sorbitol dehydrogenase \|
8816	PDPK1	3-phosphoinositide dependent protein kinase-1	1	PDK1 \|
11005	SLC2A1	solute carrier family 2 (facilitated glucose transporter), member 1	1	GLUT \|
333	AGT	angiotensinogen (serpin peptidase inhibitor, clade A, member 8)	1	angiotensin ii \|
20603	DHDDS	dehydrodolichyl diphosphate synthase	1	CPT-complex \|
4566	GRB2	growth factor receptor-bound protein 2	1	Grb-2 \|
8799	PDGFA	platelet-derived growth factor alpha polypeptide	1	PDGF \|
7662	NCF4	neutrophil cytosolic factor 4, 40kDa	1	p40phox \|
9395	PRKCB1	protein kinase C, beta 1	1	pkc beta \|
1511	CASP9	caspase 9, apoptosis-related cysteine peptidase	1	caspase 9 \|
7890	NOX3	NADPH oxidase 3	1	NOX3 \|
4141	GAPDH	glyceraldehyde-3-phosphate dehydrogenase	1	glyceraldehyde 3 phosphate dehydrogenase \|

Targets by SciMiner Full list

HUGO ID	Symbol	Name	ActualStr	Score	FlankingText
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	SOD	0.9	The main antioxidant enzymes are superoxide dismutase (SOD), SOD glutathione reductase glutathione peroxidase and catalase
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.2	nitric oxide (NO) NO by inducible nitric oxide synthase (iNOS) iNOS is up-regulated by cytokines and fatty acids subsequently impacting on
20603	DHDDS	dehydrodolichyl diphosphate synthase	CPT-complex	0.3	CPT-complex carnitine palmitoyl transferase complex F-1 6-P fructose-1 6-diphosphate F-6-P fructose-6-phosphate
11006	SLC2A2	solute carrier family 2 (facilitated glucose transporter), member 2	GLUT-2	1.3	carnitine palmitoyl transferase complex F-1 6-P fructose-1 6-diphosphate F-6-P fructose-6-phosphate GLUT-2 glucose transporter-2 GK glucokinase G-6-P glucose-6-phosphate OAA oxaloacetic acid PDX-1
6107	PDX1	pancreatic and duodenal homeobox 1	PDX-1	2.5	GLUT-2 glucose transporter-2 GK glucokinase G-6-P glucose-6-phosphate OAA oxaloacetic acid PDX-1 pancreatic duodenal homeobox gene-1 PFK phosphofructokinase PKC protein kinase C
9232	PPARA	peroxisome proliferator-activated receptor alpha	PPAR	2.5	pancreatic duodenal homeobox gene-1 PFK phosphofructokinase PKC protein kinase C PPAR peroxisome proliferator-activated receptor ROS reactive oxygen species SG secretory granule
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCP	1.1	of reactive oxygen species (ROS) ROS and uncoupling protein (UCP) UCP for the first and second phases of insulin secretion or
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCP	1.1	The production of ROS and activation of UCP are associated with high metabolic flux required to maintain the
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCP	1.1	However as a consequence of sustained ROS production and UCP activation causing excessive H leak ATP levels will fall resulting
6881	MAPK8	mitogen-activated protein kinase 8	JNK	1.8	which induce activation of various stress-activated protein kinases such as JNK p38 and IKK beta
6871	MAPK1	mitogen-activated protein kinase 1	p38	1.3	induce activation of various stress-activated protein kinases such as JNK p38 and IKK beta
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	have been suggested to phosphorylate serine insulin receptor substrate-1 (IRS-1) IRS-1
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.2	to activation of NF kappaB a transcriptional factor that increases iNOS expression and nitric oxide (NO) NO production
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	NO can induce IRS-1 S-nitrosylation
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	Both serine phosphorylation and S-nitrosylation of IRS-1 have been associated with increased proteosome-dependent degradation of signal transduction
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCP	1.1	may be important for regulation of mitochondrial uncoupling protein (UCP) UCP activity and thus disruption of cellular energy metabolism the NADPH
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCPs	1.4	leak or by proton channels known as uncoupling proteins (UCPs) UCPs
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCPs	1.4	Uncoupling agents (for for example UCPs reduce the proton gradient across the mitochondrial inner membrane and
11180	SOD2	superoxide dismutase 2, mitochondrial	MnSOD	1.9	converted to hydrogen peroxide by a manganese superoxide dismutase (MnSOD) MnSOD within mitochondria
11005	SLC2A1	solute carrier family 2 (facilitated glucose transporter), member 1	GLUT	1.3	is transported across the plasma membrane (via via specific transporters GLUT 1 and GLUT2 and is rapidly phosphorylated by a specific
11006	SLC2A2	solute carrier family 2 (facilitated glucose transporter), member 2	GLUT2	1.6	the plasma membrane (via via specific transporters GLUT 1 and GLUT2 and is rapidly phosphorylated by a specific glucokinase with high
7889	NOX1	NADPH oxidase 1	NOX1	1.4	NOX1 NOX2 or NOX3
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	2.0	NOX1 NOX2 or NOX3
7890	NOX3	NADPH oxidase 3	NOX3	0.9	NOX1 NOX2 or NOX3
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91phox	2.8	In the inactive state the integral membrane proteins gp91phox and p22phox constitute the catalytic core of the 'classical' enzyme
2577	CYBA	cytochrome b-245, alpha polypeptide	p22phox	0.8	In the inactive state the integral membrane proteins gp91phox and p22phox constitute the catalytic core of the 'classical' enzyme along with
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	gp91phox	2.8	The essential element gp91phox contains haeme and flavine adenine dinucleotide (FAD), FAD which are
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	p67phox	2.1	The additional proteins p67phox p47phox and p40phox as well as the small GTPases (Rac
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47phox	1.6	The additional proteins p67phox p47phox and p40phox as well as the small GTPases (Rac Rac
7662	NCF4	neutrophil cytosolic factor 4, 40kDa	p40phox	1.3	The additional proteins p67phox p47phox and p40phox as well as the small GTPases (Rac Rac 1 or
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Rac	0.5	p47phox and p40phox as well as the small GTPases (Rac Rac 1 or Rac 2 are required for regulation of the
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Rac	0.5	as well as the small GTPases (Rac Rac 1 or Rac 2 are required for regulation of the NADPH oxidase activity
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	by phosphorylation of several serine or threonine residues of the p47 subunit mainly by PKC promoting the subsequent translocation of the
7891	NOX4	NADPH oxidase 4	NOX4	1.2	In contrast NOX4 is an enigmatic member of the NOX family of ROS-generating
7889	NOX1	NADPH oxidase 1	NOX	1.7	In contrast NOX4 is an enigmatic member of the NOX family of ROS-generating NADPH oxidases
7891	NOX4	NADPH oxidase 4	NOX4	1.2	NOX4 has a wide tissue distribution (kidney, kidney endothelial cells osteoclasts
7889	NOX1	NADPH oxidase 1	NOX	1.7	2 is the major form of ROS generated by this NOX isoform ( Serrander et al 2007
2577	CYBA	cytochrome b-245, alpha polypeptide	p22	0.3	demonstrated increased production of the NADPH oxidase components gp91 and p22 in beta-cells obtained from animal models of type 2 diabetes
7889	NOX1	NADPH oxidase 1	NOX1	1.4	(2003) 2003 reported the expression of NADPH oxidase (NOX1, NOX1 2 or 3 components in rat islets
2577	CYBA	cytochrome b-245, alpha polypeptide	p22	0.3	RT-PCR analysis revealed mRNA expression of gp91 p22 and p47 in beta-cells of isolated rat islets
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	RT-PCR analysis revealed mRNA expression of gp91 p22 and p47 in beta-cells of isolated rat islets
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	Immunohistochemistry of pancreatic sections showed positive staining for p47 in beta-cells from the islets p47 expression was also demonstrated
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	showed positive staining for p47 in beta-cells from the islets p47 expression was also demonstrated in a clonal rat pancreatic beta-cell
7889	NOX1	NADPH oxidase 1	NOX	1.7	Further evidence in support of the rat islet NOX studies published originally by Oliveira et al
7889	NOX1	NADPH oxidase 1	NOX1	1.4	the detection of mRNA for the NADPH oxidase components from NOX1 NOX2 NOX4 including p22 as a membrane associated components and
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	2.0	detection of mRNA for the NADPH oxidase components from NOX1 NOX2 NOX4 including p22 as a membrane associated components and p47
7891	NOX4	NADPH oxidase 4	NOX4	1.2	of mRNA for the NADPH oxidase components from NOX1 NOX2 NOX4 including p22 as a membrane associated components and p47 Noxo1
2577	CYBA	cytochrome b-245, alpha polypeptide	p22	0.3	for the NADPH oxidase components from NOX1 NOX2 NOX4 including p22 as a membrane associated components and p47 Noxo1 (homologue homologue
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	NOX2 NOX4 including p22 as a membrane associated components and p47 Noxo1 (homologue homologue of p47 Noxa1 (homologue homologue of p67
19404	NOXO1	NADPH oxidase organizer 1	Noxo1	1.2	NOX4 including p22 as a membrane associated components and p47 Noxo1 (homologue homologue of p47 Noxa1 (homologue homologue of p67 and
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	a membrane associated components and p47 Noxo1 (homologue homologue of p47 Noxa1 (homologue homologue of p67 and p40 as cytosolic components
10668	NOXA1	NADPH oxidase activator 1	Noxa1	1.2	membrane associated components and p47 Noxo1 (homologue homologue of p47 Noxa1 (homologue homologue of p67 and p40 as cytosolic components of
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	p67	0.3	p47 Noxo1 (homologue homologue of p47 Noxa1 (homologue homologue of p67 and p40 as cytosolic components of rat islets and an
6871	MAPK1	mitogen-activated protein kinase 1	p40	1.3	(homologue homologue of p47 Noxa1 (homologue homologue of p67 and p40 as cytosolic components of rat islets and an insulinoma derived
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	insulinoma derived cell line RINm5F ( Uchizono et al 2006 p47 expression was confirmed by immunohistochemistry in rat islets
6871	MAPK1	mitogen-activated protein kinase 1	p38	1.3	a variety of stress-sensitive intracellular signalling pathways such as NF-kB p38 MAPK JNK/SAPK, JNK SAPK hexosamine and others
6871	MAPK1	mitogen-activated protein kinase 1	MAPK	1.3	variety of stress-sensitive intracellular signalling pathways such as NF-kB p38 MAPK JNK/SAPK, JNK SAPK hexosamine and others
6881	MAPK8	mitogen-activated protein kinase 8	JNK	1.8	stress-sensitive intracellular signalling pathways such as NF-kB p38 MAPK JNK/SAPK, JNK SAPK hexosamine and others
6886	MAPK9	mitogen-activated protein kinase 9	SAPK	2.8	intracellular signalling pathways such as NF-kB p38 MAPK JNK/SAPK, JNK SAPK hexosamine and others
7794	NFKB1	nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105)	NF-kB	0.3	activating a variety of stress-sensitive intracellular signalling pathways such as NF-kB p38 MAPK JNK/SAPK, JNK SAPK hexosamine and others
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.2	For example increased inducible nitric oxide synthase (iNOS) iNOS expression in response to redox-dependent transcription factor NF kappaB activation
8799	PDGFA	platelet-derived growth factor alpha polypeptide	PDGF	1.2	Angiotensin II Thrombin platelet-derived growth factor (PDGF) PDGF and tumour necrosis factor-alpha TNF-alpha are known to increase ROS
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	TNF-alpha	0.8	Thrombin platelet-derived growth factor (PDGF) PDGF and tumour necrosis factor-alpha TNF-alpha are known to increase ROS production in vascular smooth muscle
7889	NOX1	NADPH oxidase 1	NOX	1.7	smooth muscle cells through activation of an isoform of the NOX family NADPH oxidase
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCP	1.1	mitochondrial ROS generation may be important for regulation of mitochondrial UCP activity and thus cellular energy metabolism (see see below the
6881	MAPK8	mitogen-activated protein kinase 8	JNK	1.8	of stress-sensitive serine/threonine serine threonine kinase signalling pathways such as JNK NF-kB p38 MAPK (and and others that in turn phosphorylate
6871	MAPK1	mitogen-activated protein kinase 1	p38	1.3	serine/threonine serine threonine kinase signalling pathways such as JNK NF-kB p38 MAPK (and and others that in turn phosphorylate multiple targets
6871	MAPK1	mitogen-activated protein kinase 1	MAPK	1.3	serine threonine kinase signalling pathways such as JNK NF-kB p38 MAPK (and and others that in turn phosphorylate multiple targets including
7794	NFKB1	nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105)	NF-kB	0.5	stress-sensitive serine/threonine serine threonine kinase signalling pathways such as JNK NF-kB p38 MAPK (and and others that in turn phosphorylate multiple
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	to undergo tyrosine phosphorylation and may accelerate the degradation of IRS-1 offering a plausible explanation for the molecular basis of oxidative
6881	MAPK8	mitogen-activated protein kinase 8	JNK	1.8	data to support an important role for the activation of JNK IKK PKC and perhaps other stress- and inflammation-activated kinases in
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCPs	1.4	The UCPs which have an approximate mass of 32 kDa are members
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCPs	1.4	UCPs are located at the internal membrane of the mitochondria and
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCP	1.1	The uncoupling protein family is characterized by five UCP homologues (UCP1-UCP5), UCP1-UCP5 but UCP2 and UCP3 have a high
12518	UCP2	uncoupling protein 2 (mitochondrial, proton carrier)	UCP2	0.6	family is characterized by five UCP homologues (UCP1-UCP5), UCP1-UCP5 but UCP2 and UCP3 have a high sequence identity with UCP1
12519	UCP3	uncoupling protein 3 (mitochondrial, proton carrier)	UCP3	0.6	family is characterized by five UCP homologues (UCP1-UCP5), UCP1-UCP5 but UCP2 and UCP3 have a high sequence identity with UCP1
12519	UCP3	uncoupling protein 3 (mitochondrial, proton carrier)	UCP3	0.6	characterized by five UCP homologues (UCP1-UCP5), UCP1-UCP5 but UCP2 and UCP3 have a high sequence identity with UCP1
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCP1	1.4	but UCP2 and UCP3 have a high sequence identity with UCP1
12517	UCP1	uncoupling protein 1 (mitochondrial, proton carrier)	UCP1	1.4	It is generally accepted that UCP1 expression and activity is restricted to brown adipose tissue (BAT)
12518	UCP2	uncoupling protein 2 (mitochondrial, proton carrier)	UCP2	0.6	and its physiological role in thermogenesis is well understood whereas UCP2 and UCP3 are more widely distributed but their physiological function
12519	UCP3	uncoupling protein 3 (mitochondrial, proton carrier)	UCP3	0.6	and its physiological role in thermogenesis is well understood whereas UCP2 and UCP3 are more widely distributed but their physiological function
12519	UCP3	uncoupling protein 3 (mitochondrial, proton carrier)	UCP3	0.6	physiological role in thermogenesis is well understood whereas UCP2 and UCP3 are more widely distributed but their physiological function is yet
12518	UCP2	uncoupling protein 2 (mitochondrial, proton carrier)	UCP2	0.6	In pancreatic beta-cells UCP2 expression has been reported and its importance for metabolic regulation
12518	UCP2	uncoupling protein 2 (mitochondrial, proton carrier)	UCP2	0.6	As O 2 are activators of UCP2 activity then H translocation across the mitochondrial inner membrane is
12518	UCP2	uncoupling protein 2 (mitochondrial, proton carrier)	UCP2	0.6	In this way UCP2 has a pivotal role in beta-cell function controlling the ATP/ADP
12518	UCP2	uncoupling protein 2 (mitochondrial, proton carrier)	UCP2	0.6	TCA cycle activity will be high when UCP2 is active as reducing equivalents produced in the cycle are
12518	UCP2	uncoupling protein 2 (mitochondrial, proton carrier)	UCP2	0.6	electron-dependent generation of a proton gradient is quickly dissipated by UCP2 activity
12518	UCP2	uncoupling protein 2 (mitochondrial, proton carrier)	UCP2	0.6	insulin secretion and was associated with excessive O 2 production UCP2 activation decreased mitochondrial membrane potential and ultimately GSIS ( Leahy
12518	UCP2	uncoupling protein 2 (mitochondrial, proton carrier)	UCP2	0.6	Pancreatic islets from UCP2 knockout mice maintained GSIS following chronic hyperglycaemia while chemical removal
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	2.3	This lipid can inhibits phosphatidyl inositol 3-kinase (PI3K), PI3K which in turn results in a block in protein kinase
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	0.8	turn results in a block in protein kinase B (PKB PKB also known as Akt/PKB) Akt PKB activation ( Beeharry et
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.5	in protein kinase B (PKB PKB also known as Akt/PKB) Akt PKB activation ( Beeharry et al 2004
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	0.8	protein kinase B (PKB PKB also known as Akt/PKB) Akt PKB activation ( Beeharry et al 2004
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	2.3	Downstream targets of the PI3K/PKB PI3K PKB pathway involved in survival include GSK-3 ( Pap _amp_
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	0.8	Downstream targets of the PI3K/PKB PI3K PKB pathway involved in survival include GSK-3 ( Pap _amp_ Cooper
990	BCL2	B-cell CLL/lymphoma 2	Bcl-2	1.0	Cooper 1998 caspase-9 ( Cardone et al 1998 and the Bcl-2 family member Bad ( Datta et al 1997
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	involve tyrosine phosphorylation of IR substrates 1 and 2 (IRS-1 IRS-1 and IRS-2 ( Sun et al 1991 Burks _amp_ White
6126	IRS2	insulin receptor substrate 2	IRS-2	1.2	phosphorylation of IR substrates 1 and 2 (IRS-1 IRS-1 and IRS-2 ( Sun et al 1991 Burks _amp_ White 2001
6125	IRS1	insulin receptor substrate 1	IRS1	1.2	bind to the IR is the IRS family of which IRS1 and IRS2 are the main isoforms in insulin-sensitive tissue
6126	IRS2	insulin receptor substrate 2	IRS2	1.2	bind to the IR is the IRS family of which IRS1 and IRS2 are the main isoforms in insulin-sensitive tissue
6126	IRS2	insulin receptor substrate 2	IRS2	1.2	the IR is the IRS family of which IRS1 and IRS2 are the main isoforms in insulin-sensitive tissue
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	2.3	Those molecules include phosphatidylinositol 3-kinase (PI3K), PI3K Nck and Grb-2 of which PI3K seems to be a
7664	NCK1	NCK adaptor protein 1	Nck	0.3	Those molecules include phosphatidylinositol 3-kinase (PI3K), PI3K Nck and Grb-2 of which PI3K seems to be a central
4566	GRB2	growth factor receptor-bound protein 2	Grb-2	0.6	Those molecules include phosphatidylinositol 3-kinase (PI3K), PI3K Nck and Grb-2 of which PI3K seems to be a central insulin signalling
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	2.3	include phosphatidylinositol 3-kinase (PI3K), PI3K Nck and Grb-2 of which PI3K seems to be a central insulin signalling molecule in mediating
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	2.3	PI3K is composed of a catalytic and a regulatory subunit (p110
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	p110	1.3	is composed of a catalytic and a regulatory subunit (p110 p110 and p85 respectively
8979	PIK3R1	phosphoinositide-3-kinase, regulatory subunit 1 (alpha)	p85	0.6	of a catalytic and a regulatory subunit (p110 p110 and p85 respectively
8979	PIK3R1	phosphoinositide-3-kinase, regulatory subunit 1 (alpha)	p85	0.6	As a result of IRS tyrosine phosphorylation the p85 subunit of PI3K binds to the PH domain of IRS1/2,
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	2.3	a result of IRS tyrosine phosphorylation the p85 subunit of PI3K binds to the PH domain of IRS1/2, IRS1 2 leading
6125	IRS1	insulin receptor substrate 1	IRS1	1.2	subunit of PI3K binds to the PH domain of IRS1/2, IRS1 2 leading to an increase in the catalytic activity of
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	p110	1.3	2 leading to an increase in the catalytic activity of p110
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	2.3	A wide range of downstream targets of PI3K have been identified
8816	PDPK1	3-phosphoinositide dependent protein kinase-1	PDK1	1.3	serine/threonine serine threonine kinases such as phosphoinositide-dependent protein kinase (PDK1), PDK1 PKB PKC p70 S6 kinase and glycogen synthase kinase 3
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	0.8	serine threonine kinases such as phosphoinositide-dependent protein kinase (PDK1), PDK1 PKB PKC p70 S6 kinase and glycogen synthase kinase 3 (GSK3)
10436	RPS6KB1	ribosomal protein S6 kinase, 70kDa, polypeptide 1	p70	0.3	kinases such as phosphoinositide-dependent protein kinase (PDK1), PDK1 PKB PKC p70 S6 kinase and glycogen synthase kinase 3 (GSK3) GSK3
6204	JUN	jun oncogene	c-Jun	1.3	peroxide leads to the activation of stress kinases such as c-Jun N-terminal kinase p38 I kappaB kinase and extracellular receptor kinase
6871	MAPK1	mitogen-activated protein kinase 1	p38	1.3	the activation of stress kinases such as c-Jun N-terminal kinase p38 I kappaB kinase and extracellular receptor kinase 1/2 1 2
6871	MAPK1	mitogen-activated protein kinase 1	p38	1.3	IRS proteins or downstream kinase pathways such as NF-kappaB-activating kinases p38 MAPK JNK/SAPK, JNK SAPK PKC ( Fig 4
6871	MAPK1	mitogen-activated protein kinase 1	MAPK	1.3	proteins or downstream kinase pathways such as NF-kappaB-activating kinases p38 MAPK JNK/SAPK, JNK SAPK PKC ( Fig 4
6881	MAPK8	mitogen-activated protein kinase 8	JNK	1.8	downstream kinase pathways such as NF-kappaB-activating kinases p38 MAPK JNK/SAPK, JNK SAPK PKC ( Fig 4
6886	MAPK9	mitogen-activated protein kinase 9	SAPK	2.8	kinase pathways such as NF-kappaB-activating kinases p38 MAPK JNK/SAPK, JNK SAPK PKC ( Fig 4
6125	IRS1	insulin receptor substrate 1	IRS1	1.2	cells are complicated involving increased serine/threonine serine threonine phosphorylation of IRS1 impaired insulin-stimulated redistribution of IRS1 and PI3K between cytosol and
6125	IRS1	insulin receptor substrate 1	IRS1	1.2	serine/threonine serine threonine phosphorylation of IRS1 impaired insulin-stimulated redistribution of IRS1 and PI3K between cytosol and low-density microsomal fraction followed by
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	2.3	threonine phosphorylation of IRS1 impaired insulin-stimulated redistribution of IRS1 and PI3K between cytosol and low-density microsomal fraction followed by a reduced
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.5	cytosol and low-density microsomal fraction followed by a reduced Akt/PKB Akt PKB phosphorylation
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	0.8	and low-density microsomal fraction followed by a reduced Akt/PKB Akt PKB phosphorylation
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	2.3	associate with the insulin receptor and downstream target molecules especially PI3K ( Gual et al 2005 Evans et al 2005 resulting
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.5	et al 2005 resulting in impaired insulin action including Akt/PKB Akt PKB activation
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	0.8	al 2005 resulting in impaired insulin action including Akt/PKB Akt PKB activation
6881	MAPK8	mitogen-activated protein kinase 8	JNK	1.8	The activation of the JNK pathway reduces insulin gene expression and interferes with insulin action
6204	JUN	jun oncogene	c-Jun	1.3	There are three isozymes of c-Jun N-terminal kinase JNK1 JNK2 and JNK3 and only JNK1 has
6881	MAPK8	mitogen-activated protein kinase 8	JNK1	1.8	There are three isozymes of c-Jun N-terminal kinase JNK1 JNK2 and JNK3 and only JNK1 has been shown to
6886	MAPK9	mitogen-activated protein kinase 9	JNK2	2.8	There are three isozymes of c-Jun N-terminal kinase JNK1 JNK2 and JNK3 and only JNK1 has been shown to be
6872	MAPK10	mitogen-activated protein kinase 10	JNK3	1.3	There are three isozymes of c-Jun N-terminal kinase JNK1 JNK2 and JNK3 and only JNK1 has been shown to be
6872	MAPK10	mitogen-activated protein kinase 10	JNK3	1.3	are three isozymes of c-Jun N-terminal kinase JNK1 JNK2 and JNK3 and only JNK1 has been shown to be implicated in
6881	MAPK8	mitogen-activated protein kinase 8	JNK1	1.8	of c-Jun N-terminal kinase JNK1 JNK2 and JNK3 and only JNK1 has been shown to be implicated in type 2 diabetes
6881	MAPK8	mitogen-activated protein kinase 8	JNK1	1.8	Thus it is likely that JNK1 is a crucial mediator of the progression of both insulin
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	It has been reported that serine phosphorylation of IRS-1 inhibits insulin-stimulated tyrosine phosphorylation of IRS-1 leading to an increase
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	that serine phosphorylation of IRS-1 inhibits insulin-stimulated tyrosine phosphorylation of IRS-1 leading to an increase in insulin resistance ( Aguirre et
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	IRS-1 serine 307 phosphorylation was markedly decreased in Ad-DN-JNK-treated mice
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	An increase in IRS-1 tyrosine and Akt/PKB Akt PKB serine 473 phosphorylation was also
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.5	An increase in IRS-1 tyrosine and Akt/PKB Akt PKB serine 473 phosphorylation was also observed in Ad-DN-JNK-treated mice
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	0.8	An increase in IRS-1 tyrosine and Akt/PKB Akt PKB serine 473 phosphorylation was also observed in Ad-DN-JNK-treated mice (
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	Therefore an increase in IRS-1 serine phosphorylation may be closely associated with the development of
6881	MAPK8	mitogen-activated protein kinase 8	JNK	1.8	closely associated with the development of insulin resistance induced by JNK overexpression
6881	MAPK8	mitogen-activated protein kinase 8	JNK	1.8	These results indicate that suppression of the JNK pathway enhances insulin signalling which leads to amelioration of glucose
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	targets including the insulin receptor and IRS proteins such as IRS-1 and IRS-2
6126	IRS2	insulin receptor substrate 2	IRS-2	1.2	the insulin receptor and IRS proteins such as IRS-1 and IRS-2
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	2 O 2 caused an increase in serine phosphorylation of IRS-1 and IRS-2 decreased content of IRS-1 and insulin resistance in
6126	IRS2	insulin receptor substrate 2	IRS-2	1.2	2 caused an increase in serine phosphorylation of IRS-1 and IRS-2 decreased content of IRS-1 and insulin resistance in 3T3-L1 adipocytes
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	in serine phosphorylation of IRS-1 and IRS-2 decreased content of IRS-1 and insulin resistance in 3T3-L1 adipocytes
6107	PDX1	pancreatic and duodenal homeobox 1	PDX-1	2.5	the DNA-binding activity of pancreatic and duodenal homeobox factor-1 (PDX-1) PDX-1
6107	PDX1	pancreatic and duodenal homeobox 1	PDX-1	2.5	PDX-1 is a member of the homeodomain containing transcription factor family
11006	SLC2A2	solute carrier family 2 (facilitated glucose transporter), member 2	GLUT2	1.6	beta-cell function by regulating multiple important beta-cell genes including insulin GLUT2 and glucokinase ( Peers et al 1994 Petersen et al
6107	PDX1	pancreatic and duodenal homeobox 1	PDX-1	2.5	cells or isolated rat islets were exposed to oxidative stress PDX-1 binding to the insulin gene was markedly reduced ( Matsuoka
6881	MAPK8	mitogen-activated protein kinase 8	JNK-mediated	1.8	In addition as a potential mechanism for JNK-mediated PDX-1 inactivation it has been demonstrated that PDX-1 is translocated
6107	PDX1	pancreatic and duodenal homeobox 1	PDX-1	2.5	In addition as a potential mechanism for JNK-mediated PDX-1 inactivation it has been demonstrated that PDX-1 is translocated from
6107	PDX1	pancreatic and duodenal homeobox 1	PDX-1	2.5	mechanism for JNK-mediated PDX-1 inactivation it has been demonstrated that PDX-1 is translocated from the nucleus to the cytoplasm of beta-cell-derived
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.5	It may inhibit insulin signal transduction by inhibiting Akt/PKB Akt PKB translocation to the plasma membrane from the cytosol phosporylation
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	0.8	It may inhibit insulin signal transduction by inhibiting Akt/PKB Akt PKB translocation to the plasma membrane from the cytosol phosporylation and
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.5	plasma membrane from the cytosol phosporylation and activation of Akt/PKB Akt PKB and promoting dephosphorylation (see see Zierath 2007 for comment
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	0.8	membrane from the cytosol phosporylation and activation of Akt/PKB Akt PKB and promoting dephosphorylation (see see Zierath 2007 for comment Indeed
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	cascade leading to phosphorylation of serine/threonine serine threonine sites on IRS-1 and IRS-2 ( Le Marchand-Brustel et al 2003 Powell et
6126	IRS2	insulin receptor substrate 2	IRS-2	1.2	to phosphorylation of serine/threonine serine threonine sites on IRS-1 and IRS-2 ( Le Marchand-Brustel et al 2003 Powell et al 2004
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.2	mice increases the expression of inducible nitric oxide synthase (iNOS) iNOS in skeletal muscle which may provoke S-nitrosylation of the insulin
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	skeletal muscle which may provoke S-nitrosylation of the insulin receptor IRS-1 and Akt/PKB Akt PKB in rat soleus muscle
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	0.5	may provoke S-nitrosylation of the insulin receptor IRS-1 and Akt/PKB Akt PKB in rat soleus muscle
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	0.8	provoke S-nitrosylation of the insulin receptor IRS-1 and Akt/PKB Akt PKB in rat soleus muscle
6125	IRS1	insulin receptor substrate 1	IRS-1	1.5	S-Nitrosylation was associated increased degradation of IRS-1 impaired insulin signalling and subsequent responses ( Carvalho-Filho et al
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	iNOS	2.2	levels of S-nitrosylation associated with increased expression and activity of iNOS has emerged as an important player in the development of
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	ros can be generated through glucose metabolism in mitochondria by electron transport chain etc activity and in the plasma membrane through nadph oxidase nadph ox .
4623	GSR	glutathione reductase	glutathione reductase	1.0	the main antioxidant enzymes are superoxide dismutase sod glutathione reductase glutathione peroxidase and catalase.
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	superoxide dismutase	1.0	the main antioxidant enzymes are superoxide dismutase sod glutathione reductase glutathione peroxidase and catalase.
6081	INS	insulin	insulin	1.0	mechanism of insulin secretion stimulated by glucose and fatty acids in pancreatic beta cells
6081	INS	insulin	insulin	1.0	as a consequence voltage dependent ca channels are opened increasing intracellular ca concentration leading to insulin secretion.
9393	PRKCA	protein kinase C, alpha	protein kinase c	1.0	the nadph oxidase complex in the plasma membrane is activated through protein kinase c pkc which is activated by fatty acid derived signalling molecules.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the nadph oxidase complex in the plasma membrane is activated through protein kinase c pkc which is activated by fatty acid derived signalling molecules.
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	nitric oxide synthase	1.0	the production of nitric oxide no by inducible nitric oxide synthase inos is up regulated by cytokines and fatty acids subsequently impacting on pancreatic beta cell function.
9393	PRKCA	protein kinase C, alpha	protein kinase c	1.0	ate; f 6 p fructose 6 phosphate; glut 2 glucose transporter 2; gk glucokinase; g 6 p glucose 6 phosphate; oaa oxaloacetic acid; pdx 1 pancreatic duodenal homeobox gene 1; pfk phosphofructokinase; pkc protein kinase c; ppar peroxisome proliferator activated receptor; ros reactive oxygen species; sg secretory granule.
6107	PDX1	pancreatic and duodenal homeobox 1	pdx 1	1.0	x carnitine palmitoyl transferase complex; f 1 6 p fructose 1 6 diphosphate; f 6 p fructose 6 phosphate; glut 2 glucose transporter 2; gk glucokinase; g 6 p glucose 6 phosphate; oaa oxaloacetic acid; pdx 1 pancreatic duodenal homeobox gene 1; pfk phosphofructokinase; pkc protein kinase c; ppar peroxisome proliferator activated receptor; ros reactive oxygen species; sg secretory granule.
4195	GCK	glucokinase (hexokinase 4)	glucokinase	1.0	cpt complex carnitine palmitoyl transferase complex; f 1 6 p fructose 1 6 diphosphate; f 6 p fructose 6 phosphate; glut 2 glucose transporter 2; gk glucokinase; g 6 p glucose 6 phosphate; oaa oxaloacetic acid; pdx 1 pancreatic duodenal homeobox gene 1; pfk phosphofructokinase; pkc protein kinase c; ppar peroxisome proliferator activated receptor; ros reacti
6081	INS	insulin	insulin	1.0	the central role of reactive oxygen species ros and uncoupling protein ucp for the first and second phases of insulin secretion or induction of cell death
6081	INS	insulin	insulin	1.0	an increased atp/adp ratio leads to elevation of intracellular ca and the peak of insulin secretion in the first phase a .
6081	INS	insulin	insulin	1.0	the production of ros and activation of ucp are associated with high metabolic flux required to maintain the atp/adp ratio and to sustain insulin secretion for a prolonged period b .
6081	INS	insulin	insulin	1.0	induction of insulin resistance by oxidative stress
5960	IKBKB	inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta	ikk beta	1.0	atty acids ffa lead to an increased production of reactive oxygen species ros and reactive nitrogen species rns which induce activation of various stress activated protein kinases such as jnk p38 and ikk beta.
6125	IRS1	insulin receptor substrate 1	insulin receptor substrate 1	1.0	these kinases have been suggested to phosphorylate serine insulin receptor substrate 1 irs 1 .
5960	IKBKB	inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta	ikk beta	1.0	in addition ikk beta leads to activation of nf kappab a transcriptional factor that increases inos expression and nitric oxide no production.
6081	INS	insulin	insulin	1.0	both serine phosphorylation and s nitrosylation of irs 1 have been associated with increased proteosome dependent degradation of signal transduction associated proteins and suppressed insulin signalling.
6081	INS	insulin	insulin	1.0	these effects result in insulin resistance in the liver skeletal muscle and adipose tissue.
6081	INS	insulin	insulin	1.0	the source of ros in the insulin secreting pancreatic beta cells and in the cells which are targets for insulin action has been considered to be the mitochondrial electron transport chain.
6081	INS	insulin	insulin	1.0	while this source is undoubtably important we provide additional information and evidence for nadph oxidase dependent generation of ros both in pancreatic beta cells and in insulin sensitive cells.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	while this source is undoubtably important we provide additional information and evidence for nadph oxidase dependent generation of ros both in pancreatic beta cells and in insulin sensitive cells.
6081	INS	insulin	insulin	1.0	mportant for regulation of mitochondrial uncoupling protein ucp activity and thus disruption of cellular energy metabolism the nadph oxidase associated ros may alter parameters of signal transduction insulin secretion insulin action and cell proliferation or cell death.
6081	INS	insulin	insulin	1.0	secretion insulin action and cell proliferation or cell death.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	while mitochondrial ros generation may be important for regulation of mitochondrial uncoupling protein ucp activity and thus disruption of cellular energy metabolism the nadph oxidase associated ros may alter parameters of signal transduction insulin secretion insulin action and cell proliferation or cell death.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	thus nadph oxidase may be a useful target for intervention strategies based on reversing the negative impact of glucolipotoxicity in diabetes.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	phagocytic cells of the immune system such as macrophages and neutrophils require a plasma membrane/phagosome associated enzyme complex termed nadph oxidase to generate o 2 which is subsequently used to damage and kill pathogenic organisms.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	however it has now become clear that nadph oxidase is not restricted to the immune system but alternative isoforms may be active in may other cell types as an essential component of redox signalling mechanisms see below for further details .
11180	SOD2	superoxide dismutase 2, mitochondrial	manganese superoxide dismutase	1.0	for example superoxide anions are enzymatically converted to hydrogen peroxide by a manganese superoxide dismutase mnsod within mitochondria.
1516	CAT	catalase	catalase	1.0	a further antioxidant enzyme catalase is the major hydrogen peroxide detoxifying enzyme found exclusively in peroxisomes fig 1 turrens 2003 .
6081	INS	insulin	insulin	1.0	we will specifically discuss oxidative stress in pancreatic beta cells and insulin responsive cells in this review because they are likely to reflect the pathogenic mechanisms associated with the onset of type 2 diabetes mellitus t2dm a disease of considerable socio economic impact
6081	INS	insulin	insulin	1.0	of importance to this article insulin resistance and pancreatic beta cell insufficiency with respect to insulin production are major features in the progression of t2dm bell _amp_ polonsky 2001 ; kahn 2003 .
6081	INS	insulin	insulin	1.0	insulin resistance seems to precede and predict the development of t2dm and is common to the major metabolic tissues and organs including muscle adipose tissue and liver.
6081	INS	insulin	insulin	1.0	recent studies suggest that insulin stimulated muscle glycogen synthesis is the major metabolic pathway for disposing of excess glucose in healthy adults after a meal petersen _amp_ shulman 2002 and thus diverting glucose into anabolic
6081	INS	insulin	insulin	1.0	increased plasma concentration of free fatty acid ffa leads to intramyocellular lipid accumulation in humans and this has also been proposed to play a critical role in initiating and developing insulin resistance and also pancreatic beta cell death mcgarry 2002 ; azevedo martins et al 2006 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	this high risk may be due to i excessive levels of mitochondrial ros generation ii additional ros generation through elevated beta cell nadph oxidase activity see below and iii failure of antioxidant defence.
6081	INS	insulin	insulin	1.0	with respect to t2dm beta cell dysfunction and associated depressed insulin secretion must be evident before hyperglycaemia develops kahn 2003 .
6081	INS	insulin	insulin	1.0	it is important to emphasize at this point that damage induced by ros and/or the failure of antioxidant defence repair and biogenesis in insulin secreting and insulin target cells can contribute to the onset of t2dm and its complications.
6081	INS	insulin	insulin	1.0	y reviews which have emphasized the important role for mitochondrial derived ros we wish to present an additional explanation for ros generation nadph oxidase dependent and subsequent interference in insulin signalling and signal transduction.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	however in contrast to other scholarly reviews which have emphasized the important role for mitochondrial derived ros we wish to present an additional explanation for ros generation nadph oxidase dependent and subsequent interference in insulin signalling and signal transduction.
6081	INS	insulin	insulin	1.0	glucose stimulated insulin secretion gsis as currently understood is summarized in fig. 2 .
4195	GCK	glucokinase (hexokinase 4)	glucokinase	1.0	glucose is transported across the plasma membrane via specific transporters glut 1 and glut2 and is rapidly phosphorylated by a specific glucokinase with high k m for glucose.
6081	INS	insulin	insulin	1.0	this results in depolarization of the plasma membrane influx of extracellular ca a rapid increase in intracellular ca and activation of protein kinases which then mediate exocytosis of insulin newsholme et al 2006 2007 .
9393	PRKCA	protein kinase C, alpha	protein kinase c	1.0	however further increases in intracellular ca can stimulate mitochondrial generation of ros while ca via protein kinase c pkc activation may enhance nadph oxidase dependent generation of ros see below and thus induce oxidative stress and/or apoptosis kruman et al 1998 ; yu et al 2006 ; morgan et al 2007 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	however further increases in intracellular ca can stimulate mitochondrial generation of ros while ca via protein kinase c pkc activation may enhance nadph oxidase dependent generation of ros see below and thus induce oxidative stress and/or apoptosis kruman et al 1998 ; yu et al 2006 ; morgan et al 2007 .
1516	CAT	catalase	catalase	1.0	it is also known that beta cells have relatively low levels of free radical detoxifying and redox regulating enzymes such as superoxide dismutase glutathione peroxidase catalase and thioredoxin.
11179	SOD1	superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))	superoxide dismutase	1.0	it is also known that beta cells have relatively low levels of free radical detoxifying and redox regulating enzymes such as superoxide dismutase glutathione peroxidase catalase and thioredoxin.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the consequence of limited scavenging systems is that that upon ca stimulation of mitochondrial and nadph oxidase systems ros concentrations in beta cells may increase rapidly and so easily reach damaging levels.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	mechanisms of nadph oxidase ros production and antioxidant defences in beta cells
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	however there is an independent mechanism responsible for generation of ros in beta cells which involves activation of a membrane associated enzyme known as nadph oxidase which may contribute to oxidative stress under physiological conditions.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the production of reactive oxygen species for antimicrobial action by professional phagocytic cells e.g neutrophils and macrophages mainly occurs through nadph oxidase activation.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the 'classical' nadph oxidase which has been traditionally associated with cells of the immune system may be an isoform from what is now recognized as a large family e.g.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the additional proteins p67phox p47phox and p40phox as well as the small gtpases rac 1 or rac 2 are required for regulation of the nadph oxidase activity and are located in the cytosol during the resting state babior 1999 2002 2004 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	upon activation the six hetero subunits of the 'classical' nadph oxidase or fewer subunits associated with alternative isoforms form an active oxidase complex in a stimulus dependent manner which produces large amounts of superoxide using nadph as the electron donor hashi
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	thus specific isoforms of the o 2 generating nadph oxidase family i.e nox1 3 are an important source of ros in non phagocytic cells including pancreatic islets.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	it has been reported that nutrients such as high levels of glucose and palmitate stimulated cultured aortic smooth and endothelial cell phagocyte like nadph oxidase via pkc dependent activation inoguchi et al 2000 while a more recent study demonstrated increased production of the nadph oxidase components gp91 and p22 in beta cells obtained from animal models of
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	via pkc dependent activation inoguchi et al 2000 while a more recent study demonstrated increased production of the nadph oxidase components gp91 and p22 in beta cells obtained from animal models of type 2 diabetes nakayama et al 2005 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	2003 reported the expression of nadph oxidase nox1 2 or 3 components in rat islets.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	interestingly glucose also stimulated ros production in cultured vascular cells and ros production occurred through pkc dependent activation of nadph oxidase inoguchi et al 2000 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the precise mechanisms for participation of pkc in the activation of nadph oxidase and the physiological role of this enzyme in pancreatic beta cells still remain to be fully established.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	2007 was provided in a recent paper that described the detection of mrna for the nadph oxidase components from nox1 nox2 nox4 including p22 as a membrane associated components and p47 noxo1 homologue of p47 noxa1 homologue of p67 and p40 as cytosolic components of rat islets and an insulinoma
6081	INS	insulin	insulin	1.0	in addition recent data in vitro and in vivo suggest that activation of the same or similar stress pathways results in insulin resistance and impaired insulin secretion.
6081	INS	insulin	insulin	1.0	g the hyperglycaemia and ffa induced increases in ros and oxidative stress activation of stress sensitive pathways and the eventual development of not only the late complications of diabetes but also insulin resistance and beta cell dysfunction.
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	nitric oxide synthase	1.0	for example increased inducible nitric oxide synthase inos expression in response to redox dependent transcription factor nf kappab activation is a specific example of ros regulated gene expression.
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	tnf alpha	1.0	angiotensin ii thrombin platelet derived growth factor pdgf and tumour necrosis factor alpha tnf alpha are known to increase ros production in vascular smooth muscle cells through activation of an isoform of the nox family nadph oxidase.
8800	PDGFB	platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)	platelet derived growth factor	1.0	angiotensin ii thrombin platelet derived growth factor pdgf and tumour necrosis factor alpha tnf alpha are known to increase ros production in vascular smooth muscle cells through activation of an isoform of the nox family nadph oxidase.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	platelet derived growth factor pdgf and tumour necrosis factor alpha tnf alpha are known to increase ros production in vascular smooth muscle cells through activation of an isoform of the nox family nadph oxidase.
333	AGT	angiotensinogen (serpin peptidase inhibitor, clade A, member 8)	angiotensin ii	1.0	angiotensin ii thrombin platelet derived growth factor pdgf and tumour necrosis factor alpha tnf alpha are known to increase ros production in vascular smooth muscle cells through activation of an isoform of the no
1516	CAT	catalase	catalase	1.0	however since expression levels of antioxidant enzymes such as catalase and glutathione peroxidase are very low in beta cells compared to other tissues lenzen et al 1996 ; tiedge et al 1997 beta cells are thought of as targets for oxidative stress mediated tissue damage
6081	INS	insulin	insulin	1.0	there is strong evidence for oxidative stress dependent changes in intracellular signalling resulting in chronic inflammation and insulin resistance in vivo as reported by others brownlee 2005 ; fridlyand _amp_ philipson 2005 ; katakam et al 2005 .
6081	INS	insulin	insulin	1.0	n may be important for regulation of mitochondrial ucp activity and thus cellular energy metabolism see below the nadph oxidase associated ros may specifically alter parameters of signal transduction insulin secretion insulin action and cell proliferation or cell death.
6081	INS	insulin	insulin	1.0	secretion insulin action and cell proliferation or cell death.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	while mitochondrial ros generation may be important for regulation of mitochondrial ucp activity and thus cellular energy metabolism see below the nadph oxidase associated ros may specifically alter parameters of signal transduction insulin secretion insulin action and cell proliferation or cell death.
6091	INSR	insulin receptor	insulin receptor	1.0	ve molecules can trigger the activation of stress sensitive serine/threonine kinase signalling pathways such as jnk nf kb p38 mapk and others that in turn phosphorylate multiple targets including the insulin receptor and irs proteins.
6081	INS	insulin	insulin	1.0	ylation of irs reduces its ability to undergo tyrosine phosphorylation and may accelerate the degradation of irs 1 offering a plausible explanation for the molecular basis of oxidative stress induced insulin resistance.
6081	INS	insulin	insulin	1.0	there are convincing data to support an important role for the activation of jnk ikk pkc and perhaps other stress and inflammation activated kinases in the pathogenesis of oxidative stress induced insulin resistance and suggest that they might be attractive pharmacological targets to increase insulin sensitivity.
6081	INS	insulin	insulin	1.0	resistance and suggest that they might be attractive pharmacological targets to increase insulin sensitivity.
6081	INS	insulin	insulin	1.0	xidants against oxidative stress induced damage might lead to the discovery of additional pharmacological targets for novel therapies to prevent reverse or delay the onset of oxidative stress induced insulin resistance.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	beta cell protection through suppression of nadph oxidase
6081	INS	insulin	insulin	1.0	these observations indicate important long term effects of alanine in regulating gene expression secretory function and the integrity of insulin secreting cells.
11184	SORD	sorbitol dehydrogenase	sorbitol dehydrogenase	1.0	hyperglycaemia elevates the enzymatic convertion of glucose to the polyalcohol sorbitol which is metabolized to fructose by sorbitol dehydrogenase increasing the nadh/nad ratio.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the increase of o 2 production in pancreatic beta cells in response to elevated glucose metabolism may result in activation of nadph oxidase via increased lipid derived signalling molecules such as dag and subsequent activation of pkc as described above morgan et al 2007 .
4141	GAPDH	glyceraldehyde-3-phosphate dehydrogenase	glyceraldehyde 3 phosphate dehydrogenase	1.0	hyperglycaemia leads to overproduction of superoxide that significantly inhibits glyceraldehyde 3 phosphate dehydrogenase activity du et al 2000 and activates the pathways related to hyperglycaemia induced damage by diverting glycolytic metabolites to hexosamine synthesis.
6081	INS	insulin	insulin	1.0	initially insulin secretion is not impaired as only the first phase of insulin secretion is fully dependent on the atp/adp ratio.
6081	INS	insulin	insulin	1.0	however ca and mitochondrially derived coupling factors such as glutamate citrate acyl coa and nadph are required for the sustained second phase of insulin secretion which is much less responsive to atp/adp ratio change krausz et al 1987 .
6081	INS	insulin	insulin	1.0	several studies have indicated that chronic hyperglycaemia impaired insulin secretion and was associated with excessive o 2 production ucp2 activation decreased mitochondrial membrane potential and ultimately gsis leahy et al 1992 ; hribal et al 2003 ; mcquaid et al 2006 .
6081	INS	insulin	insulin	1.0	after acute exposure both stimulate insulin secretion.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	impairment of beta cell function may involve excessive generation of ros through increased nadph oxidase activity morgan et al 2007 .
6081	INS	insulin	insulin	1.0	this would subsequently affect mitochondrial function reducing atp production and so insulin secretion brownlee 2003 ; morgan et al 2007 .
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	protein kinase b	1.0	this lipid can inhibits phosphatidyl inositol 3 kinase pi3k which in turn results in a block in protein kinase b pkb also known as akt/pkb activation beeharry et al 2004 .
990	BCL2	B-cell CLL/lymphoma 2	bcl 2	1.0	downstream targets of the pi3k/pkb pathway involved in survival include gsk 3 pap _amp_ cooper 1998 caspase 9 cardone et al 1998 and the bcl 2 family member bad datta et al 1997 .
1511	CASP9	caspase 9, apoptosis-related cysteine peptidase	caspase 9	1.0	downstream targets of the pi3k/pkb pathway involved in survival include gsk 3 pap _amp_ cooper 1998 caspase 9 cardone et al 1998 and the bcl 2 family member bad datta et al 1997 .
6081	INS	insulin	insulin	1.0	ceramide generation is further discussed in the context of insulin resistance as described below.
6081	INS	insulin	insulin	1.0	insulin resistance and ros physiological adaptation to protection from oxidative stress
6081	INS	insulin	insulin	1.0	insulin resistance plays a central role in the development of several metabolic abnormalities and diseases such as obesity type 2 diabetes mellitus and the metabolic syndrome petersen _amp_ shulman 2006 ; hi
6081	INS	insulin	insulin	1.0	the high degree of oxidative stress has been postulated to play an important role in decreasing insulin responsiveness evans et al 2003 ; urakawa et al 2003 .
6091	INSR	insulin receptor	insulin receptor	1.0	normally glucose flux through glycolysis is stimulated following insulin receptor activation in insulin sensitive tissues such as muscle and adipose tissue; this leads to increased ros production when the reducing equivalent supply to the respiratory chain is increased by glucose
6081	INS	insulin	insulin	1.0	however insulin resistance should lead to an inhibition of insulin action and to decreased insulin dependent glucose uptake.
6081	INS	insulin	insulin	1.0	receptor ir beta subunit which contains an intrinsic tyrosine kinase activity undergoes tyrosyl autophosphorylation and is activated after insulin binding.
6091	INSR	insulin receptor	insulin receptor	1.0	insulin resistance at the molecular level may be mediated by inhibition of signal transduction at the apex of the signalling pathway which involves the insulin receptor ir beta subunit which contains an intrinsic tyrosine kinase activity undergoes tyrosyl autophosphorylation and is activated after insulin binding.
6081	INS	insulin	insulin	1.0	the major early steps of the insulin signalling pathway involve tyrosine phosphorylation of ir substrates 1 and 2 irs 1 and irs 2 sun et al 1991 ; burks _amp_ white 2001 .
6081	INS	insulin	insulin	1.0	the main docking proteins to bind to the ir is the irs family of which irs1 and irs2 are the main isoforms in insulin sensitive tissue.
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	phosphatidylinositol 3 kinase	1.0	those molecules include phosphatidylinositol 3 kinase pi3k nck and grb 2 of which pi3k seems to be a central insulin signalling molecule in mediating the metabolic effect of insulin.
6081	INS	insulin	insulin	1.0	those molecules include phosphatidylinositol 3 kinase pi3k nck and grb 2 of which pi3k seems to be a central insulin signalling molecule in mediating the metabolic effect of insulin.
10436	RPS6KB1	ribosomal protein S6 kinase, 70kDa, polypeptide 1	p70 s6 kinase	1.0	among them are serine/threonine kinases such as phosphoinositide dependent protein kinase pdk1 pkb pkc p70 s6 kinase and glycogen synthase kinase 3 gsk3 .
6204	JUN	jun oncogene	c jun	1.0	exposure of different cell lines to micromolar concentrations of hydrogen peroxide leads to the activation of stress kinases such as c jun n terminal kinase p38 i kappab kinase and extracellular receptor kinase 1/2.
6081	INS	insulin	insulin	1.0	this activation is accompanied by a down regulation of the cellular response to insulin insulin resistance leading to a reduced ability of insulin to promote glucose uptake and glycogen lipid and protein synthesis tanti et al 1994 ; kanety et al 1995 ; hotamisligil et al 1996 ; tirosh et al 1999 ; maddux et al 2001 ; evans et al 2003 ; ogihara
6081	INS	insulin	insulin	1.0	there are several major stress sensitive kinases that when activated are likely to be involved in attenuating insulin signalling via effects on irs proteins or downstream kinase pathways such as nf kappab activating kinases p38 mapk jnk/sapk pkc fig 4 .
6081	INS	insulin	insulin	1.0	the oxidative stress associated mechanisms leading to impaired insulin signalling in cells are complicated involving increased serine/threonine phosphorylation of irs1 impaired insulin stimulated redistribution of irs1 and pi3k between cytosol and low density microsomal fraction followed by a reduced akt/pkb phosphorylation.
6081	INS	insulin	insulin	1.0	receptor and downstream target molecules especially pi3k gual et al 2005 ; evans et al 2005 resulting in impaired insulin action including akt/pkb activation.
6091	INSR	insulin receptor	insulin receptor	1.0	the serine/threonine phosphorylated forms of irs molecules are less able to associate with the insulin receptor and downstream target molecules especially pi3k gual et al 2005 ; evans et al 2005 resulting in impaired insulin action including akt/pkb activation.
6081	INS	insulin	insulin	1.0	the activation of the jnk pathway reduces insulin gene expression and interferes with insulin action.
6204	JUN	jun oncogene	c jun	1.0	there are three isozymes of c jun n terminal kinase jnk1 jnk2 and jnk3 and only jnk1 has been shown to be implicated in type 2 diabetes hirosumi et al 2002 .
6081	INS	insulin	insulin	1.0	thus it is likely that jnk1 is a crucial mediator of the progression of both insulin resistance and beta cell dysfunction found in type 2 diabetes.
6081	INS	insulin	insulin	1.0	it has been reported that serine phosphorylation of irs 1 inhibits insulin stimulated tyrosine phosphorylation of irs 1 leading to an increase in insulin resistance aguirre et al 2000 2002 .
6081	INS	insulin	insulin	1.0	therefore an increase in irs 1 serine phosphorylation may be closely associated with the development of insulin resistance induced by jnk overexpression.
6081	INS	insulin	insulin	1.0	these results indicate that suppression of the jnk pathway enhances insulin signalling which leads to amelioration of glucose tolerance.
6081	INS	insulin	insulin	1.0	additional stress sensitive kinases that are reported to be involved in irs mediated insulin resistance include the mammalian target of rapamycin mtor mussig et al 2005 several isozymes of pkc including pkc beta and pkc epsilon ishizuka et al 2004 ; dey et al 2005 ; greene et al 2006 and the
5960	IKBKB	inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta	ikk beta	1.0	resistance include the mammalian target of rapamycin mtor mussig et al 2005 several isozymes of pkc including pkc beta and pkc epsilon ishizuka et al 2004 ; dey et al 2005 ; greene et al 2006 and the ikk beta nf kappab signalling cascades gao et al 2002 .
9395	PRKCB1	protein kinase C, beta 1	pkc beta	1.0	itional stress sensitive kinases that are reported to be involved in irs mediated insulin resistance include the mammalian target of rapamycin mtor mussig et al 2005 several isozymes of pkc including pkc beta and pkc epsilon ishizuka et al 2004 ; dey et al 2005 ; greene et al 2006 and the ikk beta nf kappab signalling cascades gao et al 2002 .
6091	INSR	insulin receptor	insulin receptor	1.0	once activated these kinases are able to phosphorylate multiple targets including the insulin receptor and irs proteins such as irs 1 and irs 2.
6081	INS	insulin	insulin	1.0	to date only one published study has directly evaluated the effects of oxidative stress on irs serine phosphorylation and irs protein content in the context of cellular insulin resistance bloch damti et al 2006 .
6081	INS	insulin	insulin	1.0	consistent with the molecular basis of oxidative stress induced insulin resistance proposed here these investigators found that oxidative stress h 2 o 2 caused an increase in serine phosphorylation of irs 1 and irs 2 decreased content of irs 1 and insulin resistance in 3
6081	INS	insulin	insulin	1.0	resistance proposed here these investigators found that oxidative stress h 2 o 2 caused an increase in serine phosphorylation of irs 1 and irs 2 decreased content of irs 1 and insulin resistance in 3t3 l1 adipocytes.
6081	INS	insulin	insulin	1.0	the reduction of insulin gene expression and secretion by oxidative stress has been correlated with changes in the dna binding activity of pancreatic and duodenal homeobox factor 1 pdx 1 .
6107	PDX1	pancreatic and duodenal homeobox 1	pdx 1	1.0	the reduction of insulin gene expression and secretion by oxidative stress has been correlated with changes in the dna binding activity of pancreatic and duodenal homeobox factor 1 pdx 1 .
6107	PDX1	pancreatic and duodenal homeobox 1	pdx 1	1.0	pdx 1 is a member of the homeodomain containing transcription factor family miller et al 1994 ; ohlsson et al 1993 .
6081	INS	insulin	insulin	1.0	b et al 2003 ; miyatsuka et al 2003 ; taniguchi et al 2003 ; cao et al 2004 ; kaneto et al 2005 and in maintaining normal beta cell function by regulating multiple important beta cell genes including insulin glut2 and glucokinase peers et al 1994 ; petersen et al 1994 ; waeber et al 1996 ; watada et al 1996 ; ahlgren et al 1998 ; brissova et al 2002 ; chakrabarti et al 2002 ; kulkarni et al 2004 .
4195	GCK	glucokinase (hexokinase 4)	glucokinase	1.0	atsuka et al 2003 ; taniguchi et al 2003 ; cao et al 2004 ; kaneto et al 2005 and in maintaining normal beta cell function by regulating multiple important beta cell genes including insulin glut2 and glucokinase peers et al 1994 ; petersen et al 1994 ; waeber et al 1996 ; watada et al 1996 ; ahlgren et al 1998 ; brissova et al 2002 ; chakrabarti et al 2002 ; kulkarni et al 2004 .
6081	INS	insulin	insulin	1.0	when hit cells or isolated rat islets were exposed to oxidative stress pdx 1 binding to the insulin gene was markedly reduced matsuoka et al 1997 ; kaneto et al 2001 .
6107	PDX1	pancreatic and duodenal homeobox 1	pdx 1	1.0	when hit cells or isolated rat islets were exposed to oxidative stress pdx 1 binding to the insulin gene was markedly reduced matsuoka et al 1997 ; kaneto et al 2001 .
6107	PDX1	pancreatic and duodenal homeobox 1	pdx 1	1.0	in addition as a potential mechanism for jnk mediated pdx 1 inactivation it has been demonstrated that pdx 1 is translocated from the nucleus to the cytoplasm of beta cell derived hit cells in response to oxidative stress kawamori et al 2003 .
6081	INS	insulin	insulin	1.0	increased plasma concentration of ffa and increased intramyocellular lipid content are typically associated with insulin resistant states including t2dm.
11277	SPTLC1	serine palmitoyltransferase, long chain base subunit 1	serine palmitoyltransferase	1.0	palmitoyl coa and serine are required for the initial rate determining step for ceramide synthesis catalysed by serine palmitoyltransferase spt .
6081	INS	insulin	insulin	1.0	it may inhibit insulin signal transduction by inhibiting akt/pkb translocation to the plasma membrane from the cytosol phosporylation and activation of akt/pkb and promoting dephosphorylation see zierath 2007 for comment i
6081	INS	insulin	insulin	1.0	phosporylation and activation of akt/pkb and promoting dephosphorylation see zierath 2007 for comment indeed evidence for ceramide as a common intermediate linking nutrient excess to the induction of insulin resistance in rodents has recently been published holland et al 2007 .
6081	INS	insulin	insulin	1.0	alternatively lipid induced insulin resistance could be due to ffa providing reducing equivalents for the electron transport chain leading to increased ros production.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	we suggest that saturated fatty acids can stimulate both the expression and the activity of nadph oxidase newsholme et al 2007 ; morgan et al 2007 .
6091	INSR	insulin receptor	insulin receptor	1.0	in addition diet induced obesity in mice increases the expression of inducible nitric oxide synthase inos in skeletal muscle which may provoke s nitrosylation of the insulin receptor irs 1 and akt/pkb in rat soleus muscle.
7873	NOS2A	nitric oxide synthase 2A (inducible, hepatocytes)	nitric oxide synthase	1.0	in addition diet induced obesity in mice increases the expression of inducible nitric oxide synthase inos in skeletal muscle which may provoke s nitrosylation of the insulin receptor irs 1 and akt/pkb in rat soleus muscle.
6081	INS	insulin	insulin	1.0	s nitrosylation was associated increased degradation of irs 1 impaired insulin signalling and subsequent responses carvalho filho et al 2005 fig 4 .
6081	INS	insulin	insulin	1.0	indeed elevated levels of s nitrosylation associated with increased expression and activity of inos has emerged as an important player in the development of insulin resistance in muscle.
6091	INSR	insulin receptor	insulin receptor	1.0	ros can induce inactivation of the signalling pathway between the insulin receptor and the glucose transporter system leading to the onset of insulin resistance in t2dm.
6081	INS	insulin	insulin	1.0	comparing metabolic pathways of gsis and ros production in the beta cell suggests that secretagogues causing increased insulin secretion by the gsis mechanism can also lead to increased ros production via mitochondrial and nadph oxidase mechanisms.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	hways of gsis and ros production in the beta cell suggests that secretagogues causing increased insulin secretion by the gsis mechanism can also lead to increased ros production via mitochondrial and nadph oxidase mechanisms.
6081	INS	insulin	insulin	1.0	this should lead to activation of oxidative stress concomitantly with stimulation of insulin secretion.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	as nadph oxidase is expressed at relatively high levels in the islet beta cell relative to other islet cells any future therapies based on targeting nadph oxidase in the islet and ros production may be beneficial for maintaining beta cell integrity in the difficult environment of nutrient oversupply and immune challenge.