?Cardiovascular risk in healthy men and markers of oxidative stress in diabetic men are associated with common variation in the gene for uncoupling protein 2

Dhamrait, Sukhbir S.; Stephens, Jeffrey W.; Cooper, J.; Acharya, Jayshree; Mani, Ali R.; Moore, Kevin B.; Miller, George; Humphries, Steve E.; Hurel, Steven J.; Montgomery, Hugh

doi:10.1016/j.ehj.2004.01.007

Cited by 99 publications

(88 citation statements)

References 46 publications

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“…A common variant in the promoter (Ϫ866GϾA, rs659366) is associated with higher UCP2 mRNA levels and was associated with reduced insulin secretion or type 2 diabetes in Austrian (16), Italian (17), and Japanese samples (18), as well as with reduction in insulin secretion in healthy adults and post-myocardial infarction survivors (19). In keeping with a role in the control of ROS production, Ϫ866AA homozygotes have also been reported to have higher oxidative stress markers in men with diabetes, greater risk of cardiovascular disease in healthy men (20), and higher carotid atherosclero-sis in asymptomatic women (21), although this allele is associated with a lower rate of neuropathy in patients with type 1 diabetes (22). This may, in part, be attributable to different behavior of the variants in different tissues under different environmental conditions.…”

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confidence: 72%

Variation in the UCP2-UCP3 Gene Cluster Predicts the Development of Type 2 Diabetes in Healthy Middle-Aged Men

et al. 2006

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The impact of the UCP2 ؊866G>A and UCP3 ؊55C>T variants on prospective risk of type 2 diabetes was examined over 15 years in 2,936 healthy middle-aged men (mean age 56 years). Conversion to diabetes (n ‫؍‬ 169) was associated with higher BMI, blood pressure, cholesterol, triglycerides and C-reactive protein. T he rate of mitochondrial oxidative metabolism appears to be important in the development of type 2 diabetes with reduced expression of key genes in oxidative metabolism and mitochondrial function, not only in patients with type 2 diabetes (1) but also in subjects with pre-diabetes, even when glucose tolerance is normal (2). Fuel substrate oxidation, via the respiratory chain, leads to development of a proton gradient across the mitochondrial membrane, which can be dissipated to produce ATP. This gradient can also be dissipated without the production of ATP by uncoupled metabolism, with the release of energy as heat. Therefore, the rate of oxidative metabolism depends not only on ATP requirements but also the extent to which uncoupled fuel substrate oxidation is present (3).Uncoupling protein (UCP)2 and UCP3 are members of a mitochondrial carrier protein superfamily that can facilitate the exchange of substrates across the mitochondrial inner membrane. They show high (ϳ55%) amino acid homology with UCP1 (4), the first in the family to be identified, which occurs in brown adipose tissue. UCP1 plays an important role in nonshivering thermogenesis (5), dissipating the proton gradient by proton transfer across the mitochondrial membrane with the release of heat. The uncoupling of metabolism per se also causes an increase in glycolysis and GLUT4 synthesis and translocation, as well as increased breakdown of fatty acids. This leads to reduced blood glucose and fat mass and improved glucose tolerance (6). The UCP2 and UCP3 genes are located within 8 kb of each other on chromosome 11q13 (7), and the reported association of obesity and diabetes traits (8 -13) with variation in the UCP2-UCP3 gene cluster suggests the importance of this locus in determining risk of these disorders.A substantial role for UCP2 or UCP3 in thermogenesis in humans is unlikely because these proteins are not upregulated by cold, and it has been suggested that the main function of UCP2 is protection from damage caused by reactive oxygen species (ROS) or oxidative stress (14,15). The production of ROS depends, in part, on mitochondrial membrane potential, and reduction of this potential by uncoupling reduces ROS production. In pancreatic ␤-cells, uncoupling by UCP2 has a further effect on glucosestimulated insulin secretion. A reduction in insulin secretion is seen when UCP2 is overexpressed in isolated rat islet cells or human insulinoma cells, and glucose-stimulated insulin secretion is improved in the UCP2 knockout mouse (15). A common variant in the promoter (Ϫ866GϾA, rs659366) is associated with higher UCP2 mRNA levels and was associated with reduced insulin secretion or type 2 diabetes in Austrian (16), Italian (17), and Japanese samples...

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confidence: 72%

Variation in the UCP2-UCP3 Gene Cluster Predicts the Development of Type 2 Diabetes in Healthy Middle-Aged Men

et al. 2006

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“…Human islets isolated from Ϫ866 A/A donors have lower GSIS than those isolated from Ϫ866 G/A heterozygous and G/G homozygous individuals (10). In addition, increased UCP2 expression in individuals with the homozygous Ϫ866 A allele is associated with a reduction in oxidative stress and coronary heart disease (11). These human studies suggest that the var- 1 The abbreviations used are: GSIS, glucose-stimulated insulin secretion; UCP, uncoupling protein; WT, wild type; HFD, high fat diet; FFA, free fatty acids; ROS, reactive oxygen species; ⌬⌿ m , mitochondrial membrane potential; FCCP, carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone; KRBH, Krebs-Ringer-bicarbonate-HEPES; TG, triglycerides; DCF, 2Ј,7Ј-dichlorodihydrofluorescein diacetate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Rh123, rhodamine 123; MnTBAP, Mn(III) tetrakis-(4-benzoic acid) porphyrin; EGFP, enhanced green fluorescent protein; EYFP, enhanced yellow fluorescent protein.…”

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confidence: 99%

Free Fatty Acid-induced β-Cell Defects Are Dependent on Uncoupling Protein 2 Expression

Joseph

Koshkin

Saleh

et al. 2004

Journal of Biological Chemistry

182

162

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Chronic exposure to elevated free fatty acids (lipotoxicity) induces uncoupling protein (UCP2) in the pancreatic ␤-cell, and therefore a causal link between UCP2 and ␤-cell defects associated with obesity may exist. Recently, we showed that lipid treatment in vivo and in vitro in UCP2(؊/؊) mice/islets does not result in any loss in ␤-cell glucose sensitivity. We have now assessed the mechanism of maintained ␤-cell function in UCP2(؊/؊) mice by exposing islets to 0.4 mM palmitate for 48 h. Palmitate treatment increased triglyceride concentrations in wild type (WT) but not UCP2(؊/؊) islets because of higher palmitate oxidation rates in the UCP2(؊/؊) islets. Dispersed ␤-cells from the palmitate-exposed WT islets had reduced glucose-stimulated hyperpolarization of the mitochondrial membrane potential compared with both control WT and palmitate-exposed UCP2(؊/؊) ␤-cells. The glucose-stimulated increases in the ATP/ADP ratio and cytosolic Ca 2؉ are attenuated in palmitate-treated WT but not UCP2(؊/؊) ␤-cells. Exposure to palmitate reduced glucose-stimulated insulin secretion (GSIS) in WT islets, whereas UCP2(؊/؊) islets had enhanced GSIS. Overexpression of recombinant UCP2 but not enhanced green fluorescent protein in ␤-cells resulted in a loss of glucosestimulated hyperpolarization of the mitochondrial membrane potential and GSIS similar to that seen in WT islets exposed to palmitate. Reactive oxygen species (ROS) are known to increase the activity of UCP2. We showed that ROS levels were elevated in control UCP2(؊/؊) islets as compared with WT and UCP2(؊/؊) islets overexpressing UCP2 and that palmitate increased ROS in WT and UCP2(؊/؊) islets overexpressing UCP2 but not in UCP2(؊/؊) islets. Thus, UCP2(؊/؊) islets resisted the toxic effects of palmitate by maintaining glucose-dependent metabolism-secretion coupling. We propose that higher free fatty acid oxidation rates prevent accumulation of triglyceride in UCP2(؊/؊) islets, such accumulation being a phenomenon associated with lipotoxicity.

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“…Patients were recruited from the University College London Diabetes and Cardiovascular Study (UDACS), which has been previously described [18]. Briefly, the pilot sample consists of 1011 consecutive subjects ( [19].…”

Section: Samplesmentioning

confidence: 99%

“…Baseline biochemical measurements (total cholesterol, LDL-cholesterol, HDLcholesterol and triglycerides) were performed within the local hospital accredited chemical pathology laboratory. All experimental protocols and the process for obtaining informed consent were approved by the appropriate institutional review committee [18].…”

Section: Samplesmentioning

confidence: 99%

The -765G>C Cyclooxygenase-2 Promoter Polymorphism is associated with Type 2 Diabetes Mellitus, Low High-density Lipoprotein and Manifest Angina

Rachel¹,

Thomas²

2016

J Diabetes Metab

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Background and Aims: Cycloxygenase-2 (COX-2) catalyses the rate limiting step of prostaglandin biosynthesis. Despite previous studies, it is still unclear whether COX-2 is beneficial or detrimental to cardiovascular risk. The aim of this study was to examine the -765G>C (rs20417) PTGS2 promoter gene variant, which encodes COX-2, in relation to markers of cardiovascular risk in a sample of well-characterised subjects with diabetes mellitus.

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?Cardiovascular risk in healthy men and markers of oxidative stress in diabetic men are associated with common variation in the gene for uncoupling protein 2

Abstract: This study provides the first in vivo evidence of a role for UCP2 in modifying oxidative stress and CHD risk in humans.

Cited by 99 publications

References 46 publications

Variation in the UCP2-UCP3 Gene Cluster Predicts the Development of Type 2 Diabetes in Healthy Middle-Aged Men

Variation in the UCP2-UCP3 Gene Cluster Predicts the Development of Type 2 Diabetes in Healthy Middle-Aged Men

Free Fatty Acid-induced β-Cell Defects Are Dependent on Uncoupling Protein 2 Expression

The -765G>C Cyclooxygenase-2 Promoter Polymorphism is associated with Type 2 Diabetes Mellitus, Low High-density Lipoprotein and Manifest Angina

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