Uncoupling protein-2: evidence for its function as a metabolic regulator

Saleh, Monique C.; Wheeler, Michael B.; Chan, Catherine B.

doi:10.1007/s00125-001-0737-x

Cited by 88 publications

(58 citation statements)

References 70 publications

(111 reference statements)

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“…24 In nature, ROS production is decreased by uncoupling of the respiratory chain that reduces the proton electrochemical gradient. 25 There are three major isoforms of uncoupling proteins, UCP-1 to -3, which belong to a family of inner mitochondrial membrane proteins that are believed to control several aspects of mitochondrial function, including ROS generation, fatty acid homeostasis, and mitochondrial biogenesis. 26 These isoforms have similarities in structure, but different tissue expressions in mammals.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of uncoupling protein-2 by genipin exacerbates diabetes-induced kidney proximal tubular cells apoptosis

Chen

Tang

et al. 2014

Renal Failure

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Renal tubular epithelial cell injury is a major pathological event that contributes to the development of diabetic kidney disease (DKD). Uncoupling protein-2 (UCP2), a mitochondrial membrane protein, has been reported to participate in the regulation of reactive oxygen species (ROS) generation, which contributes to tubular cell apoptosis induced by hyperglycemia. In this study, we found that genipin, a UCP2 inhibitor, dramatically boosted oxidative stress, attenuated antioxidative capacity, and exacerbated cell apoptosis accompanied with caspase-3 activation in rat renal proximal tubular cells (NRK-52E) incubated with high glucose. The present study results suggest that manipulation of UCP2 could be important in the prevention of oxidative stress damage in renal tubular epithelial cells induced by hyperglycemia in vitro.

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Section: Discussionmentioning

confidence: 99%

Downregulation of uncoupling protein-2 by genipin exacerbates diabetes-induced kidney proximal tubular cells apoptosis

Chen

Tang

et al. 2014

Renal Failure

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“…In particular, the increase of ATP/ADP ratio tightly associates to glucose-induced insulin granule release [25,26]. In addition to mitochondrial glucose oxidation, ATP synthesis and ATP/ADP ratio are regulated by uncoupling protein-2 (UCP-2) expression [27][28][29][30]. UCP-2 is a member of a family of proteins located in the mitochondrial inner membrane, which act as proton channels uncoupling mitochondrial oxidative phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients

et al. 2005

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Aims/hypothesis: Little information is available on the insulin release properties of pancreatic islets isolated from type 2 diabetic subjects. Since mitochondria represent the site where important metabolites that regulate insulin secretion are generated, we studied insulin release as well as mitochondrial function and morphology directly in pancreatic islets isolated from type 2 diabetic patients. Methods: Islets were prepared by collagenase digestion and density gradient purification, and insulin secretion in response to glucose and arginine was assessed by the batch incubation method. Adenine nucleotides, mitochondrial membrane potential, the expression of UCP-2, complex I and complex V of the respiratory chain, and nitrotyrosine levels were evaluated and correlated with insulin secretion. Results: Compared to control islets, diabetic islets showed reduced insulin secretion in response to glucose, and this defect was associated with lower ATP levels, a lower ATP/ADP ratio and impaired hyperpolarization of the mitochondrial membrane. Increased protein expression of UCP-2, complex I and complex V of the respiratory chain, and a higher level of nitrotyrosine were also found in type 2 diabetic islets. Morphology studies showed that control and diabetic beta cells had a similar number of mitochondria; however, mitochondrial density volume was significantly higher in type 2 diabetic beta cells. Conclusions/ interpretation: In pancreatic beta cells from type 2 diabetic subjects, the impaired secretory response to glucose is associated with a marked alteration of mitochondrial function and morphology. In particular, UCP-2 expression is increased (probably due to a condition of fuel overload), which leads to lower ATP, decreased ATP/ADP ratio, with consequent reduction of insulin release.

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“…Both systemically, and at the cellular level, energy metabolism is controlled by a large variety of enzymatic and non-enzymatic proteins. Uncoupling protein-2 (UCP2) is a member of the mitochondrial transporter superfamily that uncouples ATP production from mitochondrial respiration, thereby possibly dissipating energy as heat and affecting the efficiency of energy metabolism [1]. UCP2 also negatively regulates insulin secretion and may be an important link between obesity, beta cell dysfunction and type 2 diabetes [2].…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians

Kovacs

Hanson

et al. 2005

Diabetologia

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Aims/hypothesis: Uncoupling protein-2 (UCP2) is thought to play a role in insulin secretion and the development of obesity. In this study, we investigated the effects of genetic variation in UCP2 on type 2 diabetes and obesity, as well as on metabolic phenotypes related to these diseases, in Pima Indians. Methods: The coding and untranslated regions of UCP2, and approximately 1 kb of the 5′ upstream region, were sequenced in DNA samples taken from 83 extremely obese Pima Indians who were not first-degree relatives. Results: Five variants were identified: (1) a −866G/A in the 5′ upstream region; (2) a G/ A in exon 2; (3) a C/T resulting in an Ala55Val substitution in exon 4; and (4, 5) two insertion/deletions (ins/del; 45-bp and 3-bp) in the 3′ untranslated region. Among the 83 subjects whose DNA was sequenced, the −866G/A was in complete genotypic concordance with the Ala55Val and the 3-bp ins/del polymorphism. The G/A polymorphism in exon 2 was extremely rare. To capture the common variation in this gene for association analyses, the −866G/A variant (as a representative of Ala55Val and the 3-bp ins/ del polymorphism) and the 45-bp ins/del were also genotyped for 864 full-blooded Pima Indians. Neither of these variants was associated with type 2 diabetes or body mass index. However, in a subgroup of 185 subjects who had undergone detailed metabolic measurements, these variants were associated with 24-h energy expenditure as measured in a human metabolic chamber (p=0.007 for the 45-bp ins/del and p=0.03 for the −866G/A after adjusting for age, sex, family membership, fat-free mass and fat mass). Conclusions/interpretation: Our data indicate that variation in UCP2 may play a role in energy metabolism, but this gene does not contribute significantly to the aetiology of type 2 diabetes and/or obesity in Pima Indians.

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Uncoupling protein-2: evidence for its function as a metabolic regulator

Cited by 88 publications

References 70 publications

Downregulation of uncoupling protein-2 by genipin exacerbates diabetes-induced kidney proximal tubular cells apoptosis

Downregulation of uncoupling protein-2 by genipin exacerbates diabetes-induced kidney proximal tubular cells apoptosis

Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients

Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians

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