Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2019

Open Access 01-12-2019 | Type 2 Diabetes | Original investigation

Circulating levels of mitochondrial uncoupling protein 2, but not prohibitin, are lower in humans with type 2 diabetes and correlate with brachial artery flow-mediated dilation

Authors: Mamatha Kakarla, Venkata K. Puppala, Sudhi Tyagi, Amberly Anger, Kathryn Repp, Jingli Wang, Rong Ying, Michael E. Widlansky

Published in: Cardiovascular Diabetology | Issue 1/2019

Login to get access

Abstract

Background

Excessive reactive oxygen species from endothelial mitochondria in type 2 diabetes individuals (T2DM) may occur through multiple related mechanisms, including production of mitochondrial reactive oxygen species (mtROS), inner mitochondrial membrane (Δψm) hyperpolarization, changes in mitochondrial mass and membrane composition, and fission of the mitochondrial networks. Inner mitochondrial membrane proteins uncoupling protein-2 (UCP2) and prohibitin (PHB) can favorably impact mtROS and mitochondrial membrane potential (Δψm). Circulating levels of UCP2 and PHB could potentially serve as biomarker surrogates for vascular health in patients with and without T2DM.

Methods

Plasma samples and data from a total of 107 individuals with (N = 52) and without T2DM (N = 55) were included in this study. Brachial artery flow mediated dilation (FMD) was measured by ultrasound. ELISA was performed to measure serum concentrations of PHB1 and UCP2. Mitochondrial membrane potential was measured from isolated leukocytes using JC-1 dye.

Results

Serum UCP2 levels were significantly lower in T2DM subjects compared to control subjects (3.01 ± 0.34 vs. 4.11 ± 0.41 ng/mL, P = 0.04). There were no significant differences in levels of serum PHB. UCP2 levels significantly and positively correlated with FMDmm (r = 0.30, P = 0.03) in T2DM subjects only and remained significant after multivariable adjustment. Within T2DM subjects, serum PHB levels were significantly and negatively correlated with UCP2 levels (ρ = − 0.35, P = 0.03).

Conclusion

Circulating UCP2 levels are lower in T2DM patients and correlate with endothelium-dependent vasodilation in conduit vessels. UCP2 could be biomarker surrogate for overall vascular health in patients with T2DM and merits additional investigation.
Literature
1.
2.
Association AD. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(Suppl 1):S62.CrossRef
3.
Cersosimo E, DeFronzo RA. Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab Res Rev. 2006;22(6):423–36.PubMedCrossRef
4.
Baron AD. Insulin resistance and vascular function. J Diabetes Complic. 2002;16(1):92–102.CrossRef
5.
Zhang DX, Gutterman DD. Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol. 2007;292(5):H2023–31.PubMedCrossRef
6.
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20.PubMedCrossRef
7.
Kizhakekuttu TJ, Wang J, Dharmashankar K, Ying R, Gutterman DD, Vita JA, Widlansky ME. Adverse alterations in mitochondrial function contribute to type 2 diabetes mellitus-related endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol. 2012;32(10):2531–9.PubMedPubMedCentralCrossRef
8.
Tanner MJ, Wang J, Ying R, Suboc TB, Malik M, Couillard A, Branum A, Puppala V, Widlansky ME. Dynamin-related protein 1 mediates low glucose-induced endothelial dysfunction in human arterioles. Am J Physiol Heart Circ Physiol. 2017;312(3):H515–27.PubMedCrossRef
9.
Widlansky ME, Wang J, Shenouda SM, Hagen TM, Smith AR, Kizhakekuttu TJ, Kluge MA, Weihrauch D, Gutterman DD, Vita JA. Altered mitochondrial membrane potential, mass, and morphology in the mononuclear cells of humans with type 2 diabetes. Transl Res. 2010;156(1):15–25.PubMedPubMedCentralCrossRef
10.
Shenouda SM, Widlansky ME, Chen K, Xu G, Holbrook M, Tabit CE, Hamburg NM, Frame AA, Caiano TL, Kluge MA, Duess MA, Levit A, Kim B, Hartman ML, Joseph L, Shirihai OS, Vita JA. Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation. 2011;124(4):444–53.PubMedPubMedCentralCrossRef
11.
Li N, Karaca M, Maechler P. Upregulation of UCP2 in beta-cells confers partial protection against both oxidative stress and glucotoxicity. Redox Biol. 2017;13:541–9.PubMedPubMedCentralCrossRef
12.
La Sala L, Mrakic-Sposta S, Micheloni S, Prattichizzo F, Ceriello A. Glucose-sensing microRNA-21 disrupts ROS homeostasis and impairs antioxidant responses in cellular glucose variability. Cardiovasc Diabetol. 2018;17(1):105.PubMedPubMedCentralCrossRef
13.
Wang J, Alexanian A, Ying R, Kizhakekuttu TJ, Dharmashankar K, Vasquez-Vivar J, Gutterman DD, Widlansky ME. Acute exposure to low glucose rapidly induces endothelial dysfunction and mitochondrial oxidative stress: role for AMP kinase. Arterioscler Thromb Vasc Biol. 2012;32(3):712–20.PubMedCrossRef
14.
Ren X, Ren L, Wei Q, Shao H, Chen L, Liu N. Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Cardiovasc Diabetol. 2017;16(1):52.PubMedPubMedCentralCrossRef
15.
Dromparis P, Michelakis ED. Mitochondria in vascular health and disease. Annu Rev Physiol. 2013;75:95–126.PubMedCrossRef
16.
Pierelli G, Stanzione R, Forte M, Migliarino S, Perelli M, Volpe M, Rubattu S. Uncoupling protein 2: a key player and a potential therapeutic target in vascular diseases. Oxid Med Cell Longev. 2017;2017:7348372.PubMedPubMedCentralCrossRef
17.
Diano S, Horvath TL. Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends Mol Med. 2012;18(1):52–8.PubMedCrossRef
18.
Marti A, Larrarte E, Novo F, Garcia M, Martinez J. UCP2 muscle gene transfer modifies mitochondrial membrane potential. Int J Obes. 2001;25(1):68.CrossRef
19.
Ye J, Li J, Xia R, Zhou M, Yu L. Prohibitin protects proximal tubule epithelial cells against oxidative injury through mitochondrial pathways. Free Radic Res. 2015;49(11):1393–403.PubMedCrossRef
20.
Kang T, Lu W, Xu W, Anderson L, Bacanamwo M, Thompson W, Chen YE, Liu D. MicroRNA-27 (miR-27) targets prohibitin and impairs adipocyte differentiation and mitochondrial function in human adipose-derived stem cells. J Biol Chem. 2013;288(48):34394–402.PubMedPubMedCentralCrossRef
21.
Lee K-U, Lee IK, Han J, Song D-K, Kim YM, Song HS, Kim HS, Lee WJ, Koh EH, Song K-H. Effects of recombinant adenovirus-mediated uncoupling protein 2 overexpression on endothelial function and apoptosis. Circ Res. 2005;96(11):1200–7.PubMedCrossRef
22.
Blanc J, Alves-Guerra M, Esposito B, Rousset S, Gourdy P, Ricquier D, Tedgui A, Miroux B, Mallat Z. Protective role of uncoupling protein 2 in atherosclerosis. Circulation. 2003;107(3):388–90.PubMedCrossRef
23.
Xiong S, Wang P, Ma L, Gao P, Gong L, Li L, Li Q, Sun F, Zhou X, He H, Chen J, Yan Z, Liu D, Zhu Z. Ameliorating endothelial mitochondrial dysfunction restores coronary function via transient receptor potential vanilloid 1-mediated protein kinase a/uncoupling protein 2 pathway. Hypertension. 2016;67(2):451–60.PubMedCrossRef
24.
Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003;42(7):1149–60.PubMedCrossRef
25.
Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker BA, Widlansky ME, Tschakovsky ME, Green DJ. Assessment of flow mediated dilation (FMD) in humans: a methodological and technical guideline. Am J Physiol Heart Circ Physiol. 2010;300(1):H2–12.PubMedPubMedCentralCrossRef
26.
Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39(2):257–65.PubMedCrossRef
27.
28.
Dharmashankar K, Welsh A, Wang J, Kizhakekuttu TJ, Ying R, Gutterman DD, Widlansky ME. Nitric oxide synthase-dependent vasodilation of human subcutaneous arterioles correlates with noninvasive measurements of endothelial function. Am J Hypertens. 2012;25(5):528–34.PubMedCrossRef
29.
Kizhakekuttu TJ, Gutterman DD, Phillips SA, Jurva JW, Arthur EI, Das E, Widlansky ME. Measuring FMD in the brachial artery: how important is QRS-gating? J Appl Physiol. 2010;109(4):959–65.PubMedPubMedCentralCrossRef
30.
Malik M, Suboc TM, Tyagi S, Salzman N, Wang J, Ying R, Tanner MJ, Kakarla M, Baker JE, Widlansky ME. Lactobacillus plantarum 299v supplementation improves vascular endothelial function and reduces inflammatory biomarkers in men with stable coronary artery disease. Circ Res. 2018;123(9):1091–102.PubMedPubMedCentralCrossRef
31.
Widlansky ME, Puppala VK, Suboc TM, Malik M, Branum A, Signorelli K, Wang J, Ying R, Tanner MJ, Tyagi S. Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy. Vasc Med. 2017;22(3):189–96.PubMedPubMedCentralCrossRef
32.
33.
Nilius B, Droogmans G. Ion channels and their functional role in vascular endothelium. Physiol Rev. 2001;81(4):1415–59.PubMedCrossRef
34.
Team RC. R: a language and environment for statistical computing. Vienna: Team RC; 2013.
35.
Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B, Couplan E, Alves-Guerra M-C, Goubern M, Surwit R. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet. 2000;26(4):435.PubMedCrossRef
36.
Cabrera JA, Ziemba EA, Colbert R, Kelly RF, Kuskowski M, Arriaga EA, Sluiter W, Duncker DJ, Ward HB, McFalls EO. Uncoupling protein-2 expression and effects on mitochondrial membrane potential and oxidant stress in heart tissue. Transl Res. 2012;159(5):383–90.PubMedCrossRef
37.
Sun J, Pu Y, Wang P, Chen S, Zhao Y, Liu C, Shang Q, Zhu Z, Liu D. TRPV1-mediated UCP2 upregulation ameliorates hyperglycemia-induced endothelial dysfunction. Cardiovasc Diabetol. 2013;12:69.PubMedPubMedCentralCrossRef
38.
Tian XY, Wong WT, Xu A, Lu Y, Zhang Y, Wang L, Cheang WS, Wang Y, Yao X, Huang Y. Uncoupling protein-2 protects endothelial function in diet-induced obese mice. Circ Res. 2012;110(9):1211–6.PubMedCrossRef
39.
Cui Y, Xu X, Bi H, Zhu Q, Wu J, Xia X, Qiushi R, Ho PC. Expression modification of uncoupling proteins and MnSOD in retinal endothelial cells and pericytes induced by high glucose: the role of reactive oxygen species in diabetic retinopathy. Exp Eye Res. 2006;83(4):807–16.PubMedCrossRef
40.
Krempler F, Esterbauer H, Weitgasser R, Ebenbichler C, Patsch JR, Miller K, Xie M, Linnemayr V, Oberkofler H, Patsch W. A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes. 2002;51(11):3331–5.PubMedCrossRef
41.
Dhamrait SS, Stephens JW, Cooper JA, Acharya J, Mani AR, Moore K, Miller GJ, Humphries SE, Hurel SJ, Montgomery HE. 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. Eur Heart J. 2004;25(6):468–75.PubMedCrossRef
42.
Gomathi P, Samarth AP, Raj N, Sasikumar S, Murugan PS, Nallaperumal S, Selvam GS. The -866G/A polymorphism in the promoter of the UCP2 gene is associated with risk for type 2 diabetes and with decreased insulin levels. Gene. 2019;701:125–30.PubMedCrossRef
43.
Castillo RL, Herrera EA, Gonzalez-Candia A, Reyes-Farias M, de la Jara N, Pena JP, Carrasco-Pozo C. Quercetin prevents diastolic dysfunction induced by a high-cholesterol diet: role of oxidative stress and bioenergetics in hyperglycemic rats. Oxid Med Cell Longev. 2018;2018:7239123.PubMedPubMedCentralCrossRef
44.
Cortes-Oliveira C, Nicoletti CF, de Souza Pinhel MA, de Oliveira BA, Quinhoneiro DC, Noronha NY, Marchini JS, da Silva Junior WA, Junior WS, Nonino CB. UCP2 expression is associated with weight loss after hypocaloric diet intervention. Eur J Clin Nutr. 2017;71(3):402–6.PubMedCrossRef
45.
Brondani LA, Assmann TS, de Souza BM, Boucas AP, Canani LH, Crispim D. Meta-analysis reveals the association of common variants in the uncoupling protein (UCP) 1–3 genes with body mass index variability. PLoS ONE. 2014;9(5):e96411.PubMedPubMedCentralCrossRef
46.
Lee JH, Nguyen KH, Mishra S, Nyomba BG. Prohibitin is expressed in pancreatic β-cells and protects against oxidative and proapoptotic effects of ethanol. FEBS J. 2010;277(2):488–500.PubMedCrossRef
47.
Nijtmans LG, de Jong L, Sanz MA, Coates PJ, Berden JA, Back JW, Muijsers AO, van der Spek H, Grivell LA. Prohibitins act as a membrane-bound chaperone for the stabilization of mitochondrial proteins. EMBO J. 2000;19(11):2444–51.PubMedPubMedCentralCrossRef
48.
Nijtmans L, Sanz MA, Grivell L, Coates P. The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, ageing and degenerative disease. Cell Mol Life Sci. 2002;59(1):143–55.PubMedCrossRef
49.
Terashima M, Kim K-M, Adachi T, Nielsen P, Reth M, Köhler G, Lamers M. The IgM antigen receptor of B lymphocytes is associated with prohibitin and a prohibitin-related protein. EMBO J. 1994;13(16):3782–92.PubMedPubMedCentralCrossRef
50.
Liu X, Ren Z, Zhan R, Wang X, Wang X, Zhang Z, Leng X, Yang Z, Qian L. Prohibitin protects against oxidative stress-induced cell injury in cultured neonatal cardiomyocyte. Cell Stress Chaperones. 2009;14(3):311–9.PubMedCrossRef
51.
Schleicher M, Shepherd BR, Suarez Y, Fernandez-Hernando C, Yu J, Pan Y, Acevedo LM, Shadel GS, Sessa WC. Prohibitin-1 maintains the angiogenic capacity of endothelial cells by regulating mitochondrial function and senescence. J Cell Biol. 2008;180(1):101–12.PubMedPubMedCentralCrossRef
52.
Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404(6779):787–90.PubMedCrossRef
53.
Hartman ML, Shirihai OS, Holbrook M, Xu G, Kocherla M, Shah A, Fetterman JL, Kluge MA, Frame AA, Hamburg NM, Vita JA. Relation of mitochondrial oxygen consumption in peripheral blood mononuclear cells to vascular function in type 2 diabetes mellitus. Vasc Med. 2014;19(1):67–74.PubMedPubMedCentralCrossRef
Metadata
Title
Circulating levels of mitochondrial uncoupling protein 2, but not prohibitin, are lower in humans with type 2 diabetes and correlate with brachial artery flow-mediated dilation
Authors
Mamatha Kakarla
Venkata K. Puppala
Sudhi Tyagi
Amberly Anger
Kathryn Repp
Jingli Wang
Rong Ying
Michael E. Widlansky
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Type 2 Diabetes
Published in
Cardiovascular Diabetology / Issue 1/2019
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-019-0956-4

Other articles of this Issue 1/2019

Cardiovascular Diabetology 1/2019 Go to the issue

Original investigation

Elevated triglycerides rather than other lipid parameters are associated with increased urinary albumin to creatinine ratio in the general population of China: a report from the REACTION study

Original investigation

Association of glycemic variability with left ventricular diastolic function in type 2 diabetes mellitus

Original investigation

Clinical factors associated with the recovery of cardiovascular autonomic neuropathy in patients with type 2 diabetes mellitus

Original investigation

Impact of post-procedural glycemic variability on cardiovascular morbidity and mortality after transcatheter aortic valve implantation: a post hoc cohort analysis

Original investigation

Visit-to-visit variability of glycemia and vascular complications: the Hoorn Diabetes Care System cohort

Original investigation

Temporal relationship between inflammation and insulin resistance and their joint effect on hyperglycemia: the Bogalusa Heart Study
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits