Free Fatty Acid-induced β-Cell Defects Are Dependent on Uncoupling Protein 2 Expression
Open accessAbstract
Chronic exposure to elevated free fatty acids (lipotoxicity) induces uncoupling protein (UCP2) in the pancreatic beta-cell, and therefore a causal link between UCP2 and beta-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 beta-cell glucose sensitivity. We have now assessed the mechanism of maintained beta-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 beta-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(-/-) beta-cells. The glucose-stimulated increases in the ATP/ADP ratio and cytosolic Ca2+ are attenuated in palmitate-treated WT but not UCP2(-/-) beta-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 beta-cells resulted in a loss of glucose-stimulated 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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UCP2 KO protects mice from fatty acid-induced impairment in glucose-induced insulin release.
“Further, evidence indicates that the impaired insulin secretion observed during treatment of isolated islets with high glucose can be mitigated by UCP2 knockdown (176) and that UCP2 KO protects mice from fatty acid–induced impairment in glucose-induced insulin release (152, 153).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [152]
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Cites
A SIMPLE METHOD FOR THE ISOLATION AND PURIFICATION OF TOTAL LIPIDES FROM ANIMAL TISSUES
Folch, J., Lees, M., & Stanley, G. H. S. (1957) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)64849-5 · Cited by 65,189 · see citing works
Method for the Isolation of Intact Islets of Langerhans from the Rat Pancreas
Lacy, P. E., & Kostianovsky, M. (1967) · Diabetes · doi:10.2337/diab.16.1.35 · Cited by 2,775 · see citing works
Superoxide activates mitochondrial uncoupling proteins
Echtay, K. S., Roussel, D., St-Pierre, J., Jekabsons, M. B., Cadenas, S., Stuart, J. A., Harper, J. A., Roebuck, S. J., Morrison, A., Pickering, S., et al. (2002) · Nature · doi:10.1038/415096a · Cited by 1,382 · see citing works
Lenzen, S., Drinkgern, J., & Tiedge, M. (1996) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(96)02051-5 · Cited by 1,167 · see citing works
Fatty acid-induced β cell apoptosis: A link between obesity and diabetes
Shimabukuro, M., Zhou, Y.-T., Levi, M., & Unger, R. H. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2498 · Cited by 1,142 · see citing works
Arsenijevic, D., Onuma, H., Pecqueur, C., Raimbault, S., Manning, B. S., Miroux, B., Couplan, E., Alves‐Guerra, M., Goubern, M., Surwit, R. S., et al. (2000) · Nature Genetics · doi:10.1038/82565 · Cited by 1,079 · see citing works
Zhang, C.-Y., Baffy, G., Perret, P., Krauss, S., Peroni, O., Grujic, D., Hagen, T., Vidal-Puig, A. J., Boss, O., Kim, Y.-B., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00378-6 · Cited by 917 · see citing works
Self-citationUnger, R. H. (2002) · Annual Review of Medicine · doi:10.1146/annurev.med.53.082901.104057 · Cited by 875 · see citing works
Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover.
Unger, R. H., & Zhou, Y. (2001) · Diabetes · doi:10.2337/diabetes.50.2007.s118 · Cited by 476 · see citing works
Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism.
Boss, O., Hagen, T., & Lowell, B. B. (2000) · Diabetes · doi:10.2337/diabetes.49.2.143 · Cited by 414 · see citing works
Self-citationSuperoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction
Krauss, S., Zhang, C., Scorrano, L., Dalgaard, L. T., St‐Pierre, J., Grey, S. T., & Lowell, B. B. (2003) · Journal of Clinical Investigation · doi:10.1172/jci19774 · Cited by 401 · see citing works
Self-citationSuperoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction
Krauss, S., Zhang, C.-Y., Scorrano, L., Dalgaard, L. T., St-Pierre, J., Grey, S. T., & Lowell, B. B. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319774 · Cited by 401 · see citing works
Self-citationSuperoxide Activates Mitochondrial Uncoupling Protein 2 from the Matrix Side
Echtay, K. S., Murphy, M. P., Smith, R. A. J., Talbot, D. A., & Brand, M. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208262200 · Cited by 388 · see citing works
Esterbauer, H., Schneitler, C., Oberkofler, H., Ebenbichler, C. F., Paulweber, B., Sandhofer, F., Ladurner, G., Hell, E., Strosberg, A. D., Patsch, J. R., et al. (2001) · Nature Genetics · doi:10.1038/88911 · Cited by 359 · see citing works
Structure and function of the uncoupling protein from brown adipose tissue
Klingenberg, M., & Huang, S. (1999) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/s0005-2736(98)00232-6 · Cited by 359 · see citing works
Coenzyme Q is an obligatory cofactor for uncoupling protein function
Echtay, K. S., Winkler, E., & Klingenberg, M. (2000) · Nature · doi:10.1038/35046114 · Cited by 329 · see citing works
Briaud, I., Harmon, J. S., Kelpe, C. L., Segu, V. B. G., & Poitout, V. (2001) · Diabetes · doi:10.2337/diabetes.50.2.315 · Cited by 317 · see citing works
Kang, G., Joseph, J. W., Chepurny, O. G., Monaco, M., Wheeler, M. B., Bos, J. L., Schwede, F., Genieser, H.-G., & Holz, G. G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211682200 · Cited by 298 · see citing works
Self-citationChan, C. B., MacDonald, P. E., Saleh, M. C., Johns, D. C., Marbàn, E., & Wheeler, M. B. (1999) · Diabetes · doi:10.2337/diabetes.48.7.1482 · Cited by 242 · see citing works
Self-citationCarlsson, C., Borg, L., & Welsh, N. (1999) · Endocrinology · doi:10.1210/endo.140.8.6908 · Cited by 238 · see citing works
Uncoupling Protein 2 Knockout Mice Have Enhanced Insulin Secretory Capacity After a High-Fat Diet
Joseph, J. W., Koshkin, V., Zhang, C.-Y., Wang, J., Lowell, B. B., Chan, C. B., & Wheeler, M. B. (2002) · Diabetes · doi:10.2337/diabetes.51.11.3211 · Cited by 220 · see citing works
Self-citationChen, S., Ogawa, A., Ohneda, M., Unger, R. H., Foster, D. W., & McGarry, J. (1994) · Diabetes · doi:10.2337/diab.43.7.878 · Cited by 173 · see citing works
Krauss, S., Zhang, C., & Lowell, B. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012410699 · Cited by 173 · see citing works
Self-citationSesti, G., Cardellini, M., Marini, M. A., Frontoni, S., D’Adamo, M., Guerra, S. D., Lauro, D., de Nicolais, P., Sbraccia, P., Prato, S. D., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.5.1280 · Cited by 131 · see citing works
Barbu, A. R., Welsh, N., & Saldeen, J. (2002) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(02)00009-6 · Cited by 121 · see citing works
Mitochondrial functional state in clonal pancreatic β-cells exposed to free fatty acids.
Koshkin, V., Wang, X., Scherer, P. E., Chan, C. B., & Wheeler, M. B. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209709200 · Cited by 121 · see citing works
Self-citationEnergy metabolism in islets of Langerhans
Erecińska, M., Bryła, J., Michalik, M., Meglasson, M. D., & NELSON, D. S. (1992) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/0005-2728(92)90084-f · Cited by 119 · see citing works
Dhamrait, S. S. (2004) · European Heart Journal · doi:10.1016/j.ehj.2004.01.007 · Cited by 112 · see citing works
Role of apoptosis in pancreatic beta-cell death in diabetes.
Chandra, J., Zhivotovsky, B., Zaitsev, S. V., Juntti‐Berggren, L., Berggren, P., & Orrenius, S. (2001) · Diabetes · doi:10.2337/diabetes.50.2007.s44 · Cited by 110 · see citing works
Hong, Y., Fink, B. D., Dillon, J. S., & Sivitz, W. I. (2001) · Endocrinology · doi:10.1210/endo.142.1.7889 · Cited by 107 · see citing works
Self-citationSasahara, M., Nishi, M., Kawashima, H., Ueda, K., Sakagashira, S., Furuta, H., Matsumoto, E., Hanabusa, T., Sasaki, H., & Nanjo, K. (2004) · Diabetes · doi:10.2337/diabetes.53.2.482 · Cited by 101 · see citing works
Exogenous Nitric Oxide and Endogenous Glucose-Stimulated β-Cell Nitric Oxide Augment Insulin Release
Smukler, S. R., Tang, L. F., Wheeler, M. B., & Salapatek, A. M. (2002) · Diabetes · doi:10.2337/diabetes.51.12.3450 · Cited by 101 · see citing works
Self-citationCa2+ Oscillations in Pancreatic Islet Cells Secreting Glucagon and Somatostatin
Berts, A., Gylfe, E., & Hellman, B. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.1387 · Cited by 72 · see citing works
Drucker, D. J., Campos, R. V., REYNOLDS, R., Stobie, K. M., & Brubaker, P. L. (1991) · Endocrinology · doi:10.1210/endo-128-1-394 · Cited by 59 · see citing works
Schultz, V., Sussman, I., Bokvist, K. B., & Tornheim, K. (1993) · Analytical Biochemistry · doi:10.1006/abio.1993.1591 · Cited by 54 · see citing works
Brubaker, P. L., Lee, Y. C., & Drucker, D. J. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)36746-8 · Cited by 46 · see citing works
Brubaker, P. L., SO, D. C. Y., & Drucker, D. J. (1989) · Endocrinology · doi:10.1210/endo-124-6-3003 · Cited by 35 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Krauss, S., Zhang, C. Y., and Lowell, B. B. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 118 -122
- Shimabukuro, M., Zhou, Y. T., Levi, M., and Unger, R. H. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 2498 -2502
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Mitochondrial dysfunction and type 2 diabetes
Lowell, B. B., & Shulman, G. I. (2005) · Science · doi:10.1126/science.1104343 · Cited by 2,070 · see citing works
Self-citationMolecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes
Muoio, D. M., & Newgard, C. B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2327 · Cited by 1,177 · see citing works
Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3
Brand, M. D., & Esteves, T. C. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.06.002 · Cited by 785 · see citing works
Sivitz, W. I., & Yorek, M. A. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2531 · Cited by 742 · see citing works
Self-citationGlucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity
Parton, L. E., Ye, C. P., Coppari, R., Enriori, P. J., Choi, B., Zhang, C.-Y., Xu, C., Vianna, C. R., Balthasar, N., Lee, C. E., et al. (2007) · Nature · doi:10.1038/nature06098 · Cited by 700 · see citing works
Self-citationMitochondrial uncoupling, ROS generation and cardioprotection
Cadenas, S. (2018) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2018.05.019 · Cited by 591 · see citing works
Pessayre, D., & Fromenty, B. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.03.004 · Cited by 441 · see citing works
The efficiency and plasticity of mitochondrial energy transduction.
Brand, M. D. (2005) · Biochemical Society Transactions · doi:10.1042/bst0330897 · Cited by 406 · see citing works
Obesity-related derangements in metabolic regulation
Muoio, D. M., & Newgard, C. B. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.103004.142512 · Cited by 345 · see citing works
Diabetes and apoptosis: lipotoxicity
Kusminski, C. M., Shetty, S., Orci, L., Unger, R. H., & Scherer, P. E. (2009) · Apoptosis · doi:10.1007/s10495-009-0352-8 · Cited by 302 · see citing works
Powelka, A. M. (2005) · Journal of Clinical Investigation · doi:10.1172/jci26040 · Cited by 236 · see citing works
Mitochondrial uncoupling and lifespan
Mookerjee, S. A., Divakaruni, A. S., Jastroch, M., & Brand, M. D. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2010.03.010 · Cited by 169 · see citing works
Hoppa, M. B., Collins, S., Ramracheya, R., Hodson, L., Amisten, S., Zhang, Q., Johnson, P., Ashcroft, F. M., & Rorsman, P. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.09.011 · Cited by 152 · see citing works
Robson-Doucette, C. A., Sultan, S., Allister, E. M., Wikstrom, J. D., Koshkin, V., Bhattacharjee, A., Prentice, K. J., Sereda, S. B., Shirihai, O. S., & Wheeler, M. B. (2011) · Diabetes · doi:10.2337/db11-0132 · Cited by 136 · see citing works
Self-citationThe efficiency of cellular energy transduction and its implications for obesity
Harper, M.-E., Green, K., & Brand, M. D. (2008) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.28.061807.155357 · Cited by 121 · see citing works
Affourtit, C., & Brand, M. D. (2008) · Biochemical Journal · doi:10.1042/bj20070954 · Cited by 85 · see citing works
Glucolipotoxicity in Pancreatic β-Cells
Kim, J.-W., & Yoon, K.-H. (2011) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2011.35.5.444 · Cited by 82 · see citing works
On the role of uncoupling protein-2 in pancreatic beta cells
Affourtit, C., & Brand, M. D. (2008) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2008.03.022 · Cited by 78 · see citing works
Uncoupling Proteins: Role in Insulin Resistance and Insulin Insufficiency
B.Chan, C., & Harper, M.-E. (2006) · Current Diabetes Reviews · doi:10.2174/157339906777950660 · Cited by 71 · see citing works
Barlow, J., Jensen, V. H., Jastroch, M., & Affourtit, C. (2016) · Biochemical Journal · doi:10.1042/bj20151080 · Cited by 45 · see citing works
Hirschberg Jensen, V., & Affourtit, C. (2015) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2015.03.008 · Cited by 9 · see citing works
- Authors
- Joseph, J. W., Koshkin, V., Saleh, M. C., Sivitz, W. I., Zhang, C.-Y., Lowell, B. B., Chan, C. B., & Wheeler, M. B.
- Affiliations
- University of Toronto (CA)
- University of Prince Edward Island (CA)
- University of Iowa (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Wheeler, Michael B.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-12
- Volume
- 279
- Issue
- 49
- Pages
- 51049-51056
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2033573667
- Cited by
- 206
- References
- 37
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 7 · 2020: 2 · 2019: 6 · 2018: 4 · 2017: 7 · 2016: 7 · 2015: 11 · 2014: 7 · 2013: 9 · 2012: 10
- FWCI
- 15.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- UCP2, beta-cell dysfunction, lipotoxicity, free fatty acids, palmitate, glucose-stimulated insulin secretion, mitochondrial membrane potential, reactive oxygen species, triglyceride accumulation, fatty acid oxidation, obesity, pancreatic islets, ATP/ADP ratio, intracellular calcium
- MeSH terms
- Uncoupling Protein 2, Adenosine Diphosphate, Adenosine Triphosphate, Adenoviridae, Animals, Calcium, Cytosol, Dose-Response Relationship, Drug, Fatty Acids, Fatty Acids, Nonesterified, Glucose, Insulin, Ion Channels, Islets of Langerhans, Male, Membrane Potentials, Mice, Transgenic, Mitochondria, Obesity, Oxygen, Phenotype, Polymorphism, Genetic, Recombinant Proteins, Time Factors, Triglycerides, Blotting, Western, Reactive Oxygen Species, Mice, Knockout, Transgenes, Palmitic Acid, Reverse Transcriptase Polymerase Chain Reaction, Mitochondrial Proteins, Membrane Transport Proteins, Lipid Metabolism, Mice
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