|
 |
|
|||||||
|
|||||||||
© 2001 by the American Diabetes Association, Inc.
Original Articles |
Inverse Relationship Between Cytotoxicity of Free Fatty Acids in Pancreatic Islet Cells and Cellular Triglyceride Accumulation
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
Studies in Zucker diabetic fatty rats have led to the concept that chronically elevated free fatty acid (FFA) levels can cause apoptosis of triglyceride-laden pancreatic ß-cells as a result of the formation of ceramides, which induce nitric oxide (NO)-dependent cell death. This "lipotoxicity" hypothesis could explain development of type 2 diabetes in obesity. The present study examines whether prolonged exposure to FFA affects survival of isolated normal rat ß-cells and whether the outcome is related to the occurrence of triglyceride accumulation. A dose-dependent cytotoxicity was detected at 5–100 nmol/l of unbound oleate and palmitate, with necrosis occurring within 48 h and an additional apoptosis during the subsequent 6 days of culture. At equimolar concentrations, the cytotoxicity of palmitate was higher than that of oleate but lower than that of its nonmetabolized analog bromopalmitate. FFA cytotoxicity was not suppressed by etomoxir (an inhibitor of mitochondrial carnitine palmitoyltransferase I) or by antioxidants; it was not associated with inducible NO synthase expression or NO formation. An inverse correlation was observed between the percentage of dead ß-cells on day 8 and their cellular triglyceride content on day 2. For equimolar concentrations of the tested FFA, oleate caused the lowest ß-cell toxicity and the highest cytoplasmic triglyceride accumulation. On the other hand, oleate exerted the highest toxicity in islet non–ß-cells, where no FFA-induced triglyceride accumulation was detected. In conditions without triglyceride accumulation, the lower FFA concentrations caused primarily apoptosis, both in islet ß-cells and non–ß-cells. It is concluded that FFAs can cause death of normal rat islet cells through an NO-independent mechanism. The ability of normal ß-cells to form and accumulate cytoplasmic triglycerides might serve as a cytoprotective mechanism against FFA-induced apoptosis by preventing a cellular rise in toxic free fatty acyl moieties. It is conceivable that this potential is lost or insufficient in cells with a prolonged triglyceride accumulation as may occur in vivo.
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  E. Diakogiannaki, S. Dhayal, C. E Childs, P. C Calder, H. J Welters, and N. G Morgan Mechanisms involved in the cytotoxic and cytoprotective actions of saturated versus monounsaturated long-chain fatty acids in pancreatic {beta}-cells J. Endocrinol., August 1, 2007; 194(2): 283 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Cnop, L. Ladriere, P. Hekerman, F. Ortis, A. K. Cardozo, Z. Dogusan, D. Flamez, M. Boyce, J. Yuan, and D. L. Eizirik Selective Inhibition of Eukaryotic Translation Initiation Factor 2{alpha} Dephosphorylation Potentiates Fatty Acid-induced Endoplasmic Reticulum Stress and Causes Pancreatic beta-Cell Dysfunction and Apoptosis J. Biol. Chem., February 9, 2007; 282(6): 3989 - 3997. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Santangelo, P. Matarrese, R. Masella, M. C. Di Carlo, A. Di Lillo, B. Scazzocchio, E. Vecci, W. Malorni, R. Perfetti, and E. Anastasi Hepatocyte growth factor protects rat RINm5F cell line against free fatty acid-induced apoptosis by counteracting oxidative stress J. Mol. Endocrinol., January 1, 2007; 38(1): 147 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. I. Rachek, S. I. Musiyenko, S. P. LeDoux, and G. L. Wilson Palmitate Induced Mitochondrial Deoxyribonucleic Acid Damage and Apoptosis in L6 Rat Skeletal Muscle Cells Endocrinology, January 1, 2007; 148(1): 293 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Parton, P. J. McMillen, Y. Shen, E. Docherty, E. Sharpe, F. Diraison, C. P. Briscoe, and G. A. Rutter Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E982 - E994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wei, D. Wang, F. Topczewski, and M. J. Pagliassotti Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E275 - E281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Karaskov, C. Scott, L. Zhang, T. Teodoro, M. Ravazzola, and A. Volchuk Chronic Palmitate But Not Oleate Exposure Induces Endoplasmic Reticulum Stress, Which May Contribute to INS-1 Pancreatic {beta}-Cell Apoptosis Endocrinology, July 1, 2006; 147(7): 3398 - 3407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. I. Rachek, N. P. Thornley, V. I. Grishko, S. P. LeDoux, and G. L. Wilson Protection of INS-1 Cells From Free Fatty Acid-Induced Apoptosis by Targeting hOGG1 to Mitochondria. Diabetes, April 1, 2006; 55(4): 1022 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cnop, N. Welsh, J.-C. Jonas, A. Jorns, S. Lenzen, and D. L. Eizirik Mechanisms of Pancreatic {beta}-Cell Death in Type 1 and Type 2 Diabetes: Many Differences, Few Similarities Diabetes, December 1, 2005; 54(suppl_2): S97 - S107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J L M R Leroy, T Vanholder, B Mateusen, A Christophe, G Opsomer, A de Kruif, G Genicot, and A Van Soom Non-esterified fatty acids in follicular fluid of dairy cows and their effect on developmental capacity of bovine oocytes in vitro Reproduction, October 1, 2005; 130(4): 485 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Busch, E. Gurisik, D. V. Cordery, M. Sudlow, G. S. Denyer, D. R. Laybutt, W. E. Hughes, and T. J. Biden Increased Fatty Acid Desaturation and Enhanced Expression of Stearoyl Coenzyme A Desaturase Protects Pancreatic {beta}-Cells from Lipoapoptosis Diabetes, October 1, 2005; 54(10): 2917 - 2924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-H. Kim, J. W. Lee, Y. H. Suh, S. H. Hong, J. S. Choi, J. H. Lim, J. H. Song, B. Gao, and M. H. Jung Exposure to Chronic High Glucose Induces {beta}-Cell Apoptosis Through Decreased Interaction of Glucokinase With Mitochondria: Downregulation of Glucokinase in Pancreatic {beta}-Cells Diabetes, September 1, 2005; 54(9): 2602 - 2611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Scaglia and R. A. Igal Stearoyl-CoA Desaturase Is Involved in the Control of Proliferation, Anchorage-independent Growth, and Survival in Human Transformed Cells J. Biol. Chem., July 8, 2005; 280(27): 25339 - 25349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Pappan, Z. Pan, G. Kwon, C. A. Marshall, T. Coleman, I. J. Goldberg, M. L. McDaniel, and C. F. Semenkovich Pancreatic {beta}-Cell Lipoprotein Lipase Independently Regulates Islet Glucose Metabolism and Normal Insulin Secretion J. Biol. Chem., March 11, 2005; 280(10): 9023 - 9029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Briaud, L. M. Dickson, M. K. Lingohr, J. F. McCuaig, J. C. Lawrence, and C. J. Rhodes Insulin Receptor Substrate-2 Proteasomal Degradation Mediated by a Mammalian Target of Rapamycin (mTOR)-induced Negative Feedback Down-regulates Protein Kinase B-mediated Signaling Pathway in {beta}-Cells J. Biol. Chem., January 21, 2005; 280(3): 2282 - 2293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kharroubi, L. Ladriere, A. K. Cardozo, Z. Dogusan, M. Cnop, and D. L. Eizirik Free Fatty Acids and Cytokines Induce Pancreatic {beta}-Cell Apoptosis by Different Mechanisms: Role of Nuclear Factor-{kappa}B and Endoplasmic Reticulum Stress Endocrinology, November 1, 2004; 145(11): 5087 - 5096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. Moore, M. A. Ugas, D. K. Hagman, S. D. Parazzoli, and V. Poitout Evidence Against the Involvement of Oxidative Stress in Fatty Acid Inhibition of Insulin Secretion Diabetes, October 1, 2004; 53(10): 2610 - 2616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Caviglia, I. N. T. de Gomez Dumm, R. A. Coleman, and R. A. Igal Phosphatidylcholine deficiency upregulates enzymes of triacylglycerol metabolism in CHO cells J. Lipid Res., August 1, 2004; 45(8): 1500 - 1509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamashita, K. Eto, Y. Okazaki, S. Yamashita, T. Yamauchi, N. Sekine, R. Nagai, M. Noda, and T. Kadowaki Role of Uncoupling Protein-2 Up-Regulation and Triglyceride Accumulation in Impaired Glucose-Stimulated Insulin Secretion in a {beta}-Cell Lipotoxicity Model Overexpressing Sterol Regulatory Element-Binding Protein-1c Endocrinology, August 1, 2004; 145(8): 3566 - 3577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-L. Peyot, C. J. Nolan, K. Soni, E. Joly, R. Lussier, B. E. Corkey, S. P. Wang, G. A. Mitchell, and M. Prentki Hormone-Sensitive Lipase Has a Role in Lipid Signaling for Insulin Secretion but Is Nonessential for the Incretin Action of Glucagon-Like Peptide 1 Diabetes, July 1, 2004; 53(7): 1733 - 1742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Lupi, S. Del Guerra, L. Marselli, M. Bugliani, U. Boggi, F. Mosca, P. Marchetti, and S. Del Prato Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPAR{gamma}2 in the modulation of insulin secretion Am J Physiol Endocrinol Metab, April 1, 2004; 286(4): E560 - E567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Sugden and M. J. Holness Potential Role of Peroxisome Proliferator-Activated Receptor-{alpha} in the Modulation of Glucose-Stimulated Insulin Secretion Diabetes, February 1, 2004; 53(90001): S71 - 81. [Abstract] [Full Text]
|
|
|
|
|
|
R. P. Robertson, J. Harmon, P. O. T. Tran, and V. Poitout {beta}-Cell Glucose Toxicity, Lipotoxicity, and Chronic Oxidative Stress in Type 2 Diabetes Diabetes, February 1, 2004; 53(90001): S119 - 124. [Abstract] [Full Text]
|
|
|
|
|
|
X. Wang, H. Li, D. De Leo, W. Guo, V. Koshkin, I. G. Fantus, A. Giacca, C. B. Chan, S. Der, and M. B. Wheeler Gene and Protein Kinase Expression Profiling of Reactive Oxygen Species-Associated Lipotoxicity in the Pancreatic {beta}-Cell Line MIN6 Diabetes, January 1, 2004; 53(1): 129 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bagnato and R. A. Igal Overexpression of Diacylglycerol Acyltransferase-1 Reduces Phospholipid Synthesis, Proliferation, and Invasiveness in Simian Virus 40-transformed Human Lung Fibroblasts J. Biol. Chem., December 26, 2003; 278(52): 52203 - 52211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. El-Assaad, J. Buteau, M.-L. Peyot, C. Nolan, R. Roduit, S. Hardy, E. Joly, G. Dbaibo, L. Rosenberg, and M. Prentki Saturated Fatty Acids Synergize with Elevated Glucose to Cause Pancreatic {beta}-Cell Death Endocrinology, September 1, 2003; 144(9): 4154 - 4163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Kelpe, P. C. Moore, S. D. Parazzoli, B. Wicksteed, C. J. Rhodes, and V. Poitout Palmitate Inhibition of Insulin Gene Expression Is Mediated at the Transcriptional Level via Ceramide Synthesis J. Biol. Chem., August 8, 2003; 278(32): 30015 - 30021. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sorhede Winzell, H. Svensson, S. Enerback, K. Ravnskjaer, S. Mandrup, V. Esser, P. Arner, M.-C. Alves-Guerra, B. Miroux, F. Sundler, et al. Pancreatic {beta}-Cell Lipotoxicity Induced by Overexpression of Hormone-Sensitive Lipase Diabetes, August 1, 2003; 52(8): 2057 - 2065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Eitel, H. Staiger, J. Rieger, H. Mischak, H. Brandhorst, M. D. Brendel, R. G. Bretzel, H.-U. Haring, and M. Kellerer Protein Kinase C {delta} Activation and Translocation to the Nucleus Are Required for Fatty Acid-Induced Apoptosis of Insulin-Secreting Cells Diabetes, April 1, 2003; 52(4): 991 - 997. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. L. Listenberger, X. Han, S. E. Lewis, S. Cases, R. V. Farese Jr., D. S. Ory, and J. E. Schaffer Triglyceride accumulation protects against fatty acid-induced lipotoxicity PNAS, March 18, 2003; 100(6): 3077 - 3082. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Maedler, J. Oberholzer, P. Bucher, G. A. Spinas, and M. Y. Donath Monounsaturated Fatty Acids Prevent the Deleterious Effects of Palmitate and High Glucose on Human Pancreatic {beta}-Cell Turnover and Function Diabetes, March 1, 2003; 52(3): 726 - 733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Maestre, J. Jordan, S. Calvo, J. A. Reig, V. Cena, B. Soria, M. Prentki, and E. Roche Mitochondrial Dysfunction Is Involved in Apoptosis Induced by Serum Withdrawal and Fatty Acids in the {beta}-Cell Line Ins-1 Endocrinology, January 1, 2003; 144(1): 335 - 345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Berge, K. J. Tronstad, P. Bohov, L. Madsen, and R. K. Berge Impact of mitochondrial {beta}-oxidation in fatty acid-mediated inhibition of glioma cell proliferation J. Lipid Res., January 1, 2003; 44(1): 118 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Wrede, L. M. Dickson, M. K. Lingohr, I. Briaud, and C. J. Rhodes Protein Kinase B/Akt Prevents Fatty Acid-induced Apoptosis in Pancreatic beta -Cells (INS-1) J. Biol. Chem., December 13, 2002; 277(51): 49676 - 49684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Kelpe, L. M. Johnson, and V. Poitout Increasing Triglyceride Synthesis Inhibits Glucose-Induced Insulin Secretion in Isolated Rat Islets of Langerhans: A Study Using Adenoviral Expression of Diacylglycerol Acyltransferase Endocrinology, September 1, 2002; 143(9): 3326 - 3332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Lupi, F. Dotta, L. Marselli, S. Del Guerra, M. Masini, C. Santangelo, G. Patane, U. Boggi, S. Piro, M. Anello, et al. Prolonged Exposure to Free Fatty Acids Has Cytostatic and Pro-Apoptotic Effects on Human Pancreatic Islets: Evidence that {beta}-Cell Death Is Caspase Mediated, Partially Dependent on Ceramide Pathway, and Bcl-2 Regulated Diabetes, May 1, 2002; 51(5): 1437 - 1442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Laybutt, A. Sharma, D. C. Sgroi, J. Gaudet, S. Bonner-Weir, and G. C. Weir Genetic Regulation of Metabolic Pathways in beta -Cells Disrupted by Hyperglycemia J. Biol. Chem., March 22, 2002; 277(13): 10912 - 10921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Poitout and R. P. Robertson Minireview: Secondary {beta}-Cell Failure in Type 2 Diabetes--A Convergence of Glucotoxicity and Lipotoxicity Endocrinology, February 1, 2002; 143(2): 339 - 342. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |