Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Biol. Chem. 278 (20): 18368-18375

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Insulin-secreting β-Cell Dysfunction Induced by Human Lipoproteins*

Marc-Estienne Roehrich,tOaFNb Vincent Mooser,tOaFNc Vincent Lenain,tOa Joachim Herz,tOdFNe Johannes Nimpf,tOf Salman Azhar,tOg Martine Bideau,tOh Alessandro Capponi,tOh Pascal Nicod,tOa Jacques-Antoine Haefliger,tOai , and Gérard WaebertOaFNj

From the tOaDepartment of Internal Medicine and Institute of Cellular Biology and Morphology, University Hospital, Lausanne 1011, Switzerland, the tOdDepartment of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9046, the tOfDepartment of Molecular Genetics, University of Vienna, Vienna 1030, Austria, tOgGeriatric Research, Educational Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, and the tOhDivision of Endocrinology and Diabetes, University Hospital, Geneva CH 1211, Switzerland

ABSTRACT Back to Top

Abstract: Diabetes is associated with significant changes in plasma concentrations of lipoproteins. We tested the hypothesis that lipoproteins modulate the function and survival of insulin-secreting cells. We first detected the presence of several receptors that participate in the binding and processing of plasma lipoproteins and confirmed the internalization of fluorescent low density lipoprotein (LDL) and high density lipoprotein (HDL) particles in insulin-secreting β-cells. Purified human very low density lipoprotein (VLDL) and LDL particles reduced insulin mRNA levels and β-cell proliferation and induced a dose-dependent increase in the rate of apoptosis. In mice lacking the LDL receptor, islets showed a dramatic decrease in LDL uptake and were partially resistant to apoptosis caused by LDL. VLDL-induced apoptosis of β-cells involved caspase-3 cleavage and reduction in the levels of the c-Jun N-terminal kinase-interacting protein-1. In contrast, the proapoptotic signaling of lipoproteins was antagonized by HDL particles or by a small peptide inhibitor of c-Jun N-terminal kinase. The protective effects of HDL were mediated, in part, by inhibition of caspase-3 cleavage and activation of Akt/protein kinase B. In conclusion, human lipoproteins are critical regulators of β-cell survival and may therefore contribute to the β-cell dysfunction observed during the development of type 2 diabetes.


Received for publication January 6, 2003. Revision received February 4, 2003.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
High-density lipoprotein, beta cells, and diabetes.
A. von Eckardstein and C. Widmann (2014)
Cardiovasc Res
   Abstract »    Full Text »    PDF »
Cardioprotective functions of HDLs.
K.-A. Rye and P. J. Barter (2014)
J. Lipid Res. 55, 168-179
   Abstract »    Full Text »    PDF »
Regulation of signal transduction by HDL.
C. Mineo and P. W. Shaul (2013)
J. Lipid Res. 54, 2315-2324
   Abstract »    Full Text »    PDF »
Effects of High-Density Lipoprotein Elevation With Cholesteryl Ester Transfer Protein Inhibition on Insulin Secretion.
A. L. Siebel, A. K. Natoli, F. Y. T. Yap, A. L. Carey, M. Reddy-Luthmoodoo, D. Sviridov, C. I. K. Weber, G. Meneses-Lorente, C. Maugeais, J. M. Forbes, et al. (2013)
Circ. Res. 113, 167-175
   Abstract »    Full Text »    PDF »
Novel Biological Functions of High-Density Lipoprotein Cholesterol.
C. Mineo and P. W. Shaul (2012)
Circ. Res. 111, 1079-1090
   Abstract »    Full Text »    PDF »
HDLs Protect Pancreatic {beta}-Cells Against ER Stress by Restoring Protein Folding and Trafficking.
J. Petremand, J. Puyal, J.-Y. Chatton, J. Duprez, F. Allagnat, M. Frias, R. W. James, G. Waeber, J.-C. Jonas, and C. Widmann (2012)
Diabetes 61, 1100-1111
   Abstract »    Full Text »    PDF »
Effects of High-Density Lipoproteins on Pancreatic {beta}-Cell Insulin Secretion.
M. A. Fryirs, P. J. Barter, M. Appavoo, B. E. Tuch, F. Tabet, A. K. Heather, and K.-A. Rye (2010)
Arterioscler Thromb Vasc Biol 30, 1642-1648
   Abstract »    Full Text »    PDF »
Hnf1{alpha} (MODY3) Controls Tissue-Specific Transcriptional Programs and Exerts Opposed Effects on Cell Growth in Pancreatic Islets and Liver.
J.-M. Servitja, M. Pignatelli, M. A. Maestro, C. Cardalda, S. F. Boj, J. Lozano, E. Blanco, A. Lafuente, M. I. McCarthy, L. Sumoy, et al. (2009)
Mol. Cell. Biol. 29, 2945-2959
   Abstract »    Full Text »    PDF »
Generation and characterization of two novel mouse models exhibiting the phenotypes of the metabolic syndrome: Apob48-/-Lepob/ob mice devoid of ApoE or Ldlr.
D. J. Lloyd, J. McCormick, J. Helmering, K. W. Kim, M. Wang, P. Fordstrom, S. A. Kaufman, R. A. Lindberg, and M. M. Veniant (2008)
Am J Physiol Endocrinol Metab 294, E496-E505
   Abstract »    Full Text »    PDF »
ICER-1{gamma} Overexpression Drives Palmitate-mediated Connexin36 Down-regulation in Insulin-secreting Cells.
F. Allagnat, F. Alonso, D. Martin, A. Abderrahmani, G. Waeber, and J.-A. Haefliger (2008)
J. Biol. Chem. 283, 5226-5234
   Abstract »    Full Text »    PDF »
Islet Inflammation in Type 2 Diabetes: From metabolic stress to therapy.
M. Y. Donath, D. M. Schumann, M. Faulenbach, H. Ellingsgaard, A. Perren, and J. A. Ehses (2008)
Diabetes Care 31, S161-S164
   Abstract »    Full Text »    PDF »
Intramyocellular lipid content is lower with a low-fat diet than with high-fat diets, but that may not be relevant for health.
M.-P. St-Onge, B. R Newcomer, S. Buchthal, I. Aban, D. B Allison, A. Bosarge, and B. Gower (2007)
Am J Clin Nutr 86, 1316-1322
   Abstract »    Full Text »    PDF »
Direct Effect of Cholesterol on Insulin Secretion: A Novel Mechanism for Pancreatic {beta}-Cell Dysfunction.
M. Hao, W. S. Head, S. C. Gunawardana, A. H. Hasty, and D. W. Piston (2007)
Diabetes 56, 2328-2338
   Abstract »    Full Text »    PDF »
Mechanisms of {beta}-Cell Death in Type 2 Diabetes.
M. Y. Donath, J. A. Ehses, K. Maedler, D. M. Schumann, H. Ellingsgaard, E. Eppler, and M. Reinecke (2005)
Diabetes 54, S108-S113
   Abstract »    Full Text »    PDF »
ER stress and SREBP-1 activation are implicated in {beta}-cell glucolipotoxicity.
H. Wang, G. Kouri, and C. B. Wollheim (2005)
J. Cell Sci. 118, 3905-3915
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882