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

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

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

Marc-Estienne Roehrichab, Vincent Mooserac, Vincent Lenaina, Joachim Herzde, Johannes Nimpff, Salman Azharg, Martine Bideauh, Alessandro Capponih, Pascal Nicoda, Jacques-Antoine Haefligerai, and Gérard Waeberaj

From the a Department of Internal Medicine and Institute of Cellular Biology and Morphology, University Hospital, Lausanne 1011, Switzerland, the d Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9046, the f Department of Molecular Genetics, University of Vienna, Vienna 1030, Austria, g Geriatric Research, Educational Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, and the h Division of Endocrinology and Diabetes, University Hospital, Geneva CH 1211, Switzerland

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 beta -cells. Purified human very low density lipoprotein (VLDL) and LDL particles reduced insulin mRNA levels and beta -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 beta -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 beta -cell survival and may therefore contribute to the beta -cell dysfunction observed during the development of type 2 diabetes.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

b  Supported by an M.D./Ph.D. program of the Swiss National Science Foundation.

c  Supported by Swiss National Science Foundation Grant 32-62623.00 and the Placide Nicod and Octav Botnar Foundation.

e  Supported by grants from the National Institutes of Health, the Alzheimer Association, the Perot Family Foundation, and a Wolfgang-Paul award from the Humboldt Foundation.

i  Supported by Swiss National Science Foundation Grant 31-068036.02 and the Placide Nicod and Octav Botnar Foundation.

j  Supported by Swiss National Science Foundation Grant 32-48916.96, Juvenile Diabetes Research Foundation Grant 1-2001-555/600, and the Placide Nicod and Octav Botnar Foundation. To whom correspondence should be addressed: Dept. of Internal Medicine B, CHUV-University Hospital, BH 10-640, Lausanne 1011, Switzerland. Tel.: 41-21-314-09-60; Fax: 41-21-314-09-28; E-mail: gwaeber@chuv.hospvd.ch.

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

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