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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.

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