Insulin-secreting β-cell dysfunction induced by human lipoproteins

Marc Estienne Roehrich, Vincent Mooser, Vincent Lenain, Joachim Herz, Johannes Nimpf, Salman Azhar, Martine Bideau, Alessandro Capponi, Pascal Nicod, Jacques Antoine Haefliger, Gérard Waeber

Research output: Contribution to journalArticle

144 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)18368-18375
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number20
DOIs
StatePublished - May 16 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Roehrich, M. E., Mooser, V., Lenain, V., Herz, J., Nimpf, J., Azhar, S., Bideau, M., Capponi, A., Nicod, P., Haefliger, J. A., & Waeber, G. (2003). Insulin-secreting β-cell dysfunction induced by human lipoproteins. Journal of Biological Chemistry, 278(20), 18368-18375. https://doi.org/10.1074/jbc.M300102200