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

138 Citations (Scopus)

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

Fingerprint

Insulin-Secreting Cells
Lipoproteins
LDL Lipoproteins
Insulin
HDL Lipoproteins
VLDL Lipoproteins
JNK Mitogen-Activated Protein Kinases
Apoptosis
Medical problems
Caspase 3
Cells
Plasmas
Proto-Oncogene Proteins c-akt
LDL Receptors
Cell proliferation
Type 2 Diabetes Mellitus
Cell Survival
Chemical activation
Cell Proliferation
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry

Cite this

Roehrich, M. E., Mooser, V., Lenain, V., Herz, J., Nimpf, J., Azhar, S., ... 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

Insulin-secreting β-cell dysfunction induced by human lipoproteins. / Roehrich, Marc Estienne; Mooser, Vincent; Lenain, Vincent; Herz, Joachim; Nimpf, Johannes; Azhar, Salman; Bideau, Martine; Capponi, Alessandro; Nicod, Pascal; Haefliger, Jacques Antoine; Waeber, Gérard.

In: Journal of Biological Chemistry, Vol. 278, No. 20, 16.05.2003, p. 18368-18375.

Research output: Contribution to journalArticle

Roehrich, ME, Mooser, V, Lenain, V, Herz, J, Nimpf, J, Azhar, S, Bideau, M, Capponi, A, Nicod, P, Haefliger, JA & Waeber, G 2003, 'Insulin-secreting β-cell dysfunction induced by human lipoproteins', Journal of Biological Chemistry, vol. 278, no. 20, pp. 18368-18375. https://doi.org/10.1074/jbc.M300102200
Roehrich, Marc Estienne ; Mooser, Vincent ; Lenain, Vincent ; Herz, Joachim ; Nimpf, Johannes ; Azhar, Salman ; Bideau, Martine ; Capponi, Alessandro ; Nicod, Pascal ; Haefliger, Jacques Antoine ; Waeber, Gérard. / Insulin-secreting β-cell dysfunction induced by human lipoproteins. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 20. pp. 18368-18375.
@article{0703cb0ae83640799445359ed2e6072a,
title = "Insulin-secreting β-cell dysfunction induced by human lipoproteins",
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.",
author = "Roehrich, {Marc Estienne} and Vincent Mooser and Vincent Lenain and Joachim Herz and Johannes Nimpf and Salman Azhar and Martine Bideau and Alessandro Capponi and Pascal Nicod and Haefliger, {Jacques Antoine} and G{\'e}rard Waeber",
year = "2003",
month = "5",
day = "16",
doi = "10.1074/jbc.M300102200",
language = "English (US)",
volume = "278",
pages = "18368--18375",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "20",

}

TY - JOUR

T1 - Insulin-secreting β-cell dysfunction induced by human lipoproteins

AU - Roehrich, Marc Estienne

AU - Mooser, Vincent

AU - Lenain, Vincent

AU - Herz, Joachim

AU - Nimpf, Johannes

AU - Azhar, Salman

AU - Bideau, Martine

AU - Capponi, Alessandro

AU - Nicod, Pascal

AU - Haefliger, Jacques Antoine

AU - Waeber, Gérard

PY - 2003/5/16

Y1 - 2003/5/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0038381515&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038381515&partnerID=8YFLogxK

U2 - 10.1074/jbc.M300102200

DO - 10.1074/jbc.M300102200

M3 - Article

C2 - 12594227

AN - SCOPUS:0038381515

VL - 278

SP - 18368

EP - 18375

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 20

ER -