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Diabetologia
Published in: Diabetologia 5/2004

01-05-2004 | Article

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Authors: J. Buteau, W. El-Assaad, C. J. Rhodes, L. Rosenberg, E. Joly, M. Prentki

Published in: Diabetologia | Issue 5/2004

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Abstract

Aims/hypothesis

We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids.

Methods

Human islets and INS832/13 cells were cultured at glucose concentrations of 5 or 25 mmol/l in the presence or absence of palmitate. Apoptosis was evaluated by monitoring DNA fragmentation and chromatin condensation. Wild-type and protein kinase B mutants were overexpressed in INS832/13 cells using adenoviruses. Nuclear factor-κB DNA binding was assayed by electrophoretic mobility shift assay.

Results

In human pancreatic beta cells and INS832/13 cells, glucagon-like peptide-1 prevented beta cell apoptosis induced by elevated concentrations of (i) glucose (glucotoxicity), (ii) palmitate (lipotoxicity) and (iii) both glucose and palmitate (glucolipotoxicity). Overexpression of a dominant–negative protein kinase B suppressed the anti-apoptotic action of glucagon-like peptide-1 in INS832/13 cells, whereas a constitutively active protein kinase B prevented beta cell apoptosis induced by elevated glucose and palmitate. Glucagon-like peptide-1 enhanced nuclear factor-κB DNA binding activity and stimulated the expression of inhibitor of apoptosis protein-2 and Bcl-2, two anti-apoptotic genes under the control of nuclear factor-κB. Inhibition of nuclear factor-κB by BAY 11-7082 abolished the prevention of glucolipotoxicity by glucagon-like peptide-1.

Conclusions/interpretation

The results demonstrate a potent protective effect of glucagon-like peptide-1 on beta cell gluco-, lipo- and glucolipotoxicity. This effect is mediated via protein kinase B activation and possibly its downstream target nuclear factor-κB.
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Metadata
Title
Glucagon-like peptide-1 prevents beta cell glucolipotoxicity
Authors
J. Buteau
W. El-Assaad
C. J. Rhodes
L. Rosenberg
E. Joly
M. Prentki
Publication date
01-05-2004
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 5/2004
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-004-1379-6

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