Premium
Differential signaling in response to glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) stimulation in the vasculature: modulation of osteopontin expression
Author(s) -
Berglund Lisa M,
Lyssenko Valeriya,
Kotova Olga,
Zetterqvist Anna V,
Gottsäter Anders,
Vaag Allan,
Goncalves Isabel,
Groop Leif,
Gomez Maria F
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.848.3
The incretins GIP and GLP‐1 are secreted after a meal to stimulate insulin secretion and are the main target for novel drugs to treat diabetes, including inhibitors of the incretin‐degrading enzyme dipeptidyl peptidase‐4 (DPP‐4). Evidence suggests a cardioprotective role of GLP‐1, but less is known about GIP in this context. Using confocal immunohistochemistry and Western blot, we show that GIP increases the expression of the pro‐atherogenic cytokine osteopontin (OPN) in mouse aorta via local release of endothelin‐1 (Et‐1) and activation of cAMP response element binding protein (CREB). Accordingly, GIP infusion in 47 healthy humans resulted in elevated Et‐1 and OPN in plasma and a significant correlation was found between plasma Et‐1 and OPN in 100 patients with critical limb ischemia. In 150 human carotid atherosclerotic plaques, GIP receptor (GIPR) and OPN mRNA were positively correlated. Interestingly, GLP‐1 also increased OPN expression in mouse aorta and plasma OPN in humans, but via a different molecular mechanism. Inhibition of Nuclear Factor of Activated T cells (NFAT) abolished the effect of GLP‐1, whereas it had no effect on GIP‐induced OPN. Taken together, our results suggest a pro‐inflammatory role of GIP in the vasculature and warn for the use of incretin therapies, which may prolong their effects and lead to unwanted effects. Support: EASD, Swedish Heart & Lung Foundation.