Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

TY - JOUR

T1 - Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

AU - Berglund, Lisa M

AU - Lyssenko, Valeriya

AU - Ladenvall, Claes

AU - Kotova, Olga

AU - Edsfeldt, Andreas

AU - Pilgaard, Kasper

AU - Alkayyali, Sami

AU - Brøns, Charlotte

AU - Forsblom, Carol

AU - Jonsson, Anna

AU - Zetterqvist, Anna V

AU - Nitulescu, Mihaela

AU - McDavitt, Christian Ruiz

AU - Dunér, Pontus

AU - Stancáková, Alena

AU - Kuusisto, Johanna

AU - Ahlqvist, Emma

AU - Lajer, Maria

AU - Tarnow, Lise

AU - Madsbad, Sten

AU - Rossing, Peter

AU - Kieffer, Timothy J

AU - Melander, Olle

AU - Orho-Melander, Marju

AU - Nilsson, Peter

AU - Groop, Per-Henrik

AU - Vaag, Allan

AU - Lindblad, Bengt

AU - Gottsäter, Anders

AU - Laakso, Markku

AU - Goncalves, Isabel

AU - Groop, Leif

AU - Gomez, Maria F

N1 - © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

PY - 2016/1

Y1 - 2016/1

N2 - Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a "vascular disease-like" phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.

AB - Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a "vascular disease-like" phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.

U2 - 10.2337/db15-0122

DO - 10.2337/db15-0122

M3 - Journal article

C2 - 26395740

SN - 0012-1797

VL - 65

SP - 239

EP - 254

JO - Diabetes

JF - Diabetes

IS - 1

ER -