title: Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB.
abstract: 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.
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Berglund
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden Steno Diabetes Center A/S, Gentofte, Denmark.
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Kotova
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Edsfeldt
authors.affiliation: Steno Diabetes Center A/S, Gentofte, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Pilgaard
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Sami
authors.initials: S
authors.lastname: Alkayyali
authors.affiliation: Steno Diabetes Center A/S, Gentofte, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Brøns
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Jonsson
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Zetterqvist
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Nitulescu
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Christian Ruiz
authors.initials: CR
authors.lastname: McDavitt
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Dunér
authors.affiliation: Department of Medicine, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Alena
authors.initials: A
authors.lastname: Stancáková
authors.affiliation: Department of Medicine, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Ahlqvist
authors.affiliation: Steno Diabetes Center A/S, Gentofte, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Lajer
authors.affiliation: Steno Diabetes Center A/S, Gentofte, Denmark HEALTH University of Aarhus, Aarhus, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.affiliation: Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Sten
authors.initials: S
authors.lastname: Madsbad
authors.affiliation: Steno Diabetes Center A/S, Gentofte, Denmark HEALTH University of Aarhus, Aarhus, Denmark NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.affiliation: Department of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden Steno Diabetes Center A/S, Gentofte, Denmark Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Lindblad
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Gottsäter
authors.affiliation: Department of Medicine, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Department of Cardiology, Skåne University Hospital, Malmö, Sweden.
authors.forename: Isabel
authors.initials: I
authors.lastname: Goncalves
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden maria.gomez@med.lu.se.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Gomez
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001011:Aorta / Q000166:cytology; D015153:Blotting, Western; D002318:Cardiovascular Diseases / Q000235:genetics; D002339:Carotid Arteries / Q000166:cytology; D016022:Case-Control Studies; D003331:Coronary Vessels / Q000166:cytology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D055806:Microvessels / Q000166:cytology; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism; D058729:Peripheral Arterial Disease / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics*; D020521:Stroke / Q000150:complications / Q000235:genetics / Q000378:metabolism; D034421:Sus scrofa; D013552:Swine
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D019332:Endothelin-1; D012333:RNA, Messenger; D011964:Receptors, Gastrointestinal Hormone; D053495:Osteopontin; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor