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

Research output: Contribution to journalArticle

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 pro-atherogenic cytokine osteopontin (OPN) in mouse arteries, via local release of endothelin-1 (ET-1) and activation of cAMP response element binding protein (CREB). Infusion of GIP increases plasma OPN levels in healthy individuals. Plasma ET-1 and OPN levels are positively correlated in patients with critical limb ischemia. Fasting GIP levels are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared to controls. 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 to parameters 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 human, mouse, rat and pig; remarkable up-regulation is observed in endothelial and smooth muscle cells upon culture conditions yielding a "vascular disease-like" phenotype. Moreover, a common variant rs10423928 in the GIPR gene associated with increased risk of stroke in type 2 diabetes patients.

Details

Authors
  • Claes Ladenvall
  • Andreas Edsfeldt
  • Kasper Pilgaard
  • Sami Alkayyali
  • Charlotte Brøns
  • Carol Forsblom
  • Anna Jonsson
  • Anna Zetterqvist
  • Mihaela Nitulescu
  • Christian Ruiz McDavitt
  • Alena Stancáková
  • Johanna Kuusisto
  • Maria Lajer
  • Lise Tarnow
  • Sten Madsbad
  • Peter Rossing
  • Timothy J Kieffer
  • Per-Henrik Groop
  • Bengt Lindblad
  • Markku Laakso
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)239-254
JournalDiabetes
Volume65
Issue number1
Publication statusPublished - 2016
Publication categoryResearch
Peer-reviewedYes

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