Pleiotropic Effects of GIP on Islet Function Involve Osteopontin

Research output: Contribution to journalArticle

Abstract

OBJECTIVE-The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic beta-cell function by potentiating insulin secretion and beta-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS-Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies.Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of beta-cell viability and proliferation. RESULTS-The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS-These findings support beta-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional beta-cell mass in humans. Diabetes 60:2424-2433, 2011

Details

Authors
  • Kasper Pilgaard
  • Anna Jonsson
  • Jalal Taneera
  • Alexander Balhuizen
  • Peter Osmark
  • Charlotte Brons
  • Alena Stancakova
  • Johanna Kuusisto
  • Marco Bugliani
  • Richa Saxena
  • Timothy J. Kieffer
  • Tiinamaija Tuomi
  • Bo Isomaa
  • Sara Bonetti
  • Riccardo Bonadonna
  • Roberto Miccoli
  • Stefano DelPrato
  • Piero Marchetti
  • Sten Madsbad
  • Pernille Poulsen
  • Allan Vaag
  • Markku Laakso
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)2424-2433
JournalDiabetes
Volume60
Issue number9
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedYes