title: Pleiotropic effects of GIP on islet function involve osteopontin.
abstract: OBJECTIVE
  The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-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.
  
  
  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 β-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 β-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 β-cell mass in humans.
authors.affiliation: Diabetes and Endocrinology, Department of Clinical Sciences, University Hospital Malmö, Lund University, Malmö, Sweden. valeriya.lyssenko@med.lu.se
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.forename: Olga
authors.initials: O
authors.lastname: Kotova
authors.forename: Kasper
authors.initials: K
authors.lastname: Pilgaard
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
authors.forename: Anna
authors.initials: A
authors.lastname: Wendt
authors.forename: Anna
authors.initials: A
authors.lastname: Jonsson
authors.forename: Yang Z
authors.initials: YZ
authors.lastname: De Marinis
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Berglund
authors.forename: Jalal
authors.initials: J
authors.lastname: Taneera
authors.forename: Alexander
authors.initials: A
authors.lastname: Balhuizen
authors.forename: Ola
authors.initials: O
authors.lastname: Hansson
authors.forename: Peter
authors.initials: P
authors.lastname: Osmark
authors.forename: Pontus
authors.initials: P
authors.lastname: Dunér
authors.forename: Charlotte
authors.initials: C
authors.lastname: Brøns
authors.forename: Alena
authors.initials: A
authors.lastname: Stancáková
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.forename: Marco
authors.initials: M
authors.lastname: Bugliani
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.forename: Emma
authors.initials: E
authors.lastname: Ahlqvist
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Bo
authors.initials: B
authors.lastname: Isomaa
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Emily
authors.initials: E
authors.lastname: Sonestedt
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.forename: Sara
authors.initials: S
authors.lastname: Bonetti
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bonadonna
authors.forename: Roberto
authors.initials: R
authors.lastname: Miccoli
authors.forename: Stefano
authors.initials: S
authors.lastname: Delprato
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Sten
authors.initials: S
authors.lastname: Madsbad
authors.forename: Pernille
authors.initials: P
authors.lastname: Poulsen
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Maria F
authors.initials: MF
authors.lastname: Gomez
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
mesh_terms: D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D055106:Genome-Wide Association Study; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism
chemical_list: D007328:Insulin; D053495:Osteopontin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1