TY - JOUR

T1 - Link Between GIP and Osteopontin in Adipose Tissue and Insulin Resistance

AU - Ahlqvist, Emma

AU - Osmark, Peter

AU - Kuulasmaa, Tiina

AU - Pilgaard, Kasper

AU - Omar, Bilal

AU - Brøns, Charlotte

AU - Kotova, Olga

AU - Zetterqvist, Anna V

AU - Stancáková, Alena

AU - Jonsson, Anna Elisabet

AU - Hansson, Ola

AU - Kuusisto, Johanna

AU - Kieffer, Timothy J

AU - Tuomi, Tiinamaija

AU - Isomaa, Bo

AU - Madsbad, Sten

AU - Gomez, Maria F

AU - Poulsen, Pernille

AU - Laakso, Markku

AU - Degerman, Eva

AU - Pihlajamäki, Jussi

AU - Wierup, Nils

AU - Vaag, Allan

AU - Groop, Leif

AU - Lyssenko, Valeriya

PY - 2013/6

Y1 - 2013/6

N2 - Low-grade inflammation in obesity is associated with accumulation of the macrophage-derived cytokine osteopontin (OPN) in adipose tissue and induction of local as well as systemic insulin resistance. Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13 ± 0.04 vs. 0.04 ± 0.01, P <0.05) and correlated inversely with measures of insulin sensitivity (r = -0.24, P = 0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with a lower amount of the exon 9-containing isoform required for transmembrane activity. Carriers of the A allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of the GIPR rs10423928 A allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.

AB - Low-grade inflammation in obesity is associated with accumulation of the macrophage-derived cytokine osteopontin (OPN) in adipose tissue and induction of local as well as systemic insulin resistance. Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13 ± 0.04 vs. 0.04 ± 0.01, P <0.05) and correlated inversely with measures of insulin sensitivity (r = -0.24, P = 0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with a lower amount of the exon 9-containing isoform required for transmembrane activity. Carriers of the A allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of the GIPR rs10423928 A allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.

U2 - 10.2337/db12-0976

DO - 10.2337/db12-0976

M3 - Journal article

C2 - 23349498

VL - 62

SP - 2088

EP - 2094

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 6

ER -