Link Between GIP and Osteopontin in Adipose Tissue and Insulin Resistance

Abstract

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.

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

“…Similarly, GIP stimulates OPN expression in adipocytes, which was associated with insulin resistance (20,21). We also showed that a variant (rs10423928) in the GIP receptor (GIPR) gene is associated with impaired glucose-and GIP-stimulated insulin secretion and decreased BMI (19).…”

“…However, based on the impact of the variant studied here (rs10423928) on OPN concentrations after GIP infusion, it seems to be associated with a gain of function, but final proof will require additional studies to elucidate the effects of GIP on different human vessels in relation to genotype. Several splice isoforms with potentially divergent functions have been reported in cultured ECs (6), and we have observed a large number of splice isoforms in human adipose tissue, some of which seem to be regulated by SNPs in the GIPR gene (21). Additional support for a vascular role for GIP comes from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium, where a variant in the GIP gene was associated with myocardial infarction (67).…”

Genetic determinants of circulating GIP and GLP-1 concentrations

“…The minor alleles of rs1800437 and rs2287019 (P = 4.0 × 10 -11 ) in the GIPR locus were associated with lower fasting (P = 4.1 × 10 -15 ) and 2-hour (P = 1.6 × 10 -17 ) GIP concentrations. The rs1800437 SNP is in strong LD (r 2 = 0.94, D′ = 1) with the rs10423928 variant that has previously been associated with GIP concentrations in the PPP-Botnia cohorts as well as with several diabetes-related phenotypes, including insulin secretion, BMI, and expression of GIPR mRNA in islets (5,(17)(18)(19). The rs1800437 and rs2287019 variants are also in relatively strong linkage equilibrium (r 2 = 0.7, D′ = 1) with each other.…”

Increased circulating osteopontin levels in adult patients with type 1 diabetes mellitus and association with dysmetabolic profile

“…OPN was also demonstrated to induce adipose tissue inflammation, increase pro-inflammatory cytokines release in the bloodstream and, consequently, promote the development of insulin resistance (IR)-related conditions (9,10,11). Increased OPN levels were found in obese participants (12,13) and predicted coronary calcification, nephropathy and coronary artery disease in patients with type 2 diabetes, independent of traditional risk factors (14,15).…”