Novobiocin Sodium mg Neither GIP nor GIPR SNPs were associat
Neither GIP nor GIPR SNPs were associated with occurrence of fractures in the OPRA cohort (Table 4).
Discussion The basis for this study lies in the role of glucose-insulinotropic peptide (GIP) hormone in the regulation of insulin secretion as well as its anabolic effect on osteoblasts and inhibition of osteoclasts (Tsukiyama et al., 2006, Xie et al., 2005). Transgenic mice over-expressing GIP have increased cortical bone mass while GIP also appears to prevent age related decline in bone mass and bone strength (Ding et al., 2008). Thus GIP and the receptor to GIP (GIPR) genes are attractive biological candidates to understand the genetic relationship between type 2 diabetes and osteoporosis. In this study, comprising two differently aged cohorts of women, we investigated if genetic variants in GIP and GIPR displayed association with phenotypes contributing to bone phenotypes including bone quantity and structure. In the present study, BMD and BMC were not associated with GIPR; however there was an association, although only in the young women, with lower calcaneal ultrasound values and this was independent of bone density. The absence of an association with bone architecture in the spine however is in line with data from a knock-out mouse model demonstrating that the effects of GIPR deficiency on bone microarchitecture (Mieczkowska et al., 2013) differ between predominantly cortical and trabecular skeletal sites (Gaudin-Audrain et al., 2013). In the recent study from Denmark, a GIPR SNP (rs1800437), in strong linkage disequilibrium with the rs10423928 SNP used here, was analyzed. They observed an association with lower BMD and increased fracture risk which is in Novobiocin Sodium mg with our findings. Since one would expect Swedish and Danish to be genetically similar, a possible explanation for this divergent finding is that the Danish women were perimenopausal suggesting that GIPR has a more important role in the immediate period around estrogen withdrawal rather than during bone accrual or in the very elderly. GIPR expression is reduced with age (Ding et al., 2008) which would appear to support this. In our study, GIPR had an effect on body composition showing small reductions in weight and fat mass. This is largely in line with the findings of Lyssenko et al. (2011), who also demonstrated that the BMI-lowering effect of this SNP neutralized the concomitant association with impaired glucose concentration and GIP-stimulated insulin secretion. Why the GIPR rather than the GIP SNP was associated with serum levels of GIP is unclear although decreased receptor activity has been reported for the GIPR E354Q (rs1800437) variant (Gaudin-Audrain et al., 2013) which could influence the cycles of receptor desensitization/resensitization. In cultured adipocytes, the receptor has been shown to be down regulated by GIP stimulation and desensitized to further GIP stimulation for a prolonged period (Ranganath et al., 1998). Serum GIP levels are reported to be increased in postmenopausal women (Ranganath et al., 1998) and modulated by estrogen replacement therapy (Sztefko et al., 2005), in our study however, GIP does not appear to be exerting a bone anabolic effect, at least in this elderly age group. Whether age related differences in sGIP explain our observed results is uncertain. The GIP SNP rs2291725 (Gly103Ser) is a functional variant previously reported to be associated with type 2 diabetes (Chia et al., 2009) but not yet explored in relation to altered bone phenotypes. In this study, the GIP polymorphism was adversely associated with components of bone strength including density, mineral content and microarchitecture in the elderly but not the young women, even after adjustment for fat mass. The absence of an association with body composition directly contrasts with the positive association observed specifically with weight and fat mass in the young PEAK-25 cohort. The strengths of this study include being the first, to our knowledge, evaluating the importance of GIP polymorphisms in relation to bone phenotypes in human cohorts, although a receptor gene polymorphism has been reported once before. In addition, we have not only evaluated BMD but also bone strength and related phenotypes. In the elderly women, we also analyzed serum GIP, although a weakness of the investigation is that this was only available for only 363 individuals, hence the statistical power to detect association was limited. In addition, serum levels could not be determined in the young making it difficult to establish potential interaction between serum GIP levels, bone properties, body composition and genotype at different ages. A limitation of the study is the fact that neither of the SNPs has been identified as major candidate genes in GWAS for osteoporosis related phenotypes. However, since SNP based GWAS do not identify all disease risk variants, studies of variants identified in related pathways are still warranted. We also acknowledge that the results must be interpreted with caution, since the associations are modest, in the absence of stringent adjustment for multiple testing.