Genome wide association studies (GWAS) confirmed that bone mineral density is associated with multiple genetic susceptibility regions (16, 17). The correlation between vitamin D receptor gene polymorphism and osteoporosis was first revealed by Morrison et al (18) in 1994. Since then, more than one hundred gene polymorphisms related to bone metabolism regulation have been studied including sex hormones and their receptors, bone matrix component related genes, apolipoprotein E (ApoE), etc., the results have confirmed the important role of genetic factors in primary osteoporosis.
In the literature (19), the variation of GIPR gene SNP locus rs10423928 was associated with increased postprandial blood glucose and insulin. In addition, this locus was also associated with decreased body mass index (BMI), lean body mass and waist circumference (20). Therefore, we chose to study this site of GIPR gene. There is a strong linkage disequilibrium between rs10423928 and rs1800437 (located in exon 10, E354Q) (r2 = 0.99). Related studies (21, 22) have confirmed that mutations in rs1800437 can reduce the expression of GIPR in carriers. The same genetic variation is reflected in. Studies have found that patients with functional SNP loci rs10423928 linkage disequilibrium are associated with low BMD in early postmenopausal women (23).
Our study found that there is a positive correlation between the dominant model T / T of rs10423928 and BMD of the femoral neck and Wards triangle area. That is to say, if the GIPR gene rs10423928 is homozygous T / T in postmenopausal women, it will enhance BMD of the femoral neck and Wards triangle area.
Regarding the effect of GIP on bone, a study (8) found that in mice with GIPR deficiency (GIPR KO), the cortical bone becomes thinner, the number of endosteal osteoclasts increases, and the bone mineral density decreases, which indicates the bone strength and quality variety. 14 ovariectomized 12-week-old BALB / c female mice were randomly divided into 2 groups, respectively treated with GIP analog N-AcGIP (25 nmoles / kg / day bw) and normal saline, and 10 BALB // c Female rats were injected with normal saline as a control group. Micro-CT tomography and 3D reconstruction techniques found that the number of bone trabeculae increased after GIP treatment in ovariectomized mice. TRACP staining and bone microstructure indicators suggested that the number of osteoclasts decreased and bone resorption decreased (9). (N-AcGIP: It is a GIP analogue. After acetylation of the 1st tyrosine at the amino terminus, it can enhance the resistance to DPP-4 enzyme without being destroyed and inactivated by the enzyme.). Daily injection of GIP into Sprague-Dawley rats with ovary removed proved that GIP can inhibit the acceleration of bone turnover caused by estrogen loss (24). Studies have shown that transgenic mice overexpressing GIP have higher BMD and bone mineral content (BMC) compared to the control group. In addition, their serum GIP and total osteocalcin levels are increased (25).Gene knockout mice lacking GIPR disturb the cortical microstructure of bones, leading to a decrease in bone "quality", strength, and fat content (8). These observations indicate that there is a complex shared molecular mechanism between osteoporosis and diabetes, and incretin GIP can improve bone metabolism.
At present, it is found that GIP affects bone directly and indirectly (10). Direct route: GIP combined with GIPR on osteoblasts can increase intracellular Ca2 + and cAMP concentrations, thereby promoting bone alkaline phosphatase activity and type I collagen mRNA expression (14, 26), promoting bone matrix Mineralization.In addition, the addition of GIP to the cultured osteoblast precursors can promote their differentiation, increase their proliferation and show anti-apoptotic activity in pluripotent mesenchymal stem cells in the bone marrow (27). Higher levels of transforming growth factor-β (TGF-β) are known to stimulate osteoblasts, and GIP can promote the secretion of TGF-β and improve bone metabolism. For osteoclasts, GIPR expressed in osteoclasts can downregulate bone resorption, inhibit osteoclast resorption activity, and reduce the expression of osteoclast differentiation markers (such as TRACP enzyme), as well as cathepsins K and the expression of G-CSF (granulocyte colony stimulating factor) receptor (28).
Indirect route: 1. It is known that the combination of insulin and insulin receptor on the surface of osteoblast membrane will promote bone formation. GIP acts on pancreatic β cells, enhances glucose-induced insulin secretion (19), and promotes insulin secretion.2. GIP receptors (GIPR) are also distributed on fat cells, which produce inflammatory cytokines ( such as leptin, lipase, adiponectin, amylin etc. ), GIP acts on fat cells and regulates secretion of leptin and adiponectin etc. LP can promote the differentiation of bone marrow mesenchymal stem cells into osteoblasts and inhibit their differentiation into osteoclasts and adipocytes, thereby maintaining the balance of bone metabolism, maintaining bone mass and bone quality. 3. GIP can regulate endothelial cell production of vascular endothelin-1 and nitric oxide, both of which have effects on bone turnover (29) Therefore, GIP indirectly plays an important role in the process of bone conversion (30).
So far, only one study at home and abroad has investigated the correlation between GIPR and BMD. It is reported that patients with functional SNP loci rs10423928 linkage disequilibrium are associated with low BMD in early postmenopausal women (23). Some studies have found that GIP polymorphism is not related to serum GIP and young women; but it is inversely related to the following components in the elderly: bone strength, including density, mineral content and microstructure (31).Another study reported that postmenopausal women's serum GIP levels increased (32) and were regulated by estrogen replacement therapy (33).
About 50% of postprandial insulin secretion is the result of GIP. In type 2 diabetes patients, the insulinotropic effect of GIP has been reduced, and studies have shown that impaired GIP response is associated with insulin resistance (34). Assuming that patients with type 2 diabetes may express lesser amounts of GIPR or defective GIPR (35), then GIPR deficiency may be the pathophysiological mechanism of type 2 diabetes (36). Various intestinal hormones such as GIP and leptin can regulate bone turnover, which we call the "gut-bone axis" system, and there is a close relationship between bone turnover and intestinal hormones (37). Discussing the genetic polymorphism of intestinal hormones and their receptors can further clarify their important role in osteoporosis.