[MUSIC] Another example of translational metabolism, is a study of how a gut metabolic hormone maintains bone mass and protects against osteoporosis. In summary, we discovered that a mutation in the receptor for a gut hormone, GIP, known to regulate insulin secretion, greatly increases the risk for osteoporetic fractures. These results profoundly change our understanding of the pathophysiology and future treatment of osteoporosis. Food ingestion inhibits bone resorption, and the intestinal hormone GIP may be one of the mediators of this effect. As a result, mice the hormone develop osteoporosis. We, therefore, investigated almost 2,000 women to study the effect of a genetic variation in the receptor of GIP in relation to fracture risk. We found that the genetic variation in GIP was associated with decreased bone mass and a 60% increased fracture risk. These findings establish GIP as being involved both in blood glucose and bone mass regulation, but with a much more profound effect on bone metabolism compared with glucose metabolism. Suggesting that the gut hormone is essential player in the signalling of food availability and bone regulation. These results may profoundly influence future treatment of osteoporosis. So what are the potential cellular mechanisms behind the observations. Well, food ingestion decreases bone resorption and GIP may be mediating this effect. GIP which is secreted from the K cells in the duodenum stimulates production of insulin from the pancreatic beta cells, in the presence of glucose and thereby contributes to decreasing protrenial blood glucose levels. Functional GIP receptor has been demonstrated on both osteoblasts and osteoplasts. Mice overexpression GIP have increased osteoblast activity, and are rescued from age related bone loss, while lack of GIP receptor. In the GIP receptor make up mass leads to decreased bone mass. GIP receptor variant causes a substitution of glutamate to glutamine leading to decreased receptor activity. Carriers of this variant have 0.1 mmol higher glucose two hours after glucose ingestion. Compared to non-carriers of the variant, as well as lower insulin secretion and lower levels of GIP receptor, mRNA in human pancreatic islets. This suggests that the variant decreases the effect of GIP. We therefore investigated the relationship between the GIP receptor variant and bone mineral density. And risk fractures in a prospective cohold of Danish pre-menopausal women. We demonstrated that after 10 years, women with glutamine at position 354 in the GIP receptor had significantly lower bone mineral density at the hip and femoral neck compared to carriers of glutamine in the same position. Correspondingly women with glutamine at position 354 in the GIPR receptor had 60% increased risk of fractures, compared to non carriers. 16 years after baseline, the mutation is localized to transmembrane domain 6 in the GIP receptor, which is a domain with constitutive activity, and the amino acid substitution reduces the basal activity. And the receptor is expressed at a significantly decreased density relative to wild-type receptor. Our observations are functional mutations in GIP receptor, reducing bone marrow density. And increasing risk fractures supports the suggested existence of an entero-osseous axis, where GIP signals nutrients availability to the bone. Furthermore, mouse studies have shown that GIP have direct anti-apoptotic and proliferating effects on osteoblasts. Resulting in increased osteoblasts, and the GIP stimulates bone marrow cells to differentiate into osteoblasts. Our finding of a significant increased risk of fractures, further demonstrates that GIP receptor variation is associated with impaired bone-mass and bone-quality. A major analysis of several genome-wide association studies showed that the variant associated with lower insulin secretion after an oral glucose tolerance test. And with lower levels of GIP receptor, mRNA in human pancreatic islets. But with only 7% increased risk of type 2 diabetes. In our study we found that a 60% increased fracture risk for the carriers of these variants. Which may imply that variance and GIP receptor have a more profound effect on bone metabolism compared with glucose metabolism. In summary, these findings further establish GIP is involved both in blood glucose, and bone density regulation, supporting the existence of the suggested entero-osseous axis. These two studies were examples of translational metabolism that bridges the gaps between fundamental science and applied science. And where we translate the knowledge from genetics into clinically relevant patient stories. Thank you very much for listening. [MUSIC]
