Incretin action on bone: An added benefit?

Identification of the incretin hormones has led to revolutionary advances in the management of type 2 diabetes. There has been much recent excitement about the extrapancreatic actions of incretin hormones. Experimental studies have suggested that glucagon-like peptide-1 (GLP-1) could have beneficial effects on the cardiovascular system as well as the kidney, and this is currently an area of intense research. In addition, recent insights suggest that GLP-1 might have beneficial effects on the bone. GLP-1 receptor activation has been shown to lead to increased bone formation, suggesting possible beneficial effects of incretin therapies on reducing fractures1. Furthermore, glucose-dependent insulinotropic polypeptide (GIP) was found to regulate bone formation, with GIP-overexpressing mice having an increase in bone formation and a decrease in bone resorption2, whereas the GIP receptor (GIPR) knockout mice have decreased cortical bone mass, decreased trabecular bone mass or compromised bone quality3,4. These studies support the existence of an entero-osseous axis, and potential beneficial effects of agents targeting the incretin pathway on bone health.

A recent study in humans provides further support for the role of GIP in regulating bone mass and fracture risk. To examine the relevance of GIP in mediating fracture risk, Torekov et al.5 examined the association between a functional variant in the GIP gene, rs1800437, with incident fractures in a well-characterized prospective cohort. The variant, which causes a substitution of glutamate to glutamine at position 354 (Glu354Gln) in transmembrane domain 6, has been shown to lead to decreased receptor activity, and carriers of this variant have higher postprandial glucose levels with decreased insulin after oral glucose challenge, consistent with the decreased effect of GIP6. To examine the association between genetic variants in GIP with fracture risk, the authors genotyped rs1800437, and its proxy rs10423928, in 1,686 perimenopausal women from the Danish Osteoporosis Prevention Study, a multicenter, prospective, cohort study with detailed radiological assessment for fractures and bone mineral density (BMD) measurements at baseline, and after 5 and 10 years. Together, the two variants tag all genetic variation within the gene with minor allele frequency of at least 10% and r2 ≥ 0.9. With the two genotyped variants in tight linkage disequilibrium (r2 = 0.99), the authors carried out the analysis for the functional variant, rs1800437. They found that carriers of the C allele had a trend towards lower BMD at the hip at baseline, adjusting for the covariates age, hormonal treatment and body mass index (BMI), and after 10 years, women carrying the C allele of rs1800437 had significantly lower BMD at the femoral neck and hip compared with carriers of the major G allele. There was no difference in BMD at the lumbar spine between women with the different genotypes. In a Cox regression analysis adjusting for age, hormonal treatment and BMI, women with the CC genotype had an increased risk of non-vertebral fractures during mean follow up of 16 years [hazard ratio 1.6 (95% confidence interval 1.0–2.5, P < 0.05)]5.

This well-conducted candidate gene study provided several novel insights on the role of GIP in bone metabolism. With 1,686 participants and long duration of follow up, the study was adequately powered for the study on changes in BMD. In addition to detailed documentation of incident fractures at the 5- and 10-year follow-up visits, data on fractures were also extracted from the Danish National Patient Registry, thereby providing a total follow-up duration of at least 16 years. There was also detailed categorization of different types of fractures, allowing separate analyses for vertebral vs non-vertebral fractures. The findings of increased risk of non-vertebral fractures among the CC carriers is consistent with results from the GIPR knockout mice, which suggests that GIPR deficiency has particularly detrimental effects on cortical bone. Previous studies using the GIPR knockout mice found increased trabecular bone mass, but decreased bone mineralization and strength at the tibia4. Conversely, bone mass, cortical thickness and strength were all reduced at mid-femur in the GIPR knockout mice3.

This recent study adds to our understanding of the extrapancreatic effects of GIP (Figure1). GIP plays a key role in modulating nutrient intake into adipose tissue, and therefore provides an important link between nutrient intake and obesity. Furthermore, GIP was found to induce inflammation and impaired insulin signaling in the adipocyte7. The emerging insights on the important role of GIP in regulating bone mass and strength provides another fascinating perspective on the pleiotropic effects of the incretin hormones, and potentially, pharmacological agents targeting this pathway. A previous genome-wide meta-analysis confirmed the association between a variant in GIPR, and reduced insulin secretion6. Findings from this current study suggest the effects of the variant on bone metabolism are probably greater than the effect on glucose metabolism. Interestingly, recent data suggests that incretin-based therapies could have beneficial effects on bone metabolism8. A meta-analysis of all randomized clinical trials of duration more than 24 weeks suggest that treatment with dipeptidyl peptidase-4 inhibitors was associated with a reduced risk of fractures9. Given the impairment of incretin receptors and their signaling in the diabetic state10,11, and increased risk of fractures in both type 1 and type 2 diabetes, better understanding of the role of the incretin pathway in modulating bone metabolism would be an important area for further research.

Figure 1

Actions of glucose-dependent insulinotropic polypeptide (GIP) at its target organs. In addition to its well-known effects on pancreatic β-cell and insulin secretion, GIP has been found to have extrapancreatic effects on the brain, and enhancing memory, increasing glucose utilization in muscle, promoting lipogenesis and inflammation in adipose tissue, and increasing bone formation.