Periodic Reporting for period 1 - FIDELIO (Training network for research into bone Fragility In Diabetes in Europe – towards a personaLised medIcine apprOach) Période du rapport: 2019-10-01 au 2021-09-30 Résumé du contexte et des objectifs généraux du projet Diabetes currently affects around 500 million people worldwide, and this number is growing every year. While there are some treatments available to help control blood sugar, people with diabetes are still at risk of serious health problems, with diabetes affecting various organs of the body.It has recently been identified that diabetes has a long-term effect on bone health. Patients with diabetes have a higher risk of fragility fractures, compared to non-diabetic people. Fragility fractures are fractures that occur where healthy bone would not normally break, for example when falling from a standing position. Common fragility fractures include those of the hip and vertebrae (in the spine).At present we do not completely understand why diabetes is associated with extra risk of fragility fracture. Having lower bone mineral density (as with osteoporosis in old age) is a major factor in the risk of fragility fracture. However, people with type 1 and type 2 diabetes (T1D and T2D) have an even higher fracture risk, than what would be expected from bone density. Therefore, other qualities of bone, such as its structure and quality are likely to be affected by diabetes and contribute to a higher fracture risk. The overall objective of FIDELIO is to gain fundamental knowledge of the multiple genetic and environmental factors that may lie behind the observed higher risk of fragility fracture in diabetes. The FIDELIO project (Training network for research into Fractures In Diabetes in Europe – towards a personalised medicine approach) aims to -understand more about the effects of diabetes on bone health,-assess how these changes may result in a higher risk of fragility fracture,-and determine how we can use this new knowledge to help better diagnose and treat people with diabetes.FIDELIO is a four year project funded by the European Union with the aim to train 14 PhD students (Early Stage Researchers, ESRs) within a network of bone and diabetes scientific researchers, medical doctors and companies. Each student has their own individual research project investigating an aspect of bone health in diabetes. Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent WP1 EPIDEMIOLOGY, PHARMACOEPIDEMIOLOGY AND RISK FACTORS FOR FRAGILITY FRACTURES IN DIABETIC PATIENTSESR4 and ESR14 are studying Danish healthcare system data to determine the precise risk of fracture in diabetes, and factors affecting that risk. Analysis by sex, age and site of fracture will soon be published.ESR3 is studying the effects of a high fibre diet on bone in type 2 diabetes in a clinical study. Analysis of bone, muscle and fat is underway to evaluate the roles of Wnt signaling pathway and inflammation.ESR9 is investigating how blood microRNA levels are changed in diabetes, and how this might affect bone strength and quality. They have identified microRNAs of interest to test in samples from clinical studies.ESR10 has analysed data from the Rotterdam study, to identify risk factors for fracture risk in diabetes. Large genomic datasets are now being analysed to identify possible genes and biological mechanisms involved. ESR11 is investigating how the population of human gut microorganisms might change with diabetes, and contribute to higher fracture risk. Preliminary results are obtained, and advanced methods for data processing and analysis by machine learning are being developed.WP2 BONE BIOMECHANICS AND MICROARCHITECTURE IN DIABETIC PATIENTSESR6 is developing a computational model to study fracture behaviour in diabetes, based on data of bone samples from people with T2D.ESR8 has developed a new computational approach to predict individual localised bone loading from imaging data. Results have been published (doi: 10.3389/fbioe.2021.677985).ESR12 is analysing changes to bone structure and composition in samples from diabetes patients, including from exposure to higher levels of sugar in the blood. Preliminary results are obtained showing some interesting differences with healthy bone.WP3 CELLULAR AND MOLECULAR MECHANISMS OF BONE FRAGILITY IN DIABETIC PATIENTSESR1 is investigating the role of Wnt proteins, analysing tissues of a mouse model of T2D. ESR2 is investigating a protein called Dkk-1 (a Wnt inhibitor) for its role in bone fragility, analysing a mouse model of this gene mutation. Analysis will be completed over the next period.ESR5 is studying the potential contribution mitochondrial dysfunction to diabetic bone disease, using samples from patients with T2D, as well as related rare diseases. Several cell and a mouse model are being developed to study these mechanisms.ESR7 is focusing on osteocytes, the most abundant type of bone cell, and how these are affected in diabetes. They are studying cell models and diabetic mouse models, and particularly the influence of exercise.ESR13 is investigating microRNAs with altered levels in diabetes, and exactly how these changes may affect bone cells and tissues. Several microRNAs have been identified for further study in a rat model of diabetes. TRAINING PROGRAMMEThe joint training programme of residential courses has been affected by the pandemic. Thus, in this period we focused on online training for transferable skills with practical courses to be done when travel is possible. FIDELIO has organised online courses and workshops on professional development, communication, and critical appraisal of real-world evidence. Also, monthly public webinars have been organised with speakers covering a range of topics. In September 2021, the FIDELIO ESRs attended the first in-person course, the EXCITE summer school on biomedical imaging in Zurich.FIDELIO has its own project website, Twitter, Facebook and Instagram accounts. A video introducing FIDELIO will shortly be available. Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent) The underlying mechanisms of poor bone strength in diabetes are not completely understood, and the factors involved that contribute to a patient’s personal risk of fracture need more investigation. Ultimately, prevention of onset and progression of diabetes is preferable to reduce fracture risk, but we still need new strategies to help patients who have been diagnosed. New tools are required for research, clinical studies and patient care.So far, FIDELIO has obtained good results (most yet to be published) and we expect the project to achieve its objectives. Expected results include: -Identification of epidemiological factors associated with risk of fragility fractures in diabetes, and clarification of the contributions of diet and metformin use, all potentially useful to assess personalised risk of fracture. -Identification of miRNAs that can be measured in blood as potential diagnostic markers of fragility fracture. Once validated in patient blood samples these can be used to help predict fracture risk in patients.-Computational methods developed at ETH to characterise localised bone loading from high resolution bone imaging can improve the diagnosis and care of patients, complementing other diagnostic approaches and aiding future research.-FIDELIO has also studied various animal models of diabetes, describing them in detail. A new mouse model is being developed at SDU, as well as new human cell models of rare forms of diabetes. All of these results will be useful in further research into diabetic bone disease. The models are being used to investigate potential therapeutic strategies, which may involve designing new drugs, or using existing drugs that can be repurposed. FIDELIO logo
