Fidelio
FIDELIO: A European Training Network
FIDELIO is a research and training network funded by a Horizon 2020 grant (Marie Skłodowska-Curie Action 860898), running from October 2019 to March 2024. The initiative brings together 14 European institutions, including both academic and industrial partners, with the goal of advancing the understanding of bone fragility in type 2 diabetes (T2D). By deepening knowledge in this area, the network aims to facilitate the development of biomarkers for the early detection and treatment of diabetes-related bone disease.
Rationale Behind FIDELIO
Diabetes mellitus has emerged as a significant risk factor for fragility fractures. However, the underlying mechanisms differ between type 1 and type 2 diabetes.
- In type 1 diabetes (T1D), the threefold increase in fracture risk is largely attributed to low bone mineral density (BMD), likely due to a deficiency in bone-anabolic hormones.
- In type 2 diabetes (T2D), fracture risk is approximately twice as high as in non-diabetic individuals, despite normal or even elevated BMD levels. This suggests that bone fragility in T2D is driven by mechanisms independent of bone density, which remain poorly understood.
As the prevalence of diabetes continues to rise globally, particularly in aging populations, the burden of diabetes-induced osteoporosis is becoming increasingly severe. Fragility fractures in diabetic patients contribute to higher morbidity, mortality, and healthcare costs, underscoring the urgent need for personalized approaches to prevention and treatment. FIDELIO aims to address this challenge by uncovering the mechanisms underlying diabetes-related bone fragility and identifying novel therapeutic targets.
FIDELIO offers a comprehensive and multidisciplinary training program for Early Stage Researchers (ESRs) in the emerging field of diabetic bone disease. The program is designed to:
- Unravel the biological mechanisms contributing to altered bone quality and increased bone fragility in diabetes.
- Identify predictive markers for patient stratification and personalized interventions.
- Develop novel imaging techniques to assess key aspects of bone quality.
To achieve these objectives, the research integrates well-defined patient cohorts, preclinical models of diabetic bone disease, in vitro studies, genetic databases, artificial intelligence, and advanced imaging technologies. This work is carried out within a highly collaborative and interdisciplinary environment.
ESRs receive training through individual research projects, secondments, residential courses, and webinars, delivered by a diverse team of experts, including bone biologists, clinicians, epidemiologists, geneticists, engineers, entrepreneurs, and industry partners. In addition to scientific expertise, the joint training program equips ESRs with transferable and entrepreneurial skills, preparing them for a successful professional future in academia, industry, or healthcare innovation.
Our Role in FIDELIO
We have played a key role in training PhD students within this network through the following research project:
Genetics and Biological Pathways Underlying Fracture Risk in Type 2 Diabetes (T2D)
Our research focuses on the genetic factors influencing diabetic bone disease in T2D, utilizing large datasets from population-based studies and clinical cohorts. By employing genetic scores within a Mendelian Randomization (MR) framework, we assess causal relationships between potentially confounded risk factors shared by both T2D and bone health.
Key aspects of our work include:
- Validating genetic associations in GWAS cohorts.
- Identifying molecular pathways that link skeletal and glucose metabolism.
- Exploring overlapping biological mechanisms between T2D and fracture risk.
Through this research, we aim to identify novel molecular pathways that intersect T2D and bone metabolism. Additionally, we seek to determine whether the T2D allelic score has a causal relationship with bone mineral density (BMD) or fracture risk, providing insights that could lead to improved prevention and treatment strategies.
Publications
Evaluating the relationship between glycemic control and bone fragility within the UK biobank: Observational and one-sample Mendelian randomization analyses.
Evaluating the relationship between glycemic control and bone fragility within the UK Biobank: observational and one-sample Mendelian randomization analyses
Samuel Ghatan, Fjorda Koromani, Katerina Trajanoska, Evert F.S. van Velsen, Maryam Kavousi, M. Carola Zillikens, Carolina Medina-Gomez, Ling Oei, Fernando Rivadeneira
Affiliations
1 Department of Internal Medicine, Erasmus Medical Center, 3015 GD, Rotterdam, The Netherlands
2 Canada Excellence Research Chair in Genomic Medicine, Victor Philip Dahdaleh Institute of Genomic Medicine, Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, QC H3G 2M1, Montreal, QC, Canada
3 Department of Epidemiology, Erasmus Medical Center, 3015 GD, Rotterdam, The Netherlands
*Corresponding author: Fernando Rivadeneira, Street address: Dr. Molewaterplein 40, 3015 GD, Rotterdam, NL, The Netherlands (f.rivadeneira@erasmusmc.nl)
Abstract
We aimed to: (1) examine the relationship between glycemic control, BMD estimated from heel ultrasound (eBMD) and fracture risk in individuals with type 1 (T1D) and type 2 diabetes (T2D) and (2) perform a one-sample Mendelian randomization (MR) study to explore potential causal associations between glycemic control, eBMD, and fractures. This study comprised 452 131 individuals from the UK Biobank with glycated hemoglobin A1C (HbA1c) and eBMD levels. At baseline, 4078 participants were diagnosed with T1D and 23 682 with T2D. HbA1c was used to classify patients into “adequately-” (ACD; n = 17 078; HbA1c < 7.0%/53 mmol/mol) and “inadequately-” (ICD; n = 10 682; HbA1c ≥ 7.0%/53 mmol/mol) controlled diabetes. In individuals with T1D, a 1% unit (11 mmol/mol) increase in HbA1c levels was associated with a 12% increase in fracture risk (HR: 1.12, 95% CI [1.05-1.19]). Fracture risk was highest in individuals with T1D and ICD (HR 2.84, 95%CI [2.53, 3.19]), followed by those with ACD (HR 2.26, 95%CI [1.91, 2.69]), as compared to subjects without diabetes. Evidence for a non-linear association between HbA1c and fracture risk was observed (F-test ANOVA p-value = 0.002) in individuals with T2D, with risk being increased at both low and high levels of HbA1c. Fracture risk between the T2D ACD and ICD groups was not significantly different (HR: 0.97, 95%CI [0.91-1.16]), despite increased BMD. In MR analyses genetically predicted higher HbA1c levels were not significantly associated with fracture risk (causal risk ratio: 1.04, 95%CI [0.95-1.14]). We did observe evidence of a non-linear causal association with eBMD (quadratic test p-value = 0.0002), indicating U-shaped relationship between HbA1c and eBMD. We obtained evidence that lower HbA1c levels will reduce fracture risk in patients with T1D. In individuals with T2D, lowering HbA1c levels can mitigate the risk of fractures up to a threshold, beyond which the risk may begin to rise again.
Keywords: type 2 diabetes, type 1 diabetes, fractures, BMD, glycemic control, Mendelian randomization, HbA1c
For more information on this article, click here.
Defining type 2 diabetes polygenic risk scores through colocalization and network-based clustering of metabolic trait genetic associations
Defining type 2 diabetes polygenic risk scores through colocalization and network-based clustering of metabolic trait genetic associations
Affiliations
1 Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
2 The Generation R Study Group, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
3 Department of Pediatrics, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
4 Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
*Corresponding author: Fernando Rivadeneira, Street address: Dr. Molewaterplein 40, 3015 GD, Rotterdam, NL, The Netherlands (f.rivadeneira@erasmusmc.nl)
Abstract
Background: Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and gain mechanistic insight. We expanded on these approaches by performing colocalization across GWAS traits while assessing the causality and directionality of genetic associations.
Methods: We applied colocalization between T2D and 20 related metabolic traits, across 243 loci, to obtain inferences of shared casual variants. Network-based unsupervised hierarchical clustering was performed on variant-trait associations. Partitioned polygenic risk scores (PRSs) were generated for each cluster using T2D summary statistics and validated in 21,742 individuals with T2D from 3 cohorts. Inferences of directionality and causality were obtained by applying Mendelian randomization Steiger’s Z-test and further validated in a pediatric cohort without diabetes (aged 9-12 years old, n = 3866).
Results: We identified 146 T2D loci that colocalized with at least one metabolic trait locus. T2D variants within these loci were grouped into 5 clusters. The clusters corresponded to the following pathways: obesity, lipodystrophic insulin resistance, liver and lipid metabolism, hepatic glucose metabolism, and beta-cell dysfunction. We observed heterogeneity in associations between PRSs and metabolic measures across clusters. For instance, the lipodystrophic insulin resistance (Beta – 0.08 SD, 95% CI [- 0.10-0.07], p = 6.50 × 10-32) and beta-cell dysfunction (Beta – 0.10 SD, 95% CI [- 0.12, – 0.08], p = 1.46 × 10-47) PRSs were associated to lower BMI. Mendelian randomization Steiger analysis indicated that increased T2D risk in these pathways was causally associated to lower BMI. However, the obesity PRS was conversely associated with increased BMI (Beta 0.08 SD, 95% CI 0.06-0.10, p = 8.0 × 10-33). Analyses within a pediatric cohort supported this finding. Additionally, the lipodystrophic insulin resistance PRS was associated with a higher odds of chronic kidney disease (OR 1.29, 95% CI 1.02-1.62, p = 0.03).
Conclusions: We successfully partitioned T2D genetic variants into phenotypic pathways using a colocalization first approach. Partitioned PRSs were associated to unique metabolic and clinical outcomes indicating successful partitioning of disease heterogeneity. Our work expands on previous approaches by providing stronger inferences of shared causal variants, causality, and directionality of GWAS variant-trait associations.
Keywords: Clustering; Colocalization; Personalized medicine; Polygenic risk score; Type 2 diabetes.
For more information on this article, click here.
Bi-Directional Interactions between Glucose-Lowering Medications and Gut Microbiome in Patients with Type 2 Diabetes Mellitus: A Systematic Review
Bi-Directional Interactions between Glucose-Lowering Medications and Gut Microbiome in Patients with Type 2 Diabetes Mellitus: A Systematic Review
Affiliations
1 Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
2 Department of Epidemiology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
3 Department of Data Science & Biostatistics, Julius Global Health, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
Abstract
Background: Although common drugs for treating type 2 diabetes (T2D) are widely used, their therapeutic effects vary greatly. The interaction between the gut microbiome and glucose-lowering drugs is one of the main contributors to the variability in T2D progression and response to therapy. On the one hand, glucose-lowering drugs can alter gut microbiome components. On the other hand, specific gut microbiota can influence glycemic control as the therapeutic effects of these drugs. Therefore, this systematic review assesses the bi-directional relationships between common glucose-lowering drugs and gut microbiome profiles. Methods: A systematic search of Embase, Web of Science, PubMed, and Google Scholar databases was performed. Observational studies and randomised controlled trials (RCTs), published from inception to July 2023, comprising T2D patients and investigating bi-directional interactions between glucose-lowering drugs and gut microbiome, were included. Results: Summarised findings indicated that glucose-lowering drugs could increase metabolic-healthy promoting taxa (e.g., Bifidobacterium) and decrease harmful taxa (e.g., Bacteroides and Intestinibacter). Our findings also showed a significantly different abundance of gut microbiome taxa (e.g., Enterococcus faecium (i.e., E. faecium)) in T2D patients with poor compared to optimal glycemic control. Conclusions: This review provides evidence for glucose-lowering drug and gut microbiome interactions, highlighting the potential of gut microbiome modulators as co-adjuvants for T2D treatment.
Keywords: glucose-lowering medications; gut microbiome; type 2 diabetes mellitus.
For more information on this article, click here.
The Treatment Gap in Osteoporosis
The Treatment Gap in Osteoporosis
Affiliations
1 Division of Endocrinology and Diabetes, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
2 Division of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, 00128 Rome, Italy.
3 Department of Internal Medicine, Erasmus University Medical Center, PO Box 2040-Na27-24, 3015 GD Rotterdam, The Netherlands.
4 Division of Rheumatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
5 Division of Bone and Mineral Diseases, Washington University, St. Louis, MO 63110, USA.
6 Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
- DOI: 10.3390/jcm10133002
Abstract
Worldwide, there are millions of people who have been diagnosed with osteoporosis, a bone disease that increases the risk of fracture due to low bone mineral density and deterioration of bone architecture. In the US alone, there are approximately ten million men and women diagnosed with osteoporosis and this number is still growing. Diagnosis is made by measuring bone mineral density. Medications used for the treatment of osteoporosis are bisphosphonates, denosumab, raloxifene, and teriparatide. Recently, romosozumab has been added as well. In recent years, a number of advances have been made in the field of diagnostic methods and the diverse treatment options for osteoporosis. Despite these advances and a growing incidence of osteoporosis, there is a large group being left undertreated or even untreated. This group of the under/untreated has been called the treatment gap. Concerns regarding rare side effects of the medications, such as osteonecrosis of the jaw, have been reported to be one of the many causes for the treatment gap. Also, this group seems not to be sufficiently informed of the major benefits of the treatment and the diversity in treatment options. Knowledge of these could be very helpful in improving compliance and hopefully reducing the gap. In this paper, we summarize recent evidence regarding the efficacy of the various treatment options, potential side effects, and the overall benefit of treatment.
Keywords: epidemiology; fracture; glucocorticoid; osteoporosis; pharmacological treatment; review; treatment gap.
For more information on this article, click here.
Type 2 Diabetes Mellitus and Vertebral Fracture Risk
Type 2 Diabetes Mellitus and Vertebral Fracture Risk
Affiliations
1 Department of Internal Medicine, Erasmus University Medical Center, PO Box 2040-Na27-24, 3000 CA, Rotterdam, The Netherlands.
2 Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
3 Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
4 Department of Internal Medicine, Erasmus University Medical Center, PO Box 2040-Na27-24, 3000 CA, Rotterdam, The Netherlands. h.l.d.w.oei@erasmusmc.nl.
5 Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. h.l.d.w.oei@erasmusmc.nl.
6 Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands. h.l.d.w.oei@erasmusmc.nl.
Abstract
Purpose of review: The purpose of this review is to summarize the recently published evidence concerning vertebral fracture risk in individuals with diabetes mellitus.
Recent findings: Vertebral fracture risk is increased in individuals with T2DM. The presence of vertebral fractures in T2DM is associated with increased non-vertebral fracture risk and mortality. TBS could be helpful to estimate vertebral fracture risk in individuals with T2DM. An increased amount of bone marrow fat has been implicated in bone fragility in T2DM. Results from two recent studies show that both teriparatide and denosumab are effective in reducing vertebral fracture risk also in individuals with T2DM. Individuals with T2DM could benefit from systematic screening in the clinic for presence of vertebral fractures.
Keywords: BMD; Diabetes; Osteoporosis; TBS; Vertebral fractures.
For more information on this article, click here.
Microvascular Disease Associates with Larger Osteocyte Lacunae in Cortical Bone in Type 2 Diabetes Mellitus
Microvascular Disease Associates with Larger Osteocyte Lacunae in Cortical Bone in Type 2 Diabetes Mellitus
Affiliations
1 Molecular Endocrinology Department, Department M Odense University Hospital Odense Denmark.
2 Clinical Institute University of Southern Denmark Odense Denmark.
3 Institute for Biomechanics ETH Zurich Zurich Switzerland.
4 Department of Internal Medicine Erasmus MC University-Medical Center Rotterdam Rotterdam The Netherlands.
5 Steno Diabetes Centre Odense OUH Odense Denmark.
- DOI: 10.1002/jbm4.10832
Abstract
Clinical studies indicate that microvascular disease (MVD) affects bone microstructure and decreases bone strength in type 2 diabetes mellitus (T2D). Osteocytes are housed in small voids within the bone matrix and lacunae and act as sensors of mechanical forces in bone. These cells regulate osteoclastic bone resorption and osteoblastic bone formation as well as osteocytic perilacunar remodeling. We hypothesized that MVD changes morphometric osteocyte lacunar parameters in individuals with T2D. We collected iliac crest bone biopsies from 35 individuals (10 female, 25 male) with T2D with MVD (15%) or without MVD (21%) with a median age of 67 years (interquartile range [IQR] 62-72 years). The participants were included based on c-peptide levels >700 pmol L-1, absence of anti-GAD65 antibodies, and glycated hemoglobin (HbA1c) levels between 40 and 82 mmol mol-1 or 5.8% and 9.7%, respectively. We assessed osteocyte lacunar morphometric parameters in trabecular and cortical bone regions using micro-computed tomography (micro-CT) at a nominal resolution of 1.2 μm voxel size. The cortical osteocyte lacunar volume (Lc.V) was 7.7% larger (p = 0.05) and more spherical (Lc.Sr, p < 0.01) in the T2D + MVD group. Using linear regression, we found that lacunar density (Lc.N/BV) in trabecular but not cortical bone was associated with HbA1c (p < 0.05, R 2 = 0.067) independently of MVD. Furthermore, Lc.V was larger and Lc.Sr higher in the center than in the periphery of the trabecular and cortical bone regions (p < 0.05). In conclusion, these data imply that MVD may impair skeletal integrity, possibly contributing to increased skeletal fragility in T2D complicated by MVD. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Keywords: ANALYSIS/QUANTITATION OF BONE; BIOMECHANICS; BONE QCT/MICRO‐CT; CELLS OF BONE; ORTHOPEDICS; OSTEOCYTES.
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