Fellows page

FIDELIO will train 14 young researchers  for next-generation bone and diabetes research. Each ESR will be enrolled in a PhD programme to study for a doctorate and will conduct her/his own individual research project. A project summary written in a language understandable to the general public is included with each ESR profile below. Interdisciplinary training and implementation of innovative approaches are the key. The training programme and experience of different international research environments with international leaders cuts across traditional data and life sciences silos.

Lejla Emini

ESR1: Investigating the role of Wnt signalling in type 2 diabetes induced bone disease

Lejla completed her BSc in Biology at the University of Copenhagen in Denmark, then achieved her MSc in Molecular Biology at the same university. She did her master thesis at the Finsen Laboratory and Biotech Research & Innovation Centre (BRIC) which focused on construction of antibody drug conjugates (ADCs) targeting macrophages in cancer. After her studies, she worked as a research assistant at the Department of Clinical Biochemistry at Rigshospitalet in Denmark, investigating the effect of P2Y12 receptor antagonists on bone turnover in a preclinical in vivo model.

Objectives: Regulation of Wnt signaling in the monogenetic db/db mouse as well as the polygenetic TallyHo mouse. Investigation of miRNA profiles to determine which miRNAs are associated with diabetic bone disease and target Wnt signaling and whether modulating specific miRNAs may qualify as a therapeutic strategy.

Host: TU Dresden, Germany
Supervisor: Prof. Dr. Lorenz Hofbauer

A range of complications accompanies both type 1 diabetes (T1D) and type 2 diabetes mellitus (T2DM) and all of them contribute to a severely increased morbidity and mortality. One of the less investigated clinical consequences is the increased risk of fractures. In order to investigate the connections between T2DM and bone, the Wnt signaling pathway will be the primary focus in this project.

The Wnt signaling pathway comprises a group of signal transduction pathways, which begin with proteins that pass signals into the cell through cell. This is also known as an intracellular signal that then will coordinate processes such as bone formation and bone renewal. Irregularities in the Wnt signaling pathway leads to various bone disorders including failure of proper bone formation. The Wnt signaling pathway may be one such mechanism linking T2DM and bone. This can potentially give insight, why T2DM patients are more prone to bone fractures.

The aim of my PhD project is to figure out the influence of Wnt signaling on type 2 diabetes induced bone disease. For this purpose, animal models with type 2 diabetes will be generated. This model will be characterized in terms of fat, bone and blood vessels in comparison to animal models that do not have type 2 diabetes, using state-of-the-art techniques. Furthermore we will also use Wnt signaling activators (targets this pathway specifically), that will be applied to our animal model and bone cells to determine whether the reduction of bone quality can be restored.

New findings in this study will provide a better definition of the mechanism underlying the increased fracture risk in T2DM. The effects of these altered Wnt signaling pathways not only highlight the crucial role that the Wnt signaling plays in normal bone physiology but also point to the potential of the Wnt signaling pathway as a target for the development of therapeutic targets in treating bone disorders.

Diabetes mellitus, oder auch Zuckerkrankheit, ist eine weitverbreitete Stoffwechselerkrankung. Entsprechend der zugrunde liegenden Ursache kann man verschiedene Subtypen unterscheiden. Allen gemeinsam ist jedoch, dass die dauerhafte Fehlregulation des Zuckerstoffwechsels zu schwerwiegenden Folgeerscheinungen führen kann. Neben den eher bekannten Auswirkungen auf das Herz-Kreislauf-System, die Nieren, Augen und die Haut haben Patienten mit Diabetes auch ein erhöhtes Risiko für Knochenbrüche. Warum das so ist, ist bislang noch nicht vollständig geklärt. Weniger Knochenmasse, wie etwa bei Osteoporose (Knochenschwund) wird häufig nicht beobachtet und lässt vermuten das stattdessen die Knochenqualität verringert ist.

Ein zentraler Steuermechanismus im Knochen ist der Wnt-Signalweg. Dieser Signalweg kontrolliert über viele verschiedene Proteine vor allem den Aufbau von neuem Knochen. Aus dem Gleichgewicht geraten können einige dieser Proteine schwere Knochenveränderungen verursachen. Wir vermuten, dass die schlechte Knochenqualität bei Diabetes mellitus Typ 2 auch auf Störungen des Wnt-Signalweges zurückzuführen ist.

Diesen Zusammenhang genauer zu untersuchen ist das Ziel meiner Doktorarbeit. Dazu werde ich mit Tiermodellen arbeiten, die entweder gesund sind oder einen ausgeprägten Diabetes mellitus Typ 2 aufweisen. Durch den Vergleich gesunder und diabetischer Knochenmasse, dessen Gefäßsystem und des Fettgewebes werden wir in der Lage sein, Unterschiede in der Regulation dieses Signalweges aufzudecken. Abschließend soll untersucht werden ob sich durch einen gezielten Eingriff in den Wnt-Signalweg die Knochenqualität verbessern lässt.

Durch das Aufdecken neuer Zusammenhänge und Mechanismen die dem Frakturrisiko bei T2DM zu Grunde liegen könnten zukünftig neue Therapien zur Behandlung von Knochenstoffwechselstörungen entwickelt werden.

Souad Daamouch

ESR2: Role of Dkk-1 in type 1 diabetes bone fragility 

Souad graduated with a B.Sc. in Health Engineering from Nancy-Université, France. Afterwards she obtained her MSc in Pathophysiology & Personalized Medicine in Human Transplantation from Université de Strasbourg. The main objective of her project was to study histocompatibility genes in human transplantations. After her studies, she worked as a clinical research assistant at the Department of Orthopedic Surgery at Université du Luxembourg. In addition, Souad also has expertise in karate and collaborates with the Luxembourg National Team in karate to advise young athletes on the prevention of orthopedic injuries.

Objectives: Determine the cell-specific contribution of Dkk1 to impaired bone strength in T1D, investigate whether modulation of Dkk1 also affects the bone vasculature, validate the importance of Dkk1 in T1D patient cohorts.

Host: TU Dresden, Germany
Supervisor: Prof. Dr. Martina Rauner

Osteoporosis is a disease characterized by poor bone quality, meaning that bones break more easily. It is especially common in elderly people. Given that our society is becoming older, the number of people who will break a bone will further increase. Thus, it is critical to find ways to stop bones to break.

Besides aging, patients with diabetes mellitus type 1 (T1D), who are often children and adolescents, are also more likely to break their bones. However, it is not fully understood why. In order to understand what is happening, my research is focusing on understanding why patients with T1D break their bones more easily.

Our body needs sugar in form of glucose to produce energy. However, in T1D, patients cannot use the sugar properly and it accumulates in the blood. These high levels of glucose in the blood have been shown to damage the function of many organs such as the kidneys, the heart, and the eyes. Importantly, also bone strength is negatively affected.

Researchers have seen that patients suffering from T1D have high levels of a protein called Dkk-1, which hinders bones to repair. In my project, I will try to find out which cells produce Dkk-1 and how this increased production can be prevented. Using cell and molecular biological approaches, mutant mice, and patient cohorts, I hope that my research will identify new ways to help patients with T1D maintain their bone strength.

L’ostéoporose est une maladie caractérisée par une mauvaise qualité osseuse, ce qui signifie que les os se brisent plus facilement. Elle est particulièrement fréquente chez les personnes âgées. Étant donné que notre société vieillit, le nombre de personnes qui se cassent un os va encore augmenter. Il est donc essentiel de trouver des moyens d’empêcher que les os ne se brisent.

Outre le vieillissement, les patients atteints de diabète de type 1 (T1D), qui sont souvent des enfants et des adolescents, sont également plus susceptibles de se casser des os. Cependant, on ne comprend pas tout à fait pourquoi. Afin de comprendre ce qui se passe, mes recherches se focalisent sur la compréhension, des raisons pour lesquelles les patients atteints de T1D se cassent plus facilement les os.

Notre corps a besoin de sucre sous forme de glucose pour produire de l’énergie. Cependant, dans le T1D, les patients ne peuvent pas utiliser le sucre correctement et celui-ci s’accumule dans le sang. Il a été démontré que ces niveaux élevés de glucose dans le sang nuisent au fonctionnement de nombreux organes tels que les reins, le cœur et les yeux. Il est important de noter que la solidité des os est également affectée.

Les chercheurs ont constaté que les patients souffrant de T1D ont des taux élevés d’une protéine appelée Dkk-1, qui empêche les os de se réparer. Dans mon projet, je vais essayer de découvrir quelles cellules produisent Dkk-1 et comment cette production accrue peut être évitée. En utilisant des approches de biologie cellulaire et moléculaire, des souris mutantes et des cohortes de patients, j’espère que mes recherches permettront d’identifier de nouvelles façons d’aider les patients atteints de T1D afin de conserver leur solidité osseuse.

Osteoporose ist eine Krankheit, die durch eine schlechte Knochenqualität gekennzeichnet ist, was bedeutet, dass die Knochen leichter brechen. Sie tritt besonders häufig bei älteren Menschen auf. Da unsere Gesellschaft immer älter wird, wird die Zahl der Menschen, die sich einen Knochenbruch zuziehen, weiter steigen. Daher ist es entscheidend, Wege zu finden, um Knochenbrüche zu verhindern.

Patienten mit Diabetes mellitus Typ 1 (T1D) haben ein höheres Risiko, sich einen Knochen zu brechen. Die Ursache ist jedoch noch nicht vollständig geklärt. Um zu verstehen warum das so ist, erforsche ich in meiner Doktorarbeit, warum die Knochen von Patienten mit T1D leichter brechen.

Unser Körper braucht Glukose um Energie zu produzieren. Patienten mit T1D können die Glukose jedoch nicht richtig verwerten, so dass es in der Blutzirkulation ansammelt. Diese hohen Glukosekonzentrationen führen zu Organschäden, wie z.B. Funktionseinschränkungen in der Niere, den Augen, aber auch dem Knochen.

Forscher haben festgestellt, dass Patienten, die an T1D leiden, auch erhöhte Konzentrationen eines Proteins namens Dkk-1 haben, welches die Reparatur von Knochen verhindert. In meiner Doktorarbeit möchte ich daher untersuchen, welche Zellen das Dkk-1 produzieren und wie diese vermehrte Produktion verhindert werden kann. Mit Erkenntnissen aus zellulären und molekularbiologischen Methoden sowie Tiermodellen und Patientenkohorten hoffe ich, dass meine Forschung neue Behandlungsmöglichkeiten aufdecken kann, die die Knochengesundheit bei Patienten mit T1D erhalten können.

Malak Faraj

ESR3: Investigating the role of different diet regimens on bone health and fracture risk in T2D

Malak obtained her Bachelor Degree in Biology at the Lebanese University. After that she enrolled in the Master I program in Applied Animal Biology at the Lebanese University and continued with Master’s II in Physiology, Epigenetics, Development, Cell differentiation, and Cancer program at the University Grenoble Alpes in France. Further practical skills she optained during an internship in the team of “Analytical Immunology of Chronic Disease” at the Institute for Advanced Biosciences in Grenoble with a topic on the role of PD-1/PD-L1 axis in  Hepatocellular Carcinoma.

Objectives: Test efficacy of a FEHC diet on bone, muscle, and fat inflammation status and ECS in elderly diabetic subjects. Assess bone and skeletal muscle quality in relation to dietary intervention. Evaluate modulation of Wnt pathway in relation to dietary intervention.

Host: Universita Campus Bio Medico di Roma, Italy
Supervisor: Prof. Nicola Napoli

Type 2 diabetes mellitus (T2DM) is one of the most common metabolic diseases, whose prevalence is increasing worldwide with the growth of the aging population, sedentary lifestyle, and obesity. In the last years, accumulating evidences suggest that T2DM is associated with increased fracture risk, despite normal or even higher bone mineral density. Fractures in T2DM patients take longer to healompared to those in non-diabetic patients. Multiple factors can contribute to the increased fracture risk in T2DM leading to impaired bone quality. However, the exact mechanisms of how diabetes affects bone are not fully understood.

Dietary intervention is essential in T2DM management. Consuming dietary fiber is highly recommended for patients with T2DM. Dietary fiber has been shown to have a positive effect on metabolic outcomes and inflammatory status compared to a standard diet in T2DM. An unmet need is to provide a weight loss intervention that will improve bone and muscle health in T2DM patients.

The goal of our project is to provide a scientific understanding of the effects of different dietary regimens on bone health and fracture risk in T2DM. In our study, we aim to test the effect of fiber-rich diet (FEHC) on improving bone and muscle health in elderly T2DM subjects by investigating the possible molecular mechanisms that are involved in diabetic bone complications, using molecular biology, biomechanics, and imaging techniques.

Our study may improve the understanding of the molecular mechanisms and therapeutic approach of T2DM related bone and muscle fragility and may set the basis of future studies toreduce the economic and social burden of diabetic related complications and comorbidities.

Il Diabete Mellito di tipo 2 (DMT2) è uno tra i più comuni disturbi metabolici, la cui prevalenza è in continua crescita a livello mondiale parallelamente a un aumento dell’età della popolazione, a una vita sempre più sedentaria e all’obesità. Un numero crescente di studi negli ultimi anni ha evidenziato che il DMT2 è associato a un aumento del rischio di fratture, a fronte di una massa ossea normale o addirittura maggiore dei soggetti non diabetici. Le fratture nei pazienti con T2DM richiedono più tempo per guarire Rispetto a quelle dei pazienti non diabetici. Molteplici fattori possono contribuire all’aumento del rischio di frattura in DMT2 che porta a una qualità ossea compromessa. Tuttavia, i meccanismi esatti di come il diabete influisca sulle ossa non sono completamente chiari.

L’intervento dietetico alimentare è essenziale nella gestione del DMT2. Un consumo ricco di fibre con la dieta è altamente raccomandato nei pazienti affetti da DMT2. E’ stato dimostrato che, nel DMT2, una dieta ricca in fibre ha un effetto positivo sul controllo metabolico e sullo stato infiammatorio rispetto a una dieta standard. Un importante intervento clinico che non è stato ancora verificato è quello di ottenere una perdita di peso al fine di migliorare la salute ossea e muscolare nei pazienti affetti da DMT2.

L’obiettivo del nostro progetto è quello di fornire una comprensione scientifica avanzata degli effetti di diversi regimi dietetici sulla salute ossea e sulla prevenzione del rischio di frattura in T2DM. Nel nostro studio, miriamo a testare l’effetto di una dieta ricca in fibre (FEHC) sul miglioramento della salute ossea e muscolare nei soggetti anziani affetti da DMT2, studiando i possibili meccanismi molecolari che sono coinvolti nelle complicanze ossee diabetiche e utilizzando tecniche di biomeccanica e imaging.

Il nostro studio potrebbe migliorare le attuali conoscenze dei meccanismi molecolari e degli approcci terapeutici connessi alla fragilità ossea e muscolare del DMT2 e potrebbe gettare le basi per studi futuri al fine di ridurre il peso economico e sociale collegato alle complicanze  e comorbidità del DMT2.

Mohamad Nasser

ESR4: Epidemiology of fragility fractures and diabetes

Mohamad completed his B.Sc. in Pharmacy at Beirut Arab University in Lebanon in 2013, followed by a career as a senior medical sales representative at AstraZeneca. In 2017, he pursued his M.Sc. in Epidemiology at Ludwig Maximilian University of Munich (LMU) in Germany. During his studies, he worked as a research assistant at the Institute for Medical Informatics, Biometry and Epidemiology (IBE) in Munich, and at the German Cancer Research Center in Heidelberg (DKFZ). He conducted his thesis at the DKFZ-division of cancer epidemiology, investigating medication use and its association with all-cause mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort.

Objectives: To obtain a detailed epidemiology of fragility fractures in T1D and T2D, and determine whether microvascular disease a predictor of fragility fractures in patients with T1D and T2D, and whether insulin sensitivity and secretion are predictors of fractures in patients with T2D.

Host: Syddansk Universitet, Denmark
Supervisor: Dr. Morten Frost

Fragility fractures in T1D and T2D are not fully explained by classical age-related osteoporosis. Much-debated questions regarding the effect of multiple diabetes-related factors on skeletal fragility, including diabetes complications, medications and the role of insulin, remain unanswered. My research project aims to study the epidemiology of fragility fractures in diabetics.

We will be mainly using previously collected anonymized large datasets (over one million and a half participants with fractures followed for over 20 years) such as the Danish National Patient Registry and other Danish cohorts. Various statistical methodologies to identify risk factors for diabetic skeletal fragility will be implemented. In addition, we will collaborate partially with IBM (International Business Machines Corporation) to apply innovative machine learning techniques, to analyze and assess different associations.

The research is a step forward towards a better understanding of diabetic skeletal fragility. Thus, we seek to clarify if fracture risk increases earlier and if prevention strategies need to be initiated earlier in T1D as compared to T2D and the general population. Besides, the project will investigate the impact of diabetes microvascular complications, antidiabetic and anti-osteoporotic medications on fragility fracture risk. Therefore, better clinical management, improved preventive efforts, and an increased focus on individually targeted treatments may be implemented, for improved care of diabetic patients.

Knoglebrud opstået ved lavenergi ved type 1 diabetes (T1D) og type 2 diabetes (T2D) kan ikke alene forklares ved klassisk alders-relateret osteoporose. Spørgsmål vedrørende betydningen af adskillige diabetes-relaterede faktorer for knoglestyrken inklusive diabeteskomplikationer, behandling og insulins rolle er ubesvaret. Mit forskningsprojekt undersøger epidemiologien ved lavenergibrud ved diabetes.

Vi vil hovedsageligt anvende tidligere indsamlet anonymiseret data (over 1,5 millioner deltagere med knoglebrud fulgt i mere end 20 år) som Det Danske Patientregister og andre danske kohorter. Forskellige statistiske metoder vil blive brugt til at identificere risikofaktorer for knoglebrud. Desuden vil vi i samarbejde med IBM (International Business Machines Corporation) anvende machine learning (dansk: maskinlæring) teknikker til at analysere og vurdere sammenhænge mellem faktorer og knoglebrud.

Forskningen tager et skridt i retning af en bedre forståelse af nedsat knoglesygdom ved diabetes. Vi ønsker således at afklare hvis frakturrisikoen øges tidligere og om forebyggende tiltag bør påbegyndes tidligere ved T1D end T2D og den øvrige befolkning. Derudover vil projektet afklare virkningen af mikrovaskulær sygdom ved diabetes, antidiabetika og osteoporosemedicin på risikoen for et lavenergi knoglebrud. Målet er at forbedre behandlingen af diabetespatienter ved styrkelse af forebyggelsen, bedre medicinsk behandling og øget fokus på individuel behandling.

Sebastian Zanner

ESR5: Bioenergetics of human osteoblasts

Sebastian completed his B.Sc. at the University of Bayreuth in Germany and obtained his M.Sc. from the BIOSS Centre for Biological Signalling Studies at the University of Freiburg. His thesis focused on the implementation of optically controllable cell adhesion receptors (OptoIntegrins, in parts published in Communications Biology in 2019). After finishing his Master’s project, Sebastian went to Sydney for an internship and continued working on optogenetics applied to T-cell receptor clustering at the University of New South Wales.

Objectives: To investigate changes in osteoblast bioenergetics in diabetes patients, and the mechanisms by which metabolic changes may alter the osteoblast phenotype

Host: Syddansk Universitet, Denmark
Supervisor: Prof. Dr. Moustapha Kassem

Many people experience a bone fracture during their lives. The fracture site is repaired by specialized bone cells called osteoblasts and osteoclasts which build-up new bone and dissolve existing bone, respectively. This process, called bone remodeling, also happens continuously without a visible fracture. Irregularities in this process can cause decreased bone-stability and fractures to occur more frequently. This instability of bone is a big issue in various diseases, one of which is type 1 diabetes mellitus. The reasons for this may be diverse, but the causes have not yet been investigated in detail.

The aim of this project is to figure out the influence of mitochondria (the power plants of cells) on bone health. For this purpose, bone cells and animal models with compromised mitochondria will be generated in the laboratory and analyzed for their ability to form bone. Furthermore, cells and bone tissue from type 1 diabetes patients will be tested in devices for their energy expenditure and structure, respectively. This will lead to new insights and answer the question how important mitochondria are in the interplay of diabetes and bone health.

New findings in this study could lead to new medication for type 1 diabetes patients with bone disease. Patients prone to bone problems could be treated with drugs or supplements that activate mitochondria and thus improve bone health.

Mange mennesker oplever i løbet af livet at brække en knogle. Knoglebruddet repareres naturligt af specialiserede knogleceller kaldet osteoblaster og osteoklaster, der opbygger henholdsvis ny knogle og nedbryder eksisterende knogle. Denne proces, kaldet knoglemodellering, sker også, når der ikke er nogen knoglebrud. Uregelmæssigheder i remodelleringen kan medføre nedsat knoglestabilitet og øget risiko for knoglebrud. Denne ustabilitet af knoglerne er et stort problem ved mange sygdomme, herunder type 1 diabetes mellitus. Årsagerne til ustabiliteten i knoglerne ved type 1 diabetes er endnu ikke undersøgt i detaljer.

Formålet med dette projekt er at finde ud af mitokondriers (cellernes kraftværker) indflydelse på knoglesundheden. Til dette formål genereres knogleceller og dyremodeller med kompromitterede mitokondrier i laboratoriet og analyseres for deres evne til at danne knogler. Desuden vil celler og knoglevæv fra type 1-diabetes patienter blive testet for henholdsvis deres energiforbrug og struktur. Dette vil besvare spørgsmålet: Hvor vigtig er mitokondrierne i samspillet mellem diabetes og knogler?

Undersøgelsen vil afklare, om forbedring af mitokondriernes aktivitet kan gavne knoglerne hos patienter med type 1 diabetes og potentielt også patienter, der af anden grund er tilbøjelige til at udvikle eller allerede har knoglesygdom.

Viele Menschen erleiden im Laufe ihres Lebens einen Knochenbruch. Meist verläuft der Heilungsprozess komplikationslos und die Bruchstelle wird vom Körper repariert. Dies geschieht durch spezialisierte Zellen, die Knochen abbauen (Osteoklasten) und aufbauen (Osteoblasten). Diese Plastizität wird bei einem Knochenbruch deutlich, jedoch wird stetig auch ohne Fraktur Knochen auf und abgebaut, um kleine Schäden zu reparieren. Unregelmäßigkeiten in diesem Prozess, der sich Knochenumbau (bone remodeling) nennt, können dazu führen, dass die Stabilität der Knochen abnimmt und Brüche häufiger auftreten. Besonders drastisch ist das bei Menschen der Fall, die an Knochenschwund (Osteoporose) leiden, doch auch Patienten mit der Zuckerkrankheit (Diabetes) neigen stärker zu Knochenbrüchen. Die Gründe hierfür sind wahrscheinlich divers, doch genaue Ursachen sind noch nicht erforscht.

In diesem Projekt werden wir den Einfluss von Mitochondrien (den Kraftwerken der Zellen) auf die Knochengesundheit untersuchen. Dazu werden wir Zellen sowie Mäuse mit Defekten in den Mitochondrien generieren und auf ihre Fähigkeit Knochen zu bilden Untersuchen. Zudem werden wir Zellen von Typ 1 Diabetes Patienten entnehmen und deren Mitochondrien untersuchen. Knochenproben von diesen Patienten werden außerdem analysiert und auf strukturelle Unterschiede mit Proben von gesunden Personen verglichen.

Neue Erkenntnisse in dieser Studie könnten zu neuer Medikation von Patienten führen. So wäre es zum Beispiel denkbar, dass Patienten, die zu Knochenproblemen neigen mit Medikamenten oder Nahrungsergänzungsmitteln behandelt werden, welche    die Mitochondrien aktivieren und somit die Knochengesundheit verbessern. Zudem wird die Studie dazu beitragen, Gründe für Knochenprobleme bei Menschen mit Diabetes zu definieren.

ESR6: Development of diabetes-sensitive computational models of bone strength for the clinical diagnosis and pre-clinical tracking of diabetic bone fragility

Objectives: Determine the contributions of cortical porosity and AGE accumulation to bone tissue mechanics in T2DM, and incorporate these into a novel, disease-specific FE model of bone strength.

Host: UKE Hamburg, Germany
Supervisor: Prof. Dr. Björn Busse

Sara Delon

ESR7: Investigating the role of osteocyte and mechanotransduction on bone fragility in type 2 diabetes

Sara completed her B.Sc. in Cell Biology and Physiology at Université Blaise Pascal in Clermont-Ferrand, France, then obtained a M.Sc. in Cell and Tissue Engineering at Université Jean Monnet in Saint-Étienne. In a previous project she invastigated the effects of a ketogenic diet on obesity-related osteoarthritis.

Objectives: Identify osteocyte factors that are regulated by glucose metabolism and contribute to bone fragility in T2D, and characterise their involvement in the bone response to exercise and diet.

Host: Université de Genève, Switzerland
Supervisor: Prof. Serge Ferrari

Type 2 diabetes mellitus (T2DM) and osteoporosis are two chronic diseases whose prevalence (the number of cases in the population at a given time) is constantly increasing, particularly as the population is aging. Beyond known complications of T2DM such as cardiovascular, kidney, neurological and eye disorders, we now know that disturbances resulting from high blood sugar levels (hyperglycemia) have a deleterious effect on bone remodeling, the process of continuous bone formation and resorption. In fact, T2DM patients have an increased risk of fractures which can be explained by alterations of the internal structure of the bone and therefore its quality, and by the increased risk of falls. This bone fragility observed in the context of T2DM has a multifactorial origin. However, the exact mechanisms involved are complex and not yet fully understood. We hypothesize that altered bone cell functions, as well as modulated secretion of several molecules by the bone cells, could lead to a decreased bone remodeling in patients with T2DM. To investigate this hypothesis, we will specifically focus on osteocytes, the most abundant bone cell with a major role in the formation of new bone and repair of bone damage. We aim to provide further insight into the mechanisms underlying bone fragility in T2DM by using different experimental models (cell culture of bone cells in the presence of sugar, mechanically-stimulated diabetic mice) and studies involving T2DM patients.

Le diabète de type 2 et l’ostéoporose sont deux maladies chroniques dont la prévalence (nombre de cas dans la population à un moment donné) est en perpétuelle augmentation, notamment du fait du vieillissement de la population. Au-delà des complications connues du diabète de type 2 tels que des troubles cardiovasculaires, rénaux, neurologiques et oculaires, nous savons aujourd’hui que les perturbations liées à des taux élevés de sucre dans le sang (hyperglycémie) exercent un effet négatif sur le remodelage osseux, processus continu de formation et de résorption de l’os.  En effet, le diabète augmente le risque de fracture, d’une part à cause de l’altération de la structure interne de l’os et donc de sa qualité, d’autre part du fait de l’augmentation du risque de chutes chez les patients. Cette fragilité osseuse observée dans le contexte du diabète de type 2 est d’origine multifactorielle. Toutefois, les mécanismes impliqués restent complexes et ne sont pas encore totalement élucidés. Néanmoins, une altération des fonctions des cellules osseuses, ainsi qu’une modulation des niveaux de certaines molécules sécrétées par ces dernières, pourraient être à l’origine d’une diminution du remodelage osseux chez les diabétiques de type 2. Pour répondre à cette problématique, nous nous concentrerons notamment sur l’ostéocyte, cellule majoritaire du tissu osseux dont le rôle dans les processus de formation de l’os et de réparation des dommages osseux est central. C’est grâce à l’emploi de modèles expérimentaux précliniques (culture de cellules osseuses en présence de sucre, souris diabétiques soumises à une contrainte mécanique) ainsi que d’études sur des patients diabétiques, que nous allons investiguer les mécanismes à l’origine de la fragilité osseuse dans le diabète de type 2.

Matthias Walle

ESR8: Mechanoregulation of bone remodelling in type 2 diabetes using HRpQCT in vivo patient data

Matthias successfully completed his B.Sc. and M.Sc. in Mechanical Engineering at the Technical University of Munich specialising in Computational Biomechanics. He conducted his Master’s thesis at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, which focused on trabecular bone morphology. During his studies, he worked as a research assistant at the Mechanics and High Performance Computing Group at TU Munich focusing on soft tissue mechanics investigating vascular diseases.

Objectives: Develop bone imaging and computational methods for mechanobiological bone remodelling studies that can be run on desktop computers in the hospital/laboratory environment. Investigate the effects of diabetes on local mechanoregulation of bone remodelling in patients, identify its relationship to bone fragility and candidate biomarkers.

Host: ETH Zurich, Switzerland
Supervisor: Dr. Caitlyn Collins

ETH scientists use high-resolution patient imaging to monitor bone’s mechanically driven remodelling process. In FIDELIO, they are now working with clinicians at the University of Sheffield and computer scientists at IBM to improve the care of diabetic patients.

In a healthy adult, the body’s skeleton fully regenerates — or remodels — itself about every three to five years to maintain its strength. At the microscopic level, this process is orchestrated by cells, called osteocytes, which can sense and respond to local mechanical forces. Osteocytes direct bone-forming cells to regions where mechanical stimulations are high, and bone resorbing cells to areas where the stimulus is low. Through this process, excess bone tissue is removed, and new tissue is added where needed to maintain a metabolic balance.

Scientists have recently observed that diabetes may negatively impact our bone health and reduce bone strength. To unravel the underlying reasons, researchers at ETH have developed novel methods that enable monitoring of local changes in the bone microstructure over time. Utilizing one of the world’s most powerful supercomputers at the Swiss National Supercomputing Centre (CSCS), this was possible at such high spatial resolution that cellular behaviour of the mechanobiological remodelling process could be studied.

There are, however, technological challenges that prevent the use of these techniques in clinical studies. Although these computations are fast on supercomputers, they are still too slow and cumbersome to run on computer systems available within the clinics. In FIDELIO, researchers at ETH will work with IBM to push bone imaging and computational methods for bone remodelling studies from bench (supercomputer) to the bedside (clinical computing) in the hospital environment. Ultimately, these precise diagnostic tools may be used to tailor medical treatment of diabetic patients to bone health individually.

Ankita Duseja

ESR9: Role of microRNA in diabetic bone disease

Ankita completed her Bachelors in Biotechnology at VIT University, Vellore, India in 2016. After graduation she worked as a project assistant at DBT-BUILDER, Anna University in India exploring the regenerative potential of Wharton’s Jelly derived-Mesenchymal Stem Cells. She pursued her Master degree in Regenerative Biology and Medicine at the Centre for Regenerative Therapies Dresden (CRTD), TU Dresden completed her thesis in the lab of Dr. Franziska Knopf, investigating the role of macrophages during bone development and regeneration in zebrafish.

Objectives: To identify those miRNAs that are differentially expressed between T1D, T2D and healthy adult control groups. To test the osteogenic, adipogenic, and proliferative potential of the most promising miRNAs via in vitro functional studies.

Host: The University of Sheffield, United Kingdom
Supervisor: Prof. Richard Eastell

Patients with diabetes are at an increased risk for fractures, have poor bone healing and bone quality. Recent research suggests that although patients with type 1 diabetes experience low bone mineral levels while patients with type 2 diabetes experience higher bone mineral levels, both groups of patients are prone to fractures. Hence, this problem cannot be explained by usual bone density measurements. There are other related factors that influence bone quality.

Here at The University of Sheffield, UK, in collaboration with FIDELIO, I Ankita Duseja aim to study microRNAs as biomarkers to evaluate bone quality in diabetic patients. This work is under the guidance of Professor Richard Eastell, Professor of Bone Metabolism and Director of the University of Sheffield’s Mellanby Centre for Bone Research.

MicroRNAs play key roles in maintenance of bone cells and bone quality; and their abnormal levels are known to make bones prone to fractures. In my study, I will isolate miRNAs from blood or plasma of people with diabetes and study their levels. The goal of my study is to develop these microRNAs as biomarkers to be used as a diagnostic tool for better assessment of fracture risk as well as treatment options.
This project is part of my PhD work at The University of Sheffield and I am happy to be receiving funding for my work from FIDELIO.

Samuel Ghatan

ESR10: Genetics and biologic pathways underlying fracture risk in type 2 diabetes

Sam graduated with a B.Sc. in chemistry from the University of Liverpool and went on to obtain a Master’s degree in neuroscience from King’s College London, specialising in psychiatric genetics. His M.S.c. project focused on using genetics to infer a causal relationship between bone fragility and Alzheimer’s disease.

Objectives: To leverage the evidence derived from GWAS studies to identify possible plausible molecular pathways involved in both skeletal and glucose metabolism, with particular emphasis on the overlap of the biological underpinnings of T2DM and fracture risk.

Host: Erasmus Universitair Medisch Centrum Rotterdam, Netherlands
Supervisor: Dr. Ling Oei

Not all patients with type II diabetes are the same. Some may be over-weight; others may be of healthy weight.  Some may have adverse side effects, others none at all. Despite these differences among patients they are all considered to have the same disease. What makes them differ so much? Well type II diabetes is an overarching disease characterised by having too high a blood sugar level and there are many biological processes that can lead an individual to have high blood sugar.

Therefore, although they are considered to have the same disease, individuals can have different biological processes driving their diseases, leading to differing complications. One such complication is increased risk of developing fractures. Individuals with type II diabetes have a higher risk of developing fractures, despite having higher bone mineral density (BMD for short). This elevated BMD means the increased risk of fractures in these patients doesn’t seem to be driven by the usual mechanisms.

Thus, the goal of the FIDELIO consortium is to uncover the mechanisms through which fractures occur in diabetic patients. The goal of my project is to first identify sub-groups of type II diabetes patients with unique biological processes driving their disease. Then, measure the occurrence of fractures in sub-groups of individuals, with the hope that one or more sub-group have a higher occurrence then the others. Data is obtained from volunteers recruited in hospitals who have had a full range of scans and measurements taken. Next, sub-groups can be identified from these measurements using clustering algorithms, which group participants with similar measurements together. Lastly, the risk of a fracture occurring is calculated for each group.

This can highlight researchers as to the likely mechanisms driving fracture risk in type II diabetes patients. This will help lead to better treatments for patients and identify those type II diabetes patients most at risk.

Niet alle patiënten met diabetes type 2 zijn hetzelfde. Sommige hebben overgewicht; anderen kunnen een gezond gewicht hebben. Sommige ervaren nadelige bijwerkingen hebben, andere helemaal geen. Ondanks deze verschillen tussen patiënten wordt aangenomen dat ze allemaal dezelfde ziekte hebben. Wat maakt ze zo verschillend? Welnu, type 2 diabetes is een overkoepelende ziekte die wordt gekenmerkt door een te hoge bloedsuikerspiegel, maar er zijn veel verschillende biologische processen die ertoe kunnen leiden dat iemand een hoge bloedsuikerspiegel krijgt. Dus patiënten die allemaal dezelfde ziekte type 2 diabetes hebben kunnen dus toch verschillende biologische processen hebben die hun ziekte aansturen. Dit kan weer leiden tot verschillende ziekte complicaties. Een van die complicaties is een verhoogd risico op het ontwikkelen van botbreuken (fracturen). Dit hogere risico op het ontwikkelen van fracturen is ondanks een hogere botmineraaldichtheid (kortweg BMD). Deze verhoogde BMD betekent dat het verhoogde risico op fracturen bij deze type 2 diabetes patiënten niet wordt bepaald door de gebruikelijke mechanismen bij botontkalking met botbreuken.

Het doel van het FIDELIO-consortium is dus om de mechanismen te ontdekken waardoor fracturen optreden bij diabetespatiënten. Het doel van dit project is om eerst subgroepen van type 2 diabetespatiënten te identificeren die met elkaar overeenkomst hebben in de biologische processen die hun ziekte aansturen. Vervolgens zullen we het voorkomen van fracturen in deze subgroepen van individuen onderzoeken. Hierbij hopen we dat een of meer subgroepen vaker fracturen ervaren dan de patiënten in de andere groep. De gegevens worden verkregen van vrijwilligers die in ziekenhuizen zijn gerekruteerd en die een volledige reeks scans en metingen hebben ondergaan. Vervolgens kunnen uit deze metingen subgroepen worden geïdentificeerd met behulp van clusteringalgoritmen, die deelnemers met vergelijkbare metingen groeperen. Ten slotte wordt voor elke groep het risico op het optreden van een fractuur berekend.

Dit kan dit onderzoekers wijzen op de waarschijnlijke mechanismen die het risico op fracturen bij type 2 diabetespatiënten veroorzaken. Dit zal bijdragen tot betere behandelingen voor patiënten en het identificeren van die type 2 diabetespatiënten die het meeste risico lopen.

Ruolin Li

ESR11: Metformin effects on the diabetic bone and the interaction with the gut microbiome

Ruolin completed her Medical Doctor’s degree (M.D.) in preventative medicine at Sun Yat-sen University in China. She then went on to obtain a M.S.c degree in Omics from the Sino-Danish Center, consisting of two separate diplomas: one from the University of Chinese Academy of Sciences, and the other from the University of Southern Denmark, respectively. Her M.S.c project mainly focused on transcriptomics-based epigenetics in regenerative medicine. After graduation, Ruolin worked as a research assistant in the field of epidemiology and genetics of atherosclerosis at the National Center of Cardiovascular Diseases of China (also called Fuwai hospital).

Objectives: To investigate the effects of diabetes treatment (e.g., Metformin) on the decrement of bone quality, using an epidemiological approach combining different types of data for the assessment of bone parameters. Specifically, increasing evidences indicate gut microbiota plays significant roles in both diabetes progression, host metabolism and bone quality alterations. Whether the associations between metformin use and bone quality is mediated by gut microbiota will be explored by using state-of-the-art statistics analysis methods and deeply surveying other publicly-available datasets.

Host: Erasmus MC, Netherlands
Supervisor: Dr. Carolina Medina Gomez

Type 2 diabetes is rather a common disease all over the world, in general, 6 persons in every 100 have the disease worldwide. Moreover, the percentage of affected individuals can be as high as 15% among those aged 50–69, and 22% among those aged 70+. In these last two groups, bone mass loss is a common complication that will progressively worse if not treated properly, and could result in bone fractures.

In clinics, treatment for type 2 diabetes include drugs to control blood sugars, combined with a healthy diet and enough exercise. Metformin has become the preferred medicine for treating type 2 diabetes due to its high efficiency in lowering glucose production in the liver and improving the cells’ efficiency to use insulin within your body, additionally in the long-term it helps the body to be healthy in metabolism.

Remarkably, increasing evidence has indicated that metformin plays a significant role in reducing bone mass loss and the occurrence of fractures among type 2 diabetic patients. Mechanistically, one hypothesis is that part of the effect of metformin on bone is through changes in the species or abundance of gut microorganisms, which would produce different metabolites to influence human health. Different researchers have shown in both human and animal studies an increment of beneficial bacteria in the gut when treated with Metformin.

On top of this, already four different clinical trials have shown the favourable effects of probiotics consumption, which are by themselves beneficial bacteria, in bone health. In our FIDELIO project, we will analyse real world data from long term health studies of large groups of children and older adults in the Rotterdam area – “Generation R” and the “Rotterdam Study to disentangle the causal link of metformin therapy in diabetic bone quality improvement and the possible role of the gut microorganisms as a mediator of this effect.

Diabetes type 2 is een vrij veel voorkomende ziekte over de hele wereld, in het algemeen hebben 6 op de 100 personen de ziekte wereldwijd. Bovendien kan het percentage getroffen personen oplopen tot 15% onder de 50-69-jarigen en 22% onder de 70-plussers. In deze laatste twee groepen is verlies van botmassa een veel voorkomende complicatie die progressief erger zal worden als deze niet goed wordt behandeld, en kan leiden tot botbreuken.

In klinieken omvat de behandeling van diabetes type 2 onder meer geneesmiddelen om de bloedsuikerspiegel onder controle te houden, gecombineerd met een gezond dieet en voldoende lichaamsbeweging. Metformine is het voorkeursgeneesmiddel geworden voor de behandeling van diabetes type 2 vanwege de hoge efficiëntie in het verlagen van de glucoseproductie in de lever en het verbeteren van de efficiëntie van de cellen om insuline in uw lichaam te gebruiken, bovendien helpt het op de lange termijn het lichaam gezond te zijn in metabolisme.

Opmerkelijk is dat toenemend bewijs erop wijst dat metformine een belangrijke rol speelt bij het verminderen van botmassaverlies en het optreden van fracturen bij type 2 diabetespatiënten. Mechanistisch gezien is een hypothese dat een deel van het effect van metformine op het bot is door veranderingen in de soort of de overvloed aan micro-organismen in de darm, die verschillende metabolieten zouden produceren om de menselijke gezondheid te beïnvloeden. Verschillende onderzoekers hebben in zowel menselijke als dierlijke studies een toename van nuttige bacteriën in de darmen aangetoond bij behandeling met Metformine.

Bovendien hebben al vier verschillende klinische onderzoeken de gunstige effecten aangetoond van de consumptie van probiotica, die op zichzelf nuttige bacteriën zijn, voor de gezondheid van de botten. In ons FIDELIO-project zullen we gegevens uit de echte wereld analyseren van langetermijngezondheidsstudies van grote groepen kinderen en oudere volwassenen in de regio Rotterdam – ‘Generation R’ en de ‘Rotterdam Study’, om het causale verband van metforminetherapie bij diabetisch bot te ontrafelen. kwaliteitsverbetering en de mogelijke rol van de darmmicro-organismen als mediator van dit effect.

Sofie Kolibová

ESR12: Bone matrix characterization and analysis of AGE accumulation in diabetic bone

Sofie earned her B.Sc. in Forensic Analysis from the University of Chemistry and Technology, Prague. For her Master’s degree she specialized in general and applied biochemistry at the Department of Biochemistry and Microbiology. Her M.Scs. project focused on how Mason-Pfizer monkey virus is using the transport system of a host cell during infection. After her studies Sofie worked in the field of science popularization and communication.

Objectives: Characterizing bone microstructure and matrix composition in terms of AGE accumulation, mineralization degree and biomechanical properties in T2DM.

Host: UKE Hamburg, Germany
Supervisor: Dr. Katharina Jähn-Rickert

How many of you would connect diabetes mellitus with a higher rate of bone fractures?  Most likely, you wouldn’t put a link between these two medical issues. Yet, there is a higher fracture risk for diabetic patients.

The question of how diabetes weakens our skeleton is not fully understood. Many factors are at play, so an increasing number of scientists and physicians focus on this research topic. Because if we know how this disease affects bone tissue, we will be able to better and especially in time, identify at-risk patients and prevent fractures’ frequency.

One of the possibilities of studying bones is to make the structure visible. We can simply imagine it as a wood structure. On the tree trunk’s cross-section, we see annual rings, and in them, you can read like in a book, they can tell us how old the tree was or if the tree was ever sick.

The bone structure is, in a way, comparable to the wooden structure. The basic building block of bone is the osteon, and it looks just like a cross-section of a tree. We have many osteons in bone tissue. The number, size, or age of osteons provides valuable information about bone’s basic structure and mechanical properties. Osteons size is in the range of 100-200 µm, so it is possible to observe them under a conventional light microscope.

But to find the cause of bone structure decay, we need to go deeper. If we focus on a single osteon, then it is formed by a complex of concentric lamellae and imagine one lamella as the only annual ring in wood. The lamellae contain osteocytes that serve as mechanosensors of bone and regulate bone remodelling. In diabetic bone is the remodelling process often imbalanced, which leads to weakening the bones. That is why we examine osteocytes and their interconnection using light and electron microscopy.

But now, let’s focus on the lamella itself, which consists of collagen fibres. In between collagen fibres are hydroxyapatite crystals – this is the source of calcium in our bones. Collagen gives our bones elasticity, and hydroxyapatite gives us strength. These structures are already in the nanometre range, so it is not so easy to observe them. However, this is the level where diabetes starts to disrupt bone structure and function. A higher concentration of glucose in the blood is changing collagen fibres, causing lower flexibility. We need more advanced technologies such as electron microscopy or spectral methods to study these structural changes in detail.

Therefore, my work aims to describe all these changes in the diabetes-affected bone structure or, as I like to call “sugared bone” from the macroscopical perspective of osteons to individual collagen fibres. Because that is the only way to understand how the disease works and help improve the diagnosis and prevention of fractures in patients with diabetes.

Kolik z vás by spojilo cukrovku s vyšší mírou zlomenin kostí? S největší pravděpodobností byste mezi těmito dvěma zdravotními problémy nehledali souvislost. Přesto existuje u diabetiků vyšší riziko zlomenin.

Způsob, jakým cukrovka postupně oslabuje naši kostru není plně objasněný a ve hře je hodně faktorů. Což je důvod proč se tomuto tématu ve výzkumu věnuje stále větší množství vědců a lékařů. Protože pokud pochopíme, jak tato nemoc ovlivňuje kostní tkáň, budeme schopni lépe, a hlavně včas identifikovat rizikové pacienty a tím můžeme zabránit četnosti zlomenin.

Jedena z možností studia kostí je jejich struktura. Tu si můžeme zjednodušeně přiblížit na dřevě. Na průřezu kmenu stromu vidíme letokruhy a v těch lze číst jako v knize, řeknou nám, jak byl strom starý, zaznamenají požáry nebo období sucha a prozradí nám i jestli byl strom někdy nemocný.

A struktura kosti je velmi podobná, základní stavební jednotkou kosti je osten a ten vypadá jako průřez stromem. Osteonu máme v kostní tkáni hodně, množství, velikost anebo stáří osteonu nám poskytuje cenné informace o základní struktuře a mechanických vlastnostech kosti. Velikost osteonu se pohybuje v rozmezí 100-200 µm, takže je možné je pozorovat pod klasickým světelným mikroskopem. Ale abychom našli prvotní příčiny narušení kostní struktury tak musíme jít hlouběji. Pokud se zaměříme na jeden jediný osten, tak ten je tvořený komplexem soustředných lamel a jednu lamelu si představte jako jediný letokruh ve dřevě. V lamelách jsou ukotvené základní kostní buňky – osteocyty. Ty slouží jako mechanosenzory kosti a regulují neustálou přestavbu kosti – odstraňují starou a poškozenou kostní hmotu a nahrazují jí novou, tento děj se označuje jako remodelace. U kosti cukrovkáře je proces remodelace často nevyvážený, což vede k úbytku kostní hmoty, a tudíž oslabování kostí. Proto studujeme osteocyty a jejich propojení pomocí světelné mikroskopie.

Nyní se ale zaměřme na samotnou lamelu, která se skládá z kolagenových vláken. Mezi kolagenovými vlákny jsou krystaly hydroxyapatitu – to je zdroj vápníku v našich kostech. Kolagen dodává našim kostem pružnost a hydroxyapatit ji dává pevnost. Tyto struktury jsou se velikostně pohybují v rozmezí nanometrů, takže není tak snadné je pozorovat. To je však úroveň, kdy cukrovka začíná narušovat kostní strukturu a funkci. Vyšší koncentrace glukózy v krvi mění kolagenová vlákna, což způsobuje nižší ohebnost kosti. K podrobnému studiu těchto strukturálních změn potřebujeme pokročilejší technologie, jako je elektronová mikroskopie nebo spektrální metody.

Moje práce si proto klade za cíl popsat všechny tyto změny v kostní struktuře ovlivněné cukrovkou z makroskopické perspektivy osteonů na jednotlivá kolagenová vlákna. Protože jedině tak lze pochopit, jak nemoc funguje, a pomoci zlepšit diagnostiku, a především prevenci zlomenin u pacientů s diabetem.

David Carro Vázquez

ESR13: miR-203a functions as regulator of type-2 diabetic bone disease

David obtained both his Bachelor in Biochemistry and his  Master’s degree in Biotechnology from the University of Málaga, Spain, where he conducted mass spectrometry nuclear profiling of brain cancer cells In addition, he underwent placements both at the University of Ulm, Germany as well as at CNRS in Nice, France. After completing his Master project, David worked at the Charité Berlin, where his research focused on investigating the role of mesenteric fat T cells in Crohn’s disease.

Objectives: To characterize expression levels of miR-203a in different compartments of bone tissue from T2D and non-diabetic animals, and to identify novel mRNA targets under hyperglycemia compared to normal conditions. Predict and experimentally confirm the interaction of transcription factors with miR-203a promoter region, and to characterize miR-203a transcription in response to parathyroid hormone, sex hormones, and glucose. Investigate tissue expression as well as circulating levels of miR-203a together with its validated target mRNA levels in the context of onset and progression of T2D bone disease in clinical and non-clinical samples.

Host: TamiRNA GmbH, Austria
Supervisor: Dr. Matthias Hackl

MicroRNAs are small RNAs that are derived from the genome but not used in the process of protein synthesis. These molecules take part in the regulation of genes and are essential to the coordinated function of cells, tissues and organs. Changes in microRNA levels are observed in many diseases, which has led to the applications as drug targets and biomarkers. Biomarkers are molecules that inform about biological processes and therefore can aid the diagnosis, prognosis, or monitoring of disease. One of the most prevalent diseases is Type-2 diabetes mellitus (T2DM). Besides cardiovascular complications, T2DM is known to negatively affect bone, making diabetes patients more prone to develop osteoporosis and slowed bone healing following a fracture.

Therefore, the aim of this PhD project (carried out in a company in Vienna specialized for miRNA analysis called TAmiRNA GmbH) is to discover microRNAs, which could be used as biomarkers of bone degradation in T2DM patients. Specifically, we hypothesize that microRNAs could play a role in onset and progression of diabetic osteoporosis and impaired bone healing. In order to prove this, we will use highly sensitive analytical methods to quantify microRNAs with a known role in osteoporosis in the blood of various T2DM animal models: Zucker Diabetic Fatty (ZDF) rats for example develop T2DM spontaneously, and suffer from reduced bone healing, bone mass and low bone tissue formation, making it a good animal model to study the changes of microRNAs during the development of osteoporosis induced by diabetes. We aim to compare microRNA changes in blood and bone tissue of ZDF rats with low bone quality to normal rats are also used as a control.

For our studies we have to draw blood from diabetic and control rats, collect the cell-free liquid (serum), and extract total RNA including microRNAs. From that extracted total RNA we will measure the levels of our candidate microRNAs by a technique called quantitative PCR (qPCR). In this way we can observe which microRNAs have different levels between the diabetic rats with low quality bone and the normal healthy rats. The next step for our project is to statistically compare the levels of those microRNAs with important bone quality parameters such as bone density and bone microarchitecture, which were measured by our collaborator using sophisticated x-ray machines. Those microRNAs that change simultaneously with the bone parameters (meaning that they are correlated) may have a specific function within the bone tissue that leads to a change in the bone health.

This project will support the development of novel technologies for early diagnosis of osteoporosis in diabetic patients. Such methods will benefit patients since they allow an earlier prescription of osteoporotic treatments before they suffer from a high bone degradation. Furthermore, these microRNA could also be used as therapeutic targets, if we find that they are directly causing bone disease in T2DM patients. In order to provide proof of concept, in experimental and observational clinical studies involving patients will be performed in our project, to further analyze our novel microRNA candidates and establish their molecular functions in the context of diabetic bone disease.

Los microARN son pequeños ARN que se derivan del genoma pero que no se utilizan en el proceso de síntesis de proteínas. Estas moléculas participan en la regulación de los genes y son esenciales para la función coordinada de células, tejidos y órganos. Se observan cambios en los niveles de microARN en muchas enfermedades, lo que ha llevado a su uso como dianas fármacológicas y biomarcadores. Los biomarcadores son moléculas que informan sobre procesos biológicos y, por tanto, pueden ayudar al diagnóstico, pronóstico o seguimiento de una enfermedad. Una de las enfermedades más prevalentes es la diabetes mellitus tipo 2 (DM2). Además de causar complicaciones cardiovasculares, se sabe que la DM2 afecta negativamente al tejido óseo, lo que hace que los pacientes con diabetes sean más propensos a desarrollar osteoporosis y a una curación del hueso más lenta después de una fractura.

Por tanto, el objetivo de este proyecto de doctorado (realizado en una empresa de Viena especializada en análisis de mi-ARN llamada TAmiRNA GmbH) es descubrir microARNs que podrían utilizarse como biomarcadores de degradación ósea en pacientes con DM2. En concreto, planteamos la hipótesis de que los microARN podrían desempeñar un papel en la aparición y progresión de la osteoporosis diabética y de la pérdida de cicatrización ósea. Para demostrar esto, utilizaremos métodos analíticos altamente sensibles para cuantificar microARN con un papel conocido en la osteoporosis en la sangre de varios modelos animales de DM2: las ratas Zucker Diabetic Fatty (ZDF), por ejemplo, desarrollan DM2 de forma espontánea y sufren de cicatrización ósea reducida, pérdida de masa ósea y baja formación de tejido óseo, lo que las convierte en un buen modelo animal para estudiar los cambios de los microARN durante el desarrollo de la osteoporosis inducida por la diabetes. Nuestro objetivo es comparar los cambios de microARN en la sangre y el tejido óseo de ratas ZDF con baja calidad ósea con ratas normales que también se utilizan como control.

Para nuestros estudios, tenemos que extraer sangre de ratas diabéticas y de ratas control, obtener  el suero y extraer de éste el ARN total, incluidos los microARN. A partir de ese ARN total extraído, mediremos los niveles de nuestros microARN candidatos mediante una técnica llamada PCR cuantitativa (qPCR). De esta forma podemos observar qué microARNs tienen diferentes niveles entre las ratas diabéticas con un tejido óseo de baja calidad y las ratas normales sanas. El siguiente paso de nuestro proyecto es comparar estadísticamente los niveles de esos microARN con parámetros indicadores de la calidad ósea como la densidad ósea y la microarquitectura ósea, que fueron medidos por nuestro colaborador mediante máquinas de rayos X. Los microARNs que cambian simultáneamente con los parámetros óseos (lo que significa que están correlacionados) pueden tener una función específica dentro del tejido óseo que conduce a un cambio en la salud de los huesos.

Este proyecto impulsará el desarrollo de métodos novedosos para el diagnóstico precoz de la osteoporosis en pacientes diabéticos. Dichos métodos beneficiarán a los pacientes, ya que permitirán una prescripción más temprana de tratamientos osteoporóticos antes de que sufran una alta degradación ósea. Además, estos microARN también podrían usarse como dianas terapéuticas, si encontramos que están causando directamente la degradación ósea en pacientes con DM2. Con el fin de proporcionar una prueba de concepto, en nuestro proyecto se realizarán estudios clínicos experimentales y observacionales con pacientes, para analizar más a fondo nuestros nuevos candidatos a microARN y establecer sus funciones moleculares en el contexto de la enfermedad ósea diabética.

Annika Kvist

ESR14: Exploring subgroups to inform personalized treatment strategies

Annika graduated in Economics at Aalborg University, Denmark. Her Master Thesis is about the economics for Fecal Microbiota Tranplantation. She is interested in the development of research in health and health economics.

Objectives: Investigate novel analytic methods to identify homogeneous patient groups and new patterns that can inform drug safety and effectiveness studies, and tailor patient treatment plans to minimize fragility fractures in T1D and T2DM.

Host: ETH Zuerich, Switzerland
Supervisor: Prof. Andrea Burden

It has also been identified that patients with both T1D and T2D are more likely to have bone fractures, but we have not been able to find an explanation for this. T1D patients often have low bone density, which can cause the bones to be weak and brittle, but patients with T2D typically have normal or even stronger bone compared to a non-diabetic patient. Therefore, the causes, types, and consequences of fractures likely differ between T1D and T2D patients. During my PhD I will work answer these questions.

My work is based on so-called real-world healthcare data from Denmark. This is anonymized data collected during routine clinical care and includes information on diagnoses and prescription medications for all residents of Denmark. Using this data, I will first identify the frequency and types of fractures over time and the costs of fractures among both T1D and T2D. Following this, I will study if there are patterns of illnesses and medications that increase the risk of bone fractures in T1D and T2D. To do this I will use statistical and artificial intelligence approaches. Artificial intelligence is a way of making the computer “think” and be able to learn from the data provided. It can be used to find complex patterns in the data of illnesses and medications that will be hard to detect otherwise.

The overall goal of my project is to gain new insights into why patients with diabetes are more likely to get a bone fracture. If we can find the reason for the increased risk among diabetic patients, we can do more to prevent their bone fractures, which will give the patients better quality of life and reduce healthcare costs.