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Projects / Programmes source: ARIS

Association of glycemic variability and DNA methylation patterns with early signs of retinal and kidney damage in individuals with type 1 diabetes.

Research activity

Code Science Field Subfield
3.05.00  Medical sciences  Human reproduction   
3.07.00  Medical sciences  Metabolic and hormonal disorders   

Code Science Field
B480  Biomedical sciences  Endocrinology, secreting systems, diabetology 

Code Science Field
3.02  Medical and Health Sciences  Clinical medicine 
Keywords
Type 1 diabetes, diabetic nephropaty/tubulopathy, diabetic retinopathy, DNA methylation, glucose variability, children, adults
Evaluation (rules)
source: COBISS
Researchers (19)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  24578  PhD Saba Battelino  Neurobiology  Researcher  2019 - 2022  587 
2.  13023  PhD Tadej Battelino  Medical sciences  Researcher  2019 - 2022  1,230 
3.  34769  Tanja Blagus  Public health (occupational safety)  Researcher  2019 - 2022  71 
4.  13409  PhD Nataša Bratina  Human reproduction  Head  2019 - 2022  431 
5.  34849  PhD Klemen Dovč  Metabolic and hormonal disorders  Researcher  2019 - 2022  160 
6.  20707  PhD Mojca Globočnik Petrovič  Neurobiology  Researcher  2019 - 2022  259 
7.  33868  PhD Urh Grošelj  Human reproduction  Researcher  2019 - 2022  483 
8.  33344  PhD Marija Holcar  Natural sciences and mathematics  Researcher  2019 - 2020  40 
9.  28512  PhD Tinka Hovnik  Medical sciences  Researcher  2019 - 2022  107 
10.  18372  PhD Andrej Janež  Metabolic and hormonal disorders  Researcher  2019 - 2022  668 
11.  21358  PhD Primož Kotnik  Human reproduction  Researcher  2019 - 2022  247 
12.  32181  PhD Jernej Kovač  Medical sciences  Researcher  2019 - 2022  207 
13.  24288  PhD Metka Lenassi  Natural sciences and mathematics  Researcher  2019 - 2022  201 
14.  21413  PhD Damjan Osredkar  Human reproduction  Researcher  2019 - 2022  480 
15.  53973  Monika Praznik  Chemical engineering  Researcher  2020  11 
16.  54992  Inge Sotlar  Medical sciences  Researcher  2021 - 2022  10 
17.  20255  PhD Manca Tekavčič-Pompe  Neurobiology  Researcher  2019 - 2022  228 
18.  20253  PhD Katarina Trebušak Podkrajšek  Human reproduction  Researcher  2019 - 2022  405 
19.  53974  Blaž Vončina  Biochemistry and molecular biology  Researcher  2020 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  77,465 
2.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  48,238 
Abstract
It is imperative to prevent or at least delay micro- and macrovascular complications, which are the leading cause of T1D morbidity and mortality. Identification of the epigenetic biomarkers and related pathways is important in identification and subsequent prevention of the metabolic changes that could lead to disease progression and development of the chronic complications. Correlation of the epigenetic profiles of T1D patients with good or poor glycaemic control might enable identification of biomarkers important in dynamics or in the development of disease complications and their relation to epigenetic alterations. Unlike genetic changes, epigenetic variations could be reversible, which means it could provide an opportunity for therapeutic development.  The suggested project aims to determine whether glycemic variability is associated with DNA methylation patterns and early signs of diabetic complications, mainly retinal and kidney damage, in individuals with T1D. The study objectives are to evaluate the correlations between GV, DNA methylations patterns and early signs of diabetic complications in individuals with T1D, to validate these observations compared to individuals with long-duration T1D (positive control) and to healthy first-degree relatives of individuals with T1D (negative control). Based on these observations we will try to validate DNA methylation pattern (III) as an early risk marker for diabetic complications and the role of gender in altered methylation process. This information could enable risk-factor dependent and person-tailored precision medicine for each individual with type 1 diabetes. The co-primary endpoints are the between group difference (case with high GV variability vs case with low GV variability, male vs. female, case vs. positive and case vs. negative control) in DNA methylation patterns. Other key endpoints include the difference in retinal neurodegeneration/vascular changes, kidney tubulopathy/nephropathy, hearing/vestibular impairment, subclinical neuropathy, impaired coagulation, subclinical atherosclerosis and other cardiovascular risk factors, impaired cellular metabolism, and the difference in in other diabetes related complications. This is a cross-sectional registry-based, case-controlled clinical trial. We will collect data from individuals with T1D for up to five in the past and cross-sectional data from positive and negative controls. We aim to include up to 250 individuals with T1D aged between 10 and 23 years (case) recruited through pediatric diabetes outpatient clinic, 100 adult individuals with long-duration T1D through adult diabetes outpatient clinic (positive control) and healthy first-degree relatives of individuals with T1D aged between 10 and 23 years through pediatric and adult outpatient clinic (negative control) at the participating clinical site. Key inclusion criteria (case): Age between 10 and 23 years of age (inclusive), Type 1 diabetes for at least 5 years, The subject has been performing ≥ 4 daily SMBG tests for at least the last 12 months, during the last 5 years the subject has attended at least 3 diabetes clinics per year and did the annual routine diabetes laboratory checkup, the subject has been in intensive insulin treatment (either multiple daily insulin doses – MDI, or continuous subcutaneous insulin infusion – CSII) for at least the last 12 months, the subject or his/her legal guardian assent/consent participating in the study.  Additional inclusion criteria (positive control): Type 1 diabetes for more than 20 years. Key Inclusion criteria (negative control). Age between 10 and 23 years of age (inclusive), Subject is a first degree relative of an individual with T1D, Non-diabetic apparently healthy control subject, the subject or his/her legal guardian assent/consent participating in the study
Significance for science
The newly obtained data on altered methylation of DNA and the role of these modifications will enable us to identify individuals with potentially higher risk for developing devastating chronic complications of T1D. The results from this study are expected to confirm the central role of glycemic variability and its correlation with epigenetic modifications, which as a marker of glycemic control beyond HbA1c, which is not yet fully understood. Systematic evaluation of individuals with type 1 diabetes with increased risk, based on early risk markers and before actual clinical presentation of complications, will help us to develop person-tailored and more precise treatment – precision medicine. It is not completely clear which metabolic pathways are derailed in poor glycemic control, if, how they are related to the epigenetic modifications, and if, how they are contributing to the development of the disease complications. Therefore, the results of proposed study are projected to have original contribution to the existing knowledge and at the same time propose possible treatment interventions in order to prevent lifelong complications of T1D soon after their occurrence that could significantly mitigate disease burden for each individual with type 1 diabetes and his/her family.   In the proposed project we will investigate with the following unique and distinct study design characteristics: 1. Novel screening strategies with state-of-the art diagnostical/research tools will be used in order to reliably predict and consequently prevent or delay severe T1D complications and establish the role of epigenetic modifications and evaluate glycemic variability as an essential marker of glycemic control beyond HbA1c. 2. Understanding the role of DNA methylation patterns in the disease complications progression will provide further insights in to T1D pathophysiology and could help developing the epigenetic therapy and with that a development of long-awaited cure of T1D (rather than hormone replacement). 3. With a combination of transdisciplinary expertise, combining medical researchers, ophthalmologists, nephrologists, otology and audiology specialists, genetic experts, bioinformaticians, we will jointly share conceptual framework and combined disciplinary-specific approaches. 4. We will include first-degree relatives of individuals with T1D, who are at increased risk (8–15-fold) for developing type 1 diabetes. Therefore, diabetes specific autoantibody assessment will provide direct benefit to this population at risk as it will allow for recognition of T1D in an earlier stage of the disease and most possibly DKA prevention. If applicable, T1D secondary prevention studies will be presented to subsequent participants with two or more positive diabetes specific autoantibodies.
Significance for the country
The newly obtained data on altered methylation of DNA and the role of these modifications will enable us to identify individuals with potentially higher risk for developing devastating chronic complications of T1D. The results from this study are expected to confirm the central role of glycemic variability and its correlation with epigenetic modifications, which as a marker of glycemic control beyond HbA1c, which is not yet fully understood. Systematic evaluation of individuals with type 1 diabetes with increased risk, based on early risk markers and before actual clinical presentation of complications, will help us to develop person-tailored and more precise treatment – precision medicine. It is not completely clear which metabolic pathways are derailed in poor glycemic control, if, how they are related to the epigenetic modifications, and if, how they are contributing to the development of the disease complications. Therefore, the results of proposed study are projected to have original contribution to the existing knowledge and at the same time propose possible treatment interventions in order to prevent lifelong complications of T1D soon after their occurrence that could significantly mitigate disease burden for each individual with type 1 diabetes and his/her family.   In the proposed project we will investigate with the following unique and distinct study design characteristics: 1. Novel screening strategies with state-of-the art diagnostical/research tools will be used in order to reliably predict and consequently prevent or delay severe T1D complications and establish the role of epigenetic modifications and evaluate glycemic variability as an essential marker of glycemic control beyond HbA1c. 2. Understanding the role of DNA methylation patterns in the disease complications progression will provide further insights in to T1D pathophysiology and could help developing the epigenetic therapy and with that a development of long-awaited cure of T1D (rather than hormone replacement). 3. With a combination of transdisciplinary expertise, combining medical researchers, ophthalmologists, nephrologists, otology and audiology specialists, genetic experts, bioinformaticians, we will jointly share conceptual framework and combined disciplinary-specific approaches. 4. We will include first-degree relatives of individuals with T1D, who are at increased risk (8–15-fold) for developing type 1 diabetes. Therefore, diabetes specific autoantibody assessment will provide direct benefit to this population at risk as it will allow for recognition of T1D in an earlier stage of the disease and most possibly DKA prevention. If applicable, T1D secondary prevention studies will be presented to subsequent participants with two or more positive diabetes specific autoantibodies.
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