Projects / Programmes source: ARIS

Effect of antirheumatic drugs on insulin resistance and energy metabolism in skeletal muscle

Research activity

Code Science Field Subfield
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 
skeletal muscle, energy metabolism, diabetes mellitus, AMPK, antirheumatic drugs
Evaluation (rules)
source: COBISS
Researchers (20)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  19627  Ksenija Babič Benedik    Technical associate  2019 
2.  36454  PhD Maruša Bizjak  Biochemistry and molecular biology  Researcher  2017 - 2020  31 
3.  12153  PhD Jana Brguljan-Hitij  Cardiovascular system  Researcher  2018 - 2020  327 
4.  37636  Klemen Dolinar  Medical sciences  Technical associate  2017 - 2020  68 
5.  52538  Jan Gregorec  Biotechnology  Researcher  2018 
6.  15169  PhD Damijana Mojca Jurič  Neurobiology  Researcher  2017 - 2020  105 
7.  18619  PhD Maša Kandušer  Pharmacy  Researcher  2018  162 
8.  53838  Peter Kogovšek  Biochemistry and molecular biology  Researcher  2019 - 2020 
9.  17935  Jožica Košir    Technical associate  2019 
10.  28845  PhD Katja Lakota  Microbiology and immunology  Researcher  2017 - 2018  247 
11.  34385  PhD Jasna Lojk  Metabolic and hormonal disorders  Researcher  2019  68 
12.  16345  PhD Tomaž Marš  Neurobiology  Researcher  2017 - 2020  345 
13.  31530  PhD Urška Matkovič  Medical sciences  Technical associate  2017 - 2019  72 
14.  19318  PhD Katarina Miš  Neurobiology  Researcher  2017 - 2020  194 
15.  19225  PhD Mojca Pavlin  Systems and cybernetics  Researcher  2017 - 2020  264 
16.  29467  PhD Katja Perdan Pirkmajer  Microbiology and immunology  Researcher  2017 - 2020  163 
17.  28351  PhD Sergej Pirkmajer  Neurobiology  Head  2017 - 2020  466 
18.  12541  PhD Barbara Salobir  Microbiology and immunology  Researcher  2018 - 2020  256 
19.  06661  PhD Marjeta Terčelj Zorman  Microbiology and immunology  Researcher  2018 - 2020  414 
20.  10974  PhD Irena Zajc  Biochemistry and molecular biology  Technical associate  2017  134 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  77,953 
2.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  48,742 
3.  1538  University of Ljubljana, Faculty of Electrical Engineering  Ljubljana  1626965  28,012 
ABSTRACT   The problem. Type 2 diabetes increases mortality and reduces the quality of life by leading to kidney failure, blindness, and amputations. Slovenia has at least 120,000 cases of diabetes, most of which are type 2 diabetes, with annual cost amounting to more than 120 million euro. Clearly, type 2 diabetes represents a huge cost in terms of human suffering as well as economics, which underscores the need for novel therapeutic strategies. The challenge. Skeletal muscle is a major site of insulin resistance in type 2 diabetes. Pharmacological modulation of skeletal muscle metabolism has therefore been a focus of major research efforts. One of the most promising pharmacological targets is the AMP-activated protein kinase (AMPK), a cellular energy sensor that regulates different aspects of muscle energy metabolism. Activation of AMPK enhances insulin action in skeletal muscle and improves systemic glucose homeostasis. However, the search for effective pharmacological AMPK activators in skeletal muscle has been challenging. The opportunity. Data suggest that several anti-rheumatic drugs exert their effects via AMPK. This is not surprising since AMPK regulates not only energy metabolism but also inflammation. Importantly, we have recently shown that methotrexate, a widely used antirheumatic drug, promotes beneficial metabolic alterations in skeletal muscle via AMPK. Furthermore, we have shown that methotrexate likely improves glucose homeostasis in rheumatic patients, which is consistent with earlier epidemiological studies and studies in animal models. We therefore hypothesize that methotrexate and other antirheumatic drugs, which are thought to modulate AMPK activity, could be used to activate AMPK in skeletal muscle. Importantly, inflammatory rheumatic diseases are associated with insulin resistance and increased risk of type 2 diabetes. Therapies that simultaneously suppress inflammation and exert beneficial metabolic effects would therefore be particularly useful. Objectives. The overall objective of our proposal is to uncover new pharmacological strategies to activate AMPK and reduce insulin resistance in skeletal muscle. To tackle this challenge we have four specific objectives: (1) To determine whether methotrexate and sulfasalazine activate AMPK and modulate insulin action in skeletal muscle, (2) To determine whether and how antirheumatic drugs that target Jak/STAT signalling modulate insulin action and energy metabolism in skeletal muscle, (3) To explore whether activation of cyclic GMP-AMP synthase suppresses AMPK activation in skeletal muscle, (4) To investigate whether antifibrotic effects of adiponectin receptor agonists, which act via AMPK, contribute to metabolic improvements in skeletal muscle. Feasibility. The proposed project is feasible due to combination of the following factors: (1) the objectives are a continuation of our original line of research and are based on preliminary experiments, (2) project team is a group of established collaborators, (3) research will be conducted with our long-term international collaborators from Karolinska Institutet, Sweden, and University of Trieste, Italy, (4) team members are experts in complementary fields of research which will allow an interdisciplinary approach, which bridges the gap between diabetes and rheumatology research. Significance. The proposed project is significant for several reasons: (1) Identification of new fundamental molecular mechanisms and pharmacological targets in skeletal muscle could, in the long-run, benefit pharmacotherapy of type 2 diabetes and/or rheumatic disorders, (2) international collaboration and joint publications will increase the profile of Slovenian science, (3) transfer of skills and know-how from international partners will help to further improve local R&D capability, (4) training and education of undergraduate and postgraduate students will positively impact development of science in Slovenia.
Significance for science
The proposed project is scientifically relevant for several reasons:   First, diabetes mellitus is one of the biggest public health problems and the search for new anti-diabetic treatments is a major focus of current research efforts. Our project therefore addresses a research question that is of major importance to modern biomedicine. Importantly, the search for pharmacological agents that would effectively activate AMPK in skeletal muscle has been particularly challenging. If our hypotheses are confirmed experimentally, this project could provide the basis for development of new therapeutic approaches for type 2 diabetes. Notably, we will use existing anti-rheumatic drugs as a starting point, which means their profile of adverse effects is already well established.   Second, the proposed project is relevant not only for the field of diabetes research but also rheumatology. Indeed, patients with chronic inflammatory rheumatic disorders are at increased risk of developing metabolic dysregulation, insulin resistance, type 2 diabetes, and the metabolic syndrome. Antirheumatic drugs that suppress inflammation as well as exert beneficial metabolic effects would therefore be particularly useful in this respect. Vice versa may also be true: anti-diabetic drugs that promote AMPK activation might be useful not only for treatment of metabolic dysregulation but also for suppression of inflammation.   Third, we will combine expertise from different fields of science, including basic skeletal muscle research, energy metabolism, and molecular rheumatology. We will therefore investigate possible pharmacological targets in skeletal muscle in innovative ways, which will enable us to find novel solutions to this problem.   Fourth, this project will directly contribute to development of new area of research; namely, interactions between rheumatic and metabolic disorders, which have been insufficiently addressed in Slovenia.   Finally, project leader and his collaborators at Karolinska Institutet and University Medical Centre Ljubljana were the first to demonstrate that methotrexate promotes AMPK activation in skeletal muscle and the first to measure ZMP concentrations in patients treated with methotrexate. The proposed project is therefore a direct continuation of an original and promising line of research. Funding provided by this project would enable continuation of these lines of investigation, thus leading to novel original results.   Taken together, our project will address an important research question and has the potential to make a significant original contribution to the field of metabolic disorders as well as rheumatology.
Significance for the country
Direct impacts of the project will be: First, by providing training to B.Sc., M.Sc., and Ph.D. students in state-of-the-art techniques and methodologies of molecular biology and metabolic research we will help to increase their employment opportunities. In addition, our interdisciplinary approach will  increase their capability for finding innovative solutions that bridge the gaps between research fields. Second, by increasing local research capability, supported by our international collaborations with excellent research partners, we will help to attract talented young researchers to remain in Slovenia, thus reducing the brain drain, which has been a major problem for Slovenian science in recent years.   Third, we will continue with our communication activities (radio, newspapers, etc.) with lay public, thus raising awareness of the importance of metabolic disorders, such as type 2 diabetes, in modern society. In the long-run, such activities have the potential to positively impact lifestyles and health of lay public. Fourth, our continued dissemination activities, such as participation in workshops and seminars, aimed directly at various health professionals will help to promote the importance of basic science in general as well as to raise the awareness of the importance of metabolic research. Fifth, if we uncover new pharmacological targets or new ways to modulate existing targets, such as AMPK, long-term benefits for the society could be improved pharmacotherapy. Finding novel approaches by using established drugs in innovative combinations or identifying new possible therapeutic targets would be of considerable benefit to the society. Finally, identification of new treatment strategies for type 2 diabetes and/or rheumatic diseases could lead to cooperation with pharmaceutical industry or SMEs, which - by stimulating industry-funded research in Slovenia - would benefit the scientific community, industry, and society. This is a particularly important aspect since pharmaceutical industry is a major generator of economic growth, employment, innovation, and prosperity in Slovenia.
Most important scientific results Interim report, final report
Most important socioeconomically and culturally relevant results Interim report, final report
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