Projects / Programmes
Effect of antirheumatic drugs on insulin resistance and energy metabolism in skeletal muscle
| 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
Researchers (20)
Organisations (3)
Abstract
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
