Review article
https://doi.org/10.18054/pb.v121-122i3-4.10802
ATIC as a link between antirheumatic drugs and regulation of energy metabolism in skeletal muscle
Klemen Dolinar
; University of Ljubljana, Faculty of Medicine, Institute of Pathophysiology, Ljubljana, Slovenia
Alexander V Chibalin
; Karolinska Institutet, Department of Molecular Medicine and Surgery, Integrative Physiology, Stockholm, Sweden AND National Research Tomsk State University, Tomsk, Russia
Sergej Pirkmajer
orcid.org/0000-0003-1459-6936
; University of Ljubljana, Faculty of Medicine, Institute of Pathophysiology, Ljubljana, Slovenia
Abstract
Chronic inflammatory rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus, increase the risk of developing insulin resistance, metabolic syndrome, and/or type 2 diabetes. While inflammation is thought to be a major mechanism underlying metabolic dysregulation in rheumatic diseases, antirheumatic drugs that exert direct metabolic effects in addition to suppressing inflammation, might be particularly useful to prevent metabolic complications. Here we review antirheumatic drugs, such as methotrexate, that inhibit ATIC, the final enzyme in the de novo purine biosynthesis, responsible for conversion of ZMP to IMP. Inhibition of ATIC results in accumulation of ZMP, thus promoting activation of AMP-activated kinase (AMPK), a major regulator of cellular energy metabolism and one of the most promising targets for the treatment of insulin resistance and type 2 diabetes. We focus especially on ATIC inhibition and AMPK activation in skeletal muscle as this is the largest and one of the most metabolically active tissues with a major role in glucose homeostasis. As an important site of insulin resistance, skeletal muscle is also one of the main target tissues for pharmacological therapy of type 2 diabetes. Finally, we review the metabolic effects of ATIC-inhibiting antirheumatic drugs and discuss whether these drugs might improve systemic glucose homeostasis by inhibiting ATIC and activating AMPK in skeletal muscle.
Keywords
Hrčak ID:
254655
URI
Publication date:
30.12.2020.
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