Effect of diflunisal and purine synthesis inhibitors on AMP-activated protein kinase and insulin action in skeletal muscle cellsDolinar, Klemen (Avtor) Pirkmajer, Sergej (Mentor) Garcia-Roves, Pablo Miguel (Komentor) AMP-activated protein kinase (AMPK)diflunisalinhibitors of de novo purine synthesisinhibitors of folate metabolisminsulinskeletal muscle cellsBACKGROUND: Skeletal muscles are an important site of glucose uptake and utilization and therefore play an important role in whole-body glucose homeostasis, making them an important target for the treatment of diabetes. One promising approach for the treatment of diabetes is activation of AMP-activated protein kinase (AMPK), as activation of AMPK has many beneficial metabolic effects, including increased basal and insulin-stimulated glucose uptake in skeletal muscles. AIM: The main aim of this study was to examine the effects of anti-inflammatory drug diflunisal and several clinically used purine synthesis inhibitors on AMPK, insulin signaling and basal and insulin-stimulated glucose uptake in skeletal muscle cells in vitro to determine if these compounds have the potential to activate AMPK and increase insulin signaling, basal and insulin-stimulated glucose uptake in skeletal muscles in vivo. Diflunisal could activate AMPK directly and/or indirectly by uncoupling mitochondria, while purine synthesis inhibitors could activate AMPK indirectly by inhibiting metabolism of purine synthesis intermediate and direct activator of AMPK 5-aminoimidazole-4-carboxamide ribonucleotide (ZMP). RESULTS: Diflunisal activated AMPK and increased basal glucose uptake but had no effect on insulin signaling or insulin-stimulated glucose uptake. Purine synthesis inhibitors had no effect or various positive or negative effects on AMPK, basal glucose uptake, insulin signaling and/or insulin-stimulated glucose uptake. One of them, mercaptopurine, activated AMPK and increased basal glucose uptake but suppressed insulin signaling and insulin-stimulated glucose uptake. Several other purine synthesis inhibitors (mycophenolate mofetil, trimetrexate and methotrexate) promoted activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR; pharmacological precursor of ZMP) and AICAR-stimulated glucose uptake. CONCLUSIONS: Our results suggest that diflunisal and some purine synthesis inhibitors have the potential to affect AMPK, basal glucose uptake, insulin signaling and/or insulin stimulated glucose uptake in skeletal muscles and thus whole-body glucose homeostasis.20252025-12-24 07:15:11Doktorsko delo/naloga177543sl