Nidulin stimulates glucose uptake in myotubes through the IRS-AKT pathway and alters redox balance and intracellular calcium

doi:10.1007/s13659-025-00546-3

Natural Products and Bioprospecting ›› 2025, Vol. 15 ›› Issue (6): 63-63.DOI: 10.1007/s13659-025-00546-3

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Nidulin stimulates glucose uptake in myotubes through the IRS-AKT pathway and alters redox balance and intracellular calcium

Kanittha Chantarasakha¹, Arunrat Yangchum¹, Masahiko Isaka¹, Surapun Tepaamorndech²

1. National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), 111 Thailand Science Park, Phahonyothin Road, Klong Luang, Pathum Thani, 12120, Thailand;
2. Department of Microbiology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand

Received:2025-06-04 Online:2026-01-12
Contact: Surapun Tepaamorndech Email:E-mail:surapun.t@chula.ac.th
Supported by:
This research was supported by (i) Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University, Grant Number RA67/015, (ii) Ratchadapisek Sompotch Fund, Chulalongkorn University, and (iii) National Research Council of Thailand (NRCT), Grant Number N42A660851.

Nidulin stimulates glucose uptake in myotubes through the IRS-AKT pathway and alters redox balance and intracellular calcium

Kanittha Chantarasakha¹, Arunrat Yangchum¹, Masahiko Isaka¹, Surapun Tepaamorndech²

1. National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), 111 Thailand Science Park, Phahonyothin Road, Klong Luang, Pathum Thani, 12120, Thailand;
2. Department of Microbiology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand

通讯作者: Surapun Tepaamorndech Email:E-mail:surapun.t@chula.ac.th
基金资助:
This research was supported by (i) Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University, Grant Number RA67/015, (ii) Ratchadapisek Sompotch Fund, Chulalongkorn University, and (iii) National Research Council of Thailand (NRCT), Grant Number N42A660851.

Abstract

Abstract: Nidulin is a secondary metabolite of the depsidone family produced by Aspergillus spp., and has shown promises in pharmacological applications. This study aimed to investigate the effect of nidulin on glucose metabolism in skeletal muscle, the primary site of physiological glucose disposal, and its underlying mechanisms. Using a 2-[³H]-deoxy-glucose (2-DG) uptake assay, nidulin stimulated 2-DG in L6 myotubes in a dose- and time-dependent manner. This effect of nidulin was additive to insulin and metformin, and remained effective under palmitic acid-induced insulin resistance. At the molecular level, nidulin upregulated the mRNA expression and promoted membrane translocation of glucose transporters, GLUT4 and GLUT1. Although nidulin activated AMPK and p38 signaling, pharmacological inhibition of this pathway had minimal effect on nidulin-enhanced 2-DG uptake activity. Notably, nidulin activated key insulin signaling proteins, including IRS1, AKT, and p44/42, and its effect was attenuated by an AKT inhibitor. This study further compared the upstream mechanism of nidulin with that of insulin. While nidulin did not directly activate the insulin receptor β-subunit, it modulated redox homeostasis and intracellular calcium, evidenced by increased cytosolic H₂O₂ and Ca²⁺ levels. The 2-DG uptake-enhancing effect of nidulin and its activation of AKT were suppressed by either an antioxidant or calcium chelator treatment. These findings position nidulin as a promising insulin-sensitizing agent, offering mechanistic insights and therapeutic potential for improving glucose homeostasis in type 2 diabetes.

Key words: Fungal metabolite, Aspergillus, Antidiabetic agent, Insulin resistance, Insulin signaling, GLUT4

摘要： Nidulin is a secondary metabolite of the depsidone family produced by Aspergillus spp., and has shown promises in pharmacological applications. This study aimed to investigate the effect of nidulin on glucose metabolism in skeletal muscle, the primary site of physiological glucose disposal, and its underlying mechanisms. Using a 2-[³H]-deoxy-glucose (2-DG) uptake assay, nidulin stimulated 2-DG in L6 myotubes in a dose- and time-dependent manner. This effect of nidulin was additive to insulin and metformin, and remained effective under palmitic acid-induced insulin resistance. At the molecular level, nidulin upregulated the mRNA expression and promoted membrane translocation of glucose transporters, GLUT4 and GLUT1. Although nidulin activated AMPK and p38 signaling, pharmacological inhibition of this pathway had minimal effect on nidulin-enhanced 2-DG uptake activity. Notably, nidulin activated key insulin signaling proteins, including IRS1, AKT, and p44/42, and its effect was attenuated by an AKT inhibitor. This study further compared the upstream mechanism of nidulin with that of insulin. While nidulin did not directly activate the insulin receptor β-subunit, it modulated redox homeostasis and intracellular calcium, evidenced by increased cytosolic H₂O₂ and Ca²⁺ levels. The 2-DG uptake-enhancing effect of nidulin and its activation of AKT were suppressed by either an antioxidant or calcium chelator treatment. These findings position nidulin as a promising insulin-sensitizing agent, offering mechanistic insights and therapeutic potential for improving glucose homeostasis in type 2 diabetes.

关键词: Fungal metabolite, Aspergillus, Antidiabetic agent, Insulin resistance, Insulin signaling, GLUT4

Kanittha Chantarasakha, Arunrat Yangchum, Masahiko Isaka, Surapun Tepaamorndech. Nidulin stimulates glucose uptake in myotubes through the IRS-AKT pathway and alters redox balance and intracellular calcium[J]. Natural Products and Bioprospecting, 2025, 15(6): 63-63.

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Nidulin stimulates glucose uptake in myotubes through the IRS-AKT pathway and alters redox balance and intracellular calcium

Nidulin stimulates glucose uptake in myotubes through the IRS-AKT pathway and alters redox balance and intracellular calcium

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