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- Title
14-Deoxy-11,12-Didehydroandrographolide Ameliorates Glucose Intolerance Enhancing the LKB1/AMPKα/TBC1D1/GLUT4 Signaling Pathway and Inducing GLUT4 Expression in Myotubes and Skeletal Muscle of Obese Mice.
- Authors
Chen, Chih-Chieh; Lii, Chong-Kuei; Lo, Chia-Wen; Lin, Yi-Hsueh; Yang, Ya-Chen; Huang, Chin-Shiu; Chen, Haw-Wen
- Abstract
14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive component of Andrographis paniculata, has antidiabetic activity. AMP-activated protein kinase (AMPK) regulates glucose transport and ameliorates insulin resistance. The aim of the present study was to investigate whether activation of AMPK is involved in the mechanism by which deAND ameliorates insulin resistance in muscles. deAND amounts up to 40 μ M dose-dependently activated phosphorylation of AMPK α and TBC1D1 in C2C12 myotubes. In addition, deAND significantly activated phosphorylation of LKB1 at 6 h after treatment, and this activation was maintained up to 48 h. deAND increased glucose uptake at 18 h after treatment, and this increase was time dependent up to 72 h. Compound C, an inhibitor of AMPK, suppressed deAND-induced phosphorylation of AMPK α and TBC1D1 and reversed the effect on glucose uptake. In addition, the expression of GLUT4 mRNA and protein in C2C12 myotubes was up-regulated by deAND in a time-dependent manner. Promotion of GLUT4 gene transcription was verified by a pGL3-GLUT4 (837 bp) reporter assay. deAND also increased the nuclear translocation of MEF-2A and PPAR β. After 16 weeks of feeding, the high-fat diet (HFD) inhibited phosphorylation of AMPK α and TBC1D1 in skeletal muscle of obese C57BL/6JNarl mice, and deactivation of AMPK α and TBC1D1 by the HFD was abolished by deAND supplementation. Supplementation with deAND significantly promoted membrane translocation of GLUT4 compared with the HFD group. Supplementation also significantly increased GLUT4 mRNA and protein expression in skeletal muscle compared with the HFD group. The hypoglycemic effects of deAND are likely associated with activation of the LKB1/AMPK α /TBC1D1/GLUT4 signaling pathway and stimulation of MEF-2A- and PPAR β -dependent GLUT4 gene expression, which account for the glucose uptake into skeletal muscle and lower blood glucose levels.
- Subjects
TAIWAN; OBESITY; GLUCOSE intolerance; TERPENES; SKELETAL muscle; HYPERGLYCEMIA; FAT content of food; PHOSPHOTRANSFERASES; ANIMAL experimentation; LIQUID chromatography; WESTERN immunoblotting; GENE expression; CELLULAR signal transduction; CELL survival; T-test (Statistics); COMPARATIVE studies; MASS spectrometry; DESCRIPTIVE statistics; RESEARCH funding; STATISTICAL sampling; POLYMERASE chain reaction; DATA analysis software; STATISTICAL correlation; MICE; INSULIN resistance; PHOSPHORYLATION
- Publication
American Journal of Chinese Medicine, 2021, Vol 49, Issue 6, p1473
- ISSN
0192-415X
- Publication type
Article
- DOI
10.1142/S0192415X21500695