Furong Lu1, Qin Cai2, Mohammad Ishraq Zafar2, Lun Cai3, Wen Du2, Liumeng Jian2, Liping Li2, Feng Gao2. 1. Department of Integrated Chinese Traditional and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology 1277, Jiefang Avenue, Wuhan 430022, China. 2. Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology 1277, Jiefang Avenue, Wuhan 430022, China. 3. Department of Neurosurgery, Wuhan Central Hospital No. 26, Shengli Street, Wuhan 430014, China.
Abstract
INTRODUCTION/AIMS: Hydroxyisoleucine (4-HIL), derived from fenugreek seeds, improves insulin resistance in 3T3-L1 adipocytes and L6 myotubes. However, the effects of 4-HIL on liver glycogen synthesis and hepatic insulin resistance have not been described. The aim of this study was to investigate the effects of 4-HIL on glycogen synthesis in a tumor necrosis factor-α (TNF-α)-induced insulin resistance model using HepG2 cells. MATERIALS AND METHODS: HepG2 cells were divided into eight groups: control; TNF-α; and 5, 10, or 20 μM 4-HIL without or with TNF-α. Glycogen and protein expression were evaluated using a glycogen assay kit and western blotting, respectively. RESULTS: Glycogen levels did not differ between the 4-HIL groups and control (P>0.05), but were decreased significantly in the TNF-α group (P<0.05), indicating the establishment of insulin-resistant HepG2 cells. Adding 20 μM 4-HIL to TNF-α-treated cells increased glycogen levels (P<0.05). Relative to the control group, the P-IRS-1/IRS-1 and P-JNK/JNK ratios were increased (P<0.001) in the TNF-α group, whereas the P-AKT/AKT and P-GSK/GSK ratios were decreased (P<0.001). When 20 μM 4-HIL was added to TNF-α-treated cells, the P-IRS-1/IRS-1 and P-JNK/JNK ratios decreased (P<0.001 and P<0.05, respectively), whereas the P-AKT/AKT and P-GSK/GSK ratios increased (P<0.05 and P<0.001). CONCLUSIONS: 4-HIL directly or indirectly reversed TNF-α reduced glycogen levels by inhibiting JNK and IRS-1 (Ser(307)) phosphorylation and increasing AKT (Ser(473)) and GSK-3 phosphorylation. These findings demonstrate that 4-HIL modulates hepatic insulin resistance at the molecular level, and suggest that it is a novel potential therapeutic agent for the treatment of insulin resistance in patients with diabetes.
INTRODUCTION/AIMS: Hydroxyisoleucine (4-HIL), derived from fenugreek seeds, improves insulin resistance in 3T3-L1 adipocytes and L6 myotubes. However, the effects of 4-HIL on liver glycogen synthesis and hepatic insulin resistance have not been described. The aim of this study was to investigate the effects of 4-HIL on glycogen synthesis in a tumor necrosis factor-α (TNF-α)-induced insulin resistance model using HepG2 cells. MATERIALS AND METHODS: HepG2 cells were divided into eight groups: control; TNF-α; and 5, 10, or 20 μM 4-HIL without or with TNF-α. Glycogen and protein expression were evaluated using a glycogen assay kit and western blotting, respectively. RESULTS:Glycogen levels did not differ between the 4-HIL groups and control (P>0.05), but were decreased significantly in the TNF-α group (P<0.05), indicating the establishment of insulin-resistant HepG2 cells. Adding 20 μM 4-HIL to TNF-α-treated cells increased glycogen levels (P<0.05). Relative to the control group, the P-IRS-1/IRS-1 and P-JNK/JNK ratios were increased (P<0.001) in the TNF-α group, whereas the P-AKT/AKT and P-GSK/GSK ratios were decreased (P<0.001). When 20 μM 4-HIL was added to TNF-α-treated cells, the P-IRS-1/IRS-1 and P-JNK/JNK ratios decreased (P<0.001 and P<0.05, respectively), whereas the P-AKT/AKT and P-GSK/GSK ratios increased (P<0.05 and P<0.001). CONCLUSIONS:4-HIL directly or indirectly reversed TNF-α reduced glycogen levels by inhibiting JNK and IRS-1 (Ser(307)) phosphorylation and increasing AKT (Ser(473)) and GSK-3 phosphorylation. These findings demonstrate that 4-HIL modulates hepatic insulin resistance at the molecular level, and suggest that it is a novel potential therapeutic agent for the treatment of insulin resistance in patients with diabetes.
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