Antidiabetic Effect of Taxifolin in Cultured L6 Myotubes and Type 2 Diabetic Model KK-Ay/Ta Mice with Hyperglycemia and Hyperuricemia.

Kazumi Yagasaki,Shin-ichi Adachi,Fumiaki Yoshizawa,Shinji Kondo

doi:10.3390/cimb43030092

Abstract

Muscle is the largest tissue in our body and plays an important role in glucose homeostasis and hence diabetes. In the present study, we examined the effects of taxifolin (TXF) on glucose metabolism in cultured L6 muscle cells (myotubes) and in type 2 diabetic (T2D) model KK-Ay/Ta mice. TXF dose-dependently increased glucose uptake (GU) in L6 myotubes under the condition of insulin absence. This increase in GU was partially, but significantly canceled by TXF treatment in combination with either LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), which phosphorylates protein kinase B (Akt) or Compound C, an inhibitor of 5’-adenosine monophosphate-activated protein kinase (AMPK). Furthermore, TXF was demonstrated to activate (=phosphorylate) both Akt and AMPK, and promote glucose transporter 4 (GLUT4) translocation to the plasma membrane from cytosol of L6 myotubes via both PI3K/Akt and AMPK signaling pathways. Based on these in vitro findings, we conducted an in vivo experiment in KK-Ay/Ta mice with hyperglycemia and hyperuricemia. Fasting plasma glucose, insulin, uric acid levels and an index of insulin resistance (HOMA-IR) increased significantly in the T2D model mice compared with normal ones. Such rises in the T2D state were significantly suppressed by oral administration of TXF for four weeks. These results suggest that TXF is a potent antihyperglycemic and antihyperuricemic phytochemical in the T2D state.

Highlights

The skeletal muscles account for the majority (~75%) of insulin-mediated glucose uptake in the post prandial state, and plays an important role in maintaining glucose homeostasis [3]
Leucine is unique among the branched-chain amino acids (BCAAs) in its ability to stimulate protein synthesis in the muscle of food-deprived rats [4]
We have recently found a possibility that TXF promotes glucose uptake (GU) in cultured L6 myotubes under the condition of insulin absence

Summary

Introduction

T2D accounts for approximately 90% of the total [1,2], and this rising trend can be attributed to aging, urbanization, and the obesogenic environment [2]. Skeletal muscles constitute one of the largest tissues in the body, and contribute to metabolic regulations of the main nutrients such as proteins/amino acids, lipids, and glucose. The skeletal muscles account for the majority (~75%) of insulin-mediated glucose uptake in the post prandial state, and plays an important role in maintaining glucose homeostasis [3]. Leucine is unique among the branched-chain amino acids (BCAAs) in its ability to stimulate protein synthesis in the muscle of food-deprived rats [4]. The stimulatory effect of leucine on protein synthesis has been demonstrated in differentiated

Methods

Results

Conclusion