Inhibitory mechanisms of flavonoids on insulin-stimulated glucose uptake in MC3T3-G2/PA6 adipose cells.
We assessed the effects of different classes of flavonoids on insulin-stimulated 2-deoxy-D-[1-(3)H]glucose uptake by mouse MC3T3-G2/PA6 cells differentiated into mature adipose cells. Among the flavonoids examined, the flavones, apigenin and luteolin, the flavonols, kaempferol, quercetin and fisetin, an isoflavone, genistein, a flavanonol, silybin, and the flavanols, (-)-epigallocatechin gallate (EGCG) and theaflavins, significantly inhibited insulin-stimulated glucose uptake. Key structural features of flavonoids for inhibition of insulin-stimulated glucose uptake are the B-ring 4'- or 3',4'-OH group and the C-ring C2-C3 double bond of the flavones and flavonols, the A-ring 5-OH of isoflavones, and the galloyl group of EGCG and theaflavins. Luteolin significantly inhibits insulin-stimulated phosphorylation of insulin receptor-beta subunit (IR-beta), and apigenin, kaempferol, quercetin and fisetin, also tended to inhibit the IR-beta phosphorylation. On the other hand, isoflavones, flavanols or flavanonols did not affect insulin-stimulated IR-beta phosphorylation. Apigenin, luteolin, kaempferol, quercetin and fisetin also appeared to inhibit insulin-stimulated activation of Akt, a pivotal downstream effector of phosphatidylinositol 3-kinase (PI3K), and suppressed insulin-dependent translocation of a glucose transporter, (GLUT)4, into the plasma membrane. Although genistein, silybin, EGCG and theaflavins had no effect on the insulin-stimulated activation of Akt, they blocked insulin-dependent GLUT4 translocation. These results provide novel insights into the modulation by flavonoids of insulin's actions, including glucose uptake in adipocytes.
Nomura
Masaaki
M
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Takahashi
Tatsuo
T
Nagata
Naoto
N
Tsutsumi
Kikue
K
Kobayashi
Shinjiro
S
Akiba
Tetsuo
T
Yokogawa
Koichi
K
Moritani
Shuzo
S
Miyamoto
Ken-ichi
K
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D005419:Flavonoids; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; C495693:Slc2a4 protein, mouse; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose