Enhancement of insulin signaling pathway in adipocytes by oxovanadium(IV) complexes.
Recently, we have found that some oxovanadium(IV) complexes are potent insulin-mimetic compounds for treating both type I and type II diabetic animals. However, the functional mechanism of oxovanadium(IV) complexes is not fully understood. In this report, we have shown that oxovanadium(IV)-picolinate complexes such as VO(pa)(2), VO(3mpa)(2), and VO(6mpa)(2) act on the insulin signaling pathway in 3T3-L1 adipocytes. Among them, VO(3mpa)(2) was found to be the highest potent activator in inducing not only the phosphotyrosine levels of both IRbeta and IRS but also the activation of downstream kinases in the insulin receptor, such as Akt and GSK3beta, which in turn translocated the insulin-dependent GLUT4 to the plasma membrane. Then, we examined whether or not oxovanadium(IV)-picolinates exhibit the hypoglycemic activity in STZ-induced diabetic mice, and found that VO(3mpa)(2) is more effective than the others in improving the hyperglycemia of the animals. Our present data indicate that both activation of insulin signaling pathway, which follows the GLUT4 translocation to the plasma membrane, and enhancement of glucose utilization by oxovanadium(IV) complexes cause the hypoglycemic effect in diabetic animals.
Basuki
Wanny
W
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-chio, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Hiromura
Makoto
M
Adachi
Yusuke
Y
Tayama
Kojiro
K
Hattori
Masakazu
M
Sakurai
Hiromu
H
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007003:Hypoglycemia / Q000097:blood; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D010848:Picolinic Acids / Q000737:chemistry; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014638:Vanadates / Q000737:chemistry / Q000494:pharmacology*
D051275:Glucose Transporter Type 4; D007328:Insulin; D010848:Picolinic Acids; C495693:Slc2a4 protein, mouse; D019000:Phosphotyrosine; D014638:Vanadates; D011972:Receptor, Insulin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C030614:picolinic acid