title: Gliclazide protects 3T3L1 adipocytes against insulin resistance induced by hydrogen peroxide with restoration of GLUT4 translocation.
abstract: Increased oxidative stress under hyperglycemia may contribute to progressive deterioration of peripheral insulin sensitivity. In this study, we investigated whether gliclazide, a second-generation sulfonylurea, can protect 3T3L1 adipocytes from insulin resistance induced by oxidative stress, and whether gliclazide can restore insulin-stimulated glucose transporter 4 (GLUT4) translocation under oxidative stress. We incubated 3T3L1 adipocytes in hydrogen peroxide to produce oxidative stress, then administered various concentrations of gliclazide, N-acetylcystein (NAC), or glibenclamide. Cells treated with these drugs were next exposed to insulin, subsequent glucose uptake was measured, and the insulin-stimulated GLUT4 translocation was monitored in living cells. We found that hydrogen peroxide treatment alone suppressed glucose uptake by insulin stimulation to 65.9%+/-7.8% of the corresponding controls (P<.01). However, addition of 0.1 to 10 micromol/L gliclazide to hydrogen peroxide-treated cells dose-dependently restored glucose uptake, with 5 micromol/L gliclazide significantly restoring glucose uptake to 93.3+/-6.6% (P<.01) even under hydrogen peroxide. Treatment with the known anti-oxidant NAC also dose-dependently (0.1-10 mmol/L) restored insulin-induced glucose uptake in the presence of hydrogen peroxide. However, glibenclamide (0.1-10 micromol/L), another second-generation sulfonylurea, failed to improve glucose uptake. Similarly, treatment with 5 micromol/L gliclazide or 10 mmol/L NAC significantly overcome the reduction in insulin-stimulated GLUT4 translocation by hydrogen peroxide (P<.01), whereas 5 micromol/L glibenclamide did not. Therefore our data regarding gliclazide further characterize its mechanism of hypoglycemic effect: the observed improvements in insulin sensitivity and in GLUT4 translocation indicate that gliclazide counters the hydrogen peroxide-induced insulin resistance in 3T3L1 adipocytes and also would further augment the hypoglycemic effect of this drug as insulinotropic sulfonylurea.
authors.affiliation: Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shimoyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Kazuto
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Katsuta
authors.forename: Eisuke
authors.initials: E
authors.lastname: Ito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Seki
authors.forename: Kenji
authors.initials: K
authors.lastname: Ushikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katahira
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohno
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagamatsu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishida
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects*; D000818:Animals; D005907:Gliclazide / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D051379:Mice; D018384:Oxidative Stress; D021381:Protein Transport
chemical_list: D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D006861:Hydrogen Peroxide; D005907:Gliclazide; D005947:Glucose