Troglitazone prevents and reverses dexamethasone induced insulin resistance on glycogen synthesis in 3T3 adipocytes.

Abstract

Troglitazone lowers blood glucose levels in Type II diabetic patients. To evaluate the insulin sensitizing action of troglitazone on glycogen synthesis we have used dexamethasone-treated 3T3 adipocytes as an in vitro model. Differentiated 3T3 adipocytes were incubated with 100 nM dexamethasone for 6 days. Troglitazone (1.0 microM) or metformin (1.0 mM) with or without 200 nM insulin was added during the last 4 days. At the end, insulin (100 nM) stimulated glycogen synthesis was determined using (14)C-glucose. Dexamethasone caused a 50% reduction in glycogen synthesis. Troglitazone caused an approximately 3 fold increase in glycogen synthesis from 43.9+/-3.4 to 120+/-16.2 nmols h(-1). Under identical conditions metformin had no significant effect. When cells were incubated with troglitazone and dexamethasone simultaneously for 6 days, troglitazone but not metformin completely prevented dexamethasone-induced insulin resistance. RU 486 (1.0 microM) also completely prevented the insulin resistance. Chronic incubation with dexamethasone and insulin resulted in a 73% reduction in glycogen synthesis. In these adipocytes, troglitazone was partially active with glycogen synthesis rising from 23.1+/-3.0 to 44.4+/-4.5 nmol h(-1), P<0.01 while metformin was inactive. Troglitazone stimulated 2-deoxyglucose uptake by 2 - 3 fold in dexamethasone-treated adipocytes. Metformin also increased glucose uptake significantly. Troglitazone did not affect insulin binding while a 2 fold increase was observed in normal adipocytes where it exhibited a modest effect. Since the effect of troglitazone was greater in dexamethasone-treated adipocytes, troglitazone is likely to act by preventing dexamethasone-induced alterations which may include (i) binding to glucocorticoid receptor and (ii) effect on glucose uptake. These data demonstrate the direct insulin sensitizing action of troglitazone on glycogen synthesis and suggest a pharmacological profile different from metformin.