Stimulation of glucose uptake and improvement of insulin resistance by aromadendrin

Agents that stimulate glucose uptake and improve insulin resistance may be useful in the management of type 2 diabetes mellitus (DM). Thus, the aims of this study were to assess the effects of aromadendrin, a flavonoid from Gleditsia sinensis Lam., on stimulation of glucose uptake and improvement of insulin resistance and to characterize the molecular mechanisms underlying these activities. Insulin-stimulated glucose uptake was measured in HepG2 cells and in differentiated 3T3-L1 adipocytes using 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG), a fluorescent D-glucose analog. Expression of the peroxisome proliferator-activated receptor-γ2 (PPARγ2) and adipocyte-specific fatty acid binding protein (aP2) mRNAs and the PPARγ2 protein was analyzed in adipocytes using RT-PCR and immunoblotting, respectively. Insulin-stimulated protein kinase B (Akt/PKB) phosphorylation was measured in high glucose-induced, insulin-resistant HepG2 cells. Similar to 30 μmol/l rosiglitazone, treatment with 30 μmol/l aromadendrin significantly stimulated insulin-sensitive glucose uptake in both HepG2 cells and 3T3-L1 adipocytes. Aromadendrin treatment also enhanced adipogenesis and caused increases in the expression of PPARγ2 and aP2 mRNAs and the PPARγ2 protein in differentiated 3T3-L1 adipocytes. In high glucose-induced, insulin-resistant HepG2 cells, aromadendrin reversed the inhibition of Akt/PKB phosphorylation in response to insulin, which could be abrogated by pretreatment with LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. Aromadendrin treatment induced adipogenesis by increases in PPARγ2 expression, resulting in stimulation of glucose uptake and ameliorated insulin resistance. These findings suggest that aromadendrin may represent a potential therapeutic candidate for the management of type 2 DM.