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Dexamethasone-Induced Insulin Resistance in 3T3-L1 Adipocytes Is

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Dexamethasone-Induced Insulin Resistance in 3T3-L1 Adipocytes Is Dexamethasone-Induced Insulin Resistance in 3T3-L1 Adipocytes Is Due to Inhibition of Glucose Transport Rather Than Insulin Signal Transduction Hideyuki Sakoda, Takehide Ogihara, Motonobu Anai, Makoto Funaki, Kouichi Inukai, Hideki Katagiri, Yasushi Fukushima, Yukiko Onishi, Hiraku Ono, Midori Fujishiro, Masatoshi Kikuchi, Yoshitomo Oka, and Tomoichiro Asano Glucocorticoids reportedly induce insulin resistance. In ment clearly inhibited the increases in glucose uptake this study, we investigated the mechanism of glucocor- produced by these agents. Thus, in conclusion, the ticoid-induced insulin resistance using 3T3-L1 adip- GLUT1 decrease may be involved in the dexametha- ocytes in which treatment with dexamethasone has sone-induced decrease in basal glucose transport activ- been shown to impair the insulin-induced increase in ity, and the mechanism of dexamethasone-induced glucose uptake. In 3T3-L1 adipocytes treated with dex- insulin resistance in glucose transport activity (rather amethasone, the GLUT1 protein expression level was than the inhibition of phosphatidylinositol 3-kinase decreased by 30%, which possibly caused decreased activation resulting from a decreased IRS-1 content) is basal glucose uptake. On the other hand, dexametha- likely to underlie impaired glucose transporter regula- sone treatment did not alter the amount of GLUT4 pro- tion. Diabetes 49:1700–1708, 2000 tein in total cell lysates but decreased the insulin-stim- ulated GLUT4 translocation to the plasma membrane, which possibly caused decreased insulin-stimulated glucose uptake. Dexamethasone did not alter tyrosine phosphorylation of insulin receptors, and it significantly esearch has shown that glucocorticoids are hor- decreased protein expression and tyrosine phospho- mones that induce insulin resistance and that rylation of insulin receptor substrate (IRS)-1. Inter- their clinical use often exacerbates diabetes estingly, however, protein expression and tyrosine (1–3). This glucocorticoid-induced insulin resis- phosphorylation of IRS-2 were increased. To investi- R tance has been demonstrated not only in clinical cases but gate whether the reduced IRS-1 content is involved in also in animal experiments (4,5) and in vitro experiments insulin resistance, IRS-1 was overexpressed in dexa- methasone-treated 3T3-L1 adipocytes using an aden- using isolated or cultured cells (6–8). For example, in skele- ovirus transfection system. Despite protein expression tal muscle of glucocorticoid-treated rats, increases in glucose and phosphorylation levels of IRS-1 being normalized, uptake induced by insulin, IGF-I, or hypoxia were found to insulin-induced 2-deoxy-D-[3H]glucose uptake impaired be decreased (9,10). Similar observations were reported in by dexamethasone showed no significant improvement. primarily cultured adipocytes (11). Insulin-stimulated recruit- Subsequently, we examined the effect of dexamethasone ment of GLUT4 to the cell surface is also reportedly inhibited on the glucose uptake increase induced by overexpres- by dexamethasone in muscle and adipose tissue (12). sion of GLUT2-tagged p110␣, constitutively active Akt To date, two possible mechanisms underlying dexam- (myristoylated Akt), oxidative stress (30 mU glucose ethasone-induced insulin resistance have been suggested. oxidase for 2 h), 2 mmol/l 5-aminoimidazole-4-carbox- One possibility is the downregulation of insulin receptor sub- amide ribonucleoside for 30 min, and osmotic shock (600 mmol/l sorbitol for 30 min). Dexamethasone treat- strate (IRS)-1 expression by dexamethasone (as has been observed in 3T3-L1 adipocytes [13,14]) because IRS-1 plays From the Third Department of Internal Medicine (M.A., K.I., H.K., Y.F., a major role in the activation of phosphatidylinositol Y.On., H.O., M.Fuj., T.A.), Faculty of Medicine, University of Tokyo, 3-kinase (PI3-K), which is essential for GLUT4 translocation Bunkyo-ku, Tokyo; the Institute for Adult Disease (H.S., T.O., M.Fun., (15,16). On the other hand, in the liver, dexamethasone M.K.), Asahi Life Foundation, Shinjuku-ku, Tokyo; and the Third Department of Internal Medicine (Y.Ok.), Yamaguchi University School of Medicine, Ube, treatment reportedly decreased IRS-1 phosphorylation and Yamaguchi, Japan. IRS-1–associated PI3-K levels despite an increased IRS-1 Address correspondence and reprint requests to Tomoichiro Asano, protein content (17). When taking these reports into con- MD, Third Department of Internal Medicine, Faculty of Medicine, Univer- sity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail: asano-tky@ sideration, impaired PI3-K activation may be regarded as a umin.ac.jp. cause of insulin resistance in both liver and muscle. Received for publication 27 October 1999 and accepted in revised form The other possibility is that dexamethasone impairs the 29 June 2000. GLUT4 translocation step independently of insulin signaling. 2-DG, 2-deoxy-D-[3H]glucose; AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; AMPK, 5ЈAMP-activated protein kinase; DMEM, Dulbecco’s This possibility may be supported by evidence that glucocor- modified Eagle’s medium; ECL, enhanced chemiluminescence; IRS, insulin ticoids inhibit not only insulin-induced but also hypoxia- receptor substrate; myrAkt, myristoylated Akt; PDK, phosphoinositide- induced GLUT4 translocation to the cell surface in skeletal dependent protein kinase; PI3-K, phosphatidylinositol 3-kinase; PI-3,4-P , 2 muscle (10). Thus, whether the step in early insulin signaling phosphatidylinositol-3,4-diphosphate; PI-3,4,5-P3, phosphatidylinositol- 3,4,5-triphosphate; PMSF, phenylmethylsulfonyl fluoride. in which IRS-1 is involved or whether the impairment of 1700 DIABETES, VOL. 49, OCTOBER 2000 H. SAKODA AND ASSOCIATES GLUT4 translocation machinery is the main cause of insulin lysis buffer containing 20 mmol/l Tris, pH 7.5, 137 mmol/l NaCl, 1 mmol/l resistance in muscle or adipose tissues remains unclear. CaCl2, 1 µmol/l PMSF, and 100 µmol/l sodium orthovanadate. Lysates were In this study, we attempted to determine which hypothesis immunoprecipitated with anti–IRS-1 or anti-phosphotyrosine monoclonal antibody as described above. PI3-K activity in the immunoprecipitates was is more likely to be the mechanism of dexamethasone- assayed as reported previously (24). induced insulin resistance in adipocytes. For this purpose, we Glucose uptake. The cells were serum starved for 3 h. Next, glucose-free incu- overexpressed IRS-1 in dexamethasone-treated 3T3-L1 cells bation was performed for 45 min in Krebs-Ringer phosphate buffer. Cells were then incubated with or without 10–6 mol/l insulin for 15 min, and 2-deoxy-D- using an adenovirus system to normalize the decreased IRS-1 3 content and examined the insulin responsiveness of glucose [ H]glucose (2-DG) uptake was measured as described previously (19). uptake. In addition, we investigated whether dexamethasone impairs the increased glucose uptake induced by overex- RESULTS pression of GLUT2-tagged p110␣ or constitutively active Akt Effect of dexamethasone on glucose transport activity (myristoylated Akt [myrAkt]), oxidative stress, 5-aminoimi- and glucose transporter protein expression into dazole-4-carboxamide ribonucleoside (AICAR), or osmotic 3T3-L1 adipocytes. The 24-h incubation with dexametha- shock. Based on these results, we concluded that dexam- sone decreased 2-DG uptake into 3T3-L1 adipocytes under ethasone-induced insulin resistance affecting GLUT4 translo- both basal and insulin-stimulated conditions. This effect of cation in 3T3-L1 adipocytes is principally located beyond the dexamethasone was concentration dependent, and 1 µmol/l early insulin-signaling step and is thus likely to involve the dexamethasone decreased 2-DG uptake in the basal and GLUT4 translocation machinery. 1-µmol/l insulin-stimulated conditions by 54 and 41%, respec- tively (Fig. 1A). Decreased 2-DG uptake resulting from dex- RESEARCH DESIGN AND METHODS amethasone was also observed when cells were stimulated Antibodies. Affinity-purified antibodies against IRS-1, IRS-2, p85␣, p110␣, with lower doses of insulin (Fig. 1B) or IGF-I (Fig. 1C). These p110␤, GLUT1, and GLUT4 were prepared as previously described (18,19). Anti- dose-response curves suggest that dexamethasone impaired phosphotyrosine monoclonal antibody (4G10) was purchased from Upstate Biotechnology (Lake Placid, NY). Anti-Akt antibody and anti-phospho-Akt responsiveness to insulin or IGF-I but not sensitivity regard- (Ser473) antibody were purchased from New England Biolabs (Beverly, MA). ing glucose transport activity. Cell culture. The 3T3-L1 fibroblasts were maintained in Dulbecco’s modified To determine the GLUT1 and GLUT4 glucose transporter Eagle’s medium (DMEM) containing 10% donor calf serum (Life Technologies) expression levels in 3T3-L1 adipocytes, total cell lysates were in an atmosphere of 10% CO at 37°C. Two days after the fibroblasts had 2 immunoblotted with anti-GLUT1 antibody and anti-GLUT4 reached confluence, differentiation was induced by treating the cells with DMEM containing 0.5 mmol/l 3-isobutyl-1-methylxanthine, 4 µg/ml dexam- antibody, respectively. The amount of GLUT1 protein in the ethasone, and 10% fetal bovine serum for 48 h. Cells were fed DMEM supple- dexamethasone-treated cells was reduced to 70% of that in mented with 10% fetal bovine serum every other day for the next 4–10 days. control cells (Fig. 2A). In contrast, expression of GLUT4 pro- More than 90% of cells expressed the adipocyte phenotype. tein did not differ significantly between the dexamethasone- The
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