在脂肪細胞及第2型糖尿病患使用 Rosiglitazone活化Peroxisome Proliferator-Activated Receptor-γ後對Acid Labile Subunit表現量的影響

Abstract

Object: To determine the effect of rosiglitazone on acid labile subunit expression in adipocyte and type 2 diabetes patients after activation of peroxisome proliferator-activated receptor-γ Background: Acid-labile subunit (ALS) is crucial protein for maintaining the insulin-like growth factor (IGF) system. Recently, ALS was found to control animal growth as well as carbohydrate and fat metabolism. The aim of the study was to evaluate the change of ALS expression in adipocyte and human with type 2 diabetes after rosiglitazone treatment. Methods: Hep3B and 3T3-L1 were used after two generation of subculture. 3T3-L1 was inducted in adipocyte in adipogenic media. ALS expression was evaluated by Western blot and reverse transcription-PCR every day during adipocytes differentiation. Rosiglitazone treatment (4.5 μM) of differentiated adipocyte was analyzed. Subcutaneous and omental adipose tissues were obtained from 104 subjects during weight reduction surgery and other abdominal surgery. IGFALS mRNA expression was analyzed by real-time PCR. To evaluate whether rosiglitazone affected circulating ALS in humans, we measured serum ALS concentration at three time points over 24 weeks in 61 diabetic subjects randomized to either Rosiglitazone (2mg/d) or placebo (30 in the treatment group and 31 in the placebo group). Additional time point was measured 4 weeks after discontinuation of drug. Results: In vitro, ALS expression was up-regulated during adipocyte differentiation and reduced by rosiglitazone. Omental IGFALS mRNA expression correlated with BMI, total cholesterol, triglyceride, HOMA2 %B, hsCRP and adiponectin. Adjusted IGFALS mRNA expression increased in subjects with metabolic syndrome (p=0.047).In human study, serum ALS concentration significantly correlated with age, gender, body mass index (BMI), and triglyceride. HbA1c and fasting plasma glucose decreased within group over the time (Ptrend=0.0003 and Ptrend=0.0004, respectively). BW, BMI, total cholesterol, low-density lipoprotein cholesterol, and HOMA2 %B significantly increased in treatment group (Ptrend<0.0001, Ptrend<0.0001,Ptrend=0.0001, Ptrend=0.0004 and Ptrend=0.0113 respectively). Overall, rosiglitazone did not decrease ALS serum concentration (Ptrend=0.4741). In subgroup analysis, rosiglitazone decreased ALS in the group with middle tertile (1551, 67mU/ml>ALS≥1071.16 mU/ml) of baseline ALS concentration (Adjusted Ptrend=0.0468). Multivariate linear regression analysis showed change of serum ALS correlated with rosiglitazone treatment, age, and variation of body weight, total cholesterol, HbA1c, and fasting plasma insulin. Conclusion: ALS expression is up-regulated during adipocyte differentiation. IGFALS mRNA expression also correlates with risk factors of metabolic syndrome. Rosiglitazone suppresses ALS expression in vitro and in vivo. This change may be related to age, change of glycaemia, hyperinsulinemia and adiposity.