We conducted a systematic review and meta-analysis of randomized controlled trials（RCTs） to determine the effectiveness and safety of incretin-based therapies（IBTs） for the treatment of type 2 diabetes（T2DM） wit...We conducted a systematic review and meta-analysis of randomized controlled trials（RCTs） to determine the effectiveness and safety of incretin-based therapies（IBTs） for the treatment of type 2 diabetes（T2DM） with nonalcoholic fatty liver disease（NAFLD）. Electronic databases such as the Cochrane library, EMbase, Pub Med, and three Chinese databases were searched for RCTs that compared IBTs with other treatments or placebo for T2 DM with NAFLD. Two reviewers independently assessed the risk of bias, extracted, and analyzed the data. A meta-analysis was performed using Revman 5.2. Publication bias was evaluated. Seven RCTs involving 532 patients were ultimately included. The results of meta-analysis（random-effects model） revealed that IBTs had a significant reduction in serum ALT（WMD –12.30, 95% CI –17.53~–7.06） and BMI（WMD –2.64, 95% CI –4.35~–0.94）. However, there was no significant difference in other outcomes including Hb A1 c, AST, TC, TG and HOMA-RA. IBTs were well tolerated by patients but the evidence was limited. The significant decrease in hepatic biochemical markers following treatment with IBTs, as well as improvements in BMI, suggested that IBTs may be an effective option for T2 DM with NAFLD.展开更多
Thiazolidinediones(TZDs),such as rosiglitazone(RSG),which activates peroxisome proliferator activated receptor-y(PPARy),are a potent class of oral antidiabetic agents with good durability.However,the clinical use of T...Thiazolidinediones(TZDs),such as rosiglitazone(RSG),which activates peroxisome proliferator activated receptor-y(PPARy),are a potent class of oral antidiabetic agents with good durability.However,the clinical use of TZDs is challenging because of their side effects,including weight gain and hepatotoxicity.Here,we found that bavachinin(BVC),a lead natural product,additively activates PPARγ with lowdose RSG to preserve the maximum antidiabetic effects while reducing weight gain and hepatotoxicity in db/db mice caused by RSG monotherapy.Structural and biochemical assays demonstrated that an unexplored hotspot around Met329 and Ser332 in helix 5 is triggered by BVC cobinding to RSG-bound PPARy,thereby allosterically stabilizing the active state of the activation-function 2 motif responsible for additive activation with RSG.Based on this hotspot,we discovered a series of new classes of allosteric agonists inducing the activity of TZDs in the same manner as BVC.Together,our data illustrate that the hotspot of PPARγ is druggable for the discovery of new allosteric synergists,and the combination thera py of allosteric synergists and TZD drugs may provide a potential alternative approach to the treatment of type 2 diabetes mellitus.展开更多
文摘We conducted a systematic review and meta-analysis of randomized controlled trials（RCTs） to determine the effectiveness and safety of incretin-based therapies（IBTs） for the treatment of type 2 diabetes（T2DM） with nonalcoholic fatty liver disease（NAFLD）. Electronic databases such as the Cochrane library, EMbase, Pub Med, and three Chinese databases were searched for RCTs that compared IBTs with other treatments or placebo for T2 DM with NAFLD. Two reviewers independently assessed the risk of bias, extracted, and analyzed the data. A meta-analysis was performed using Revman 5.2. Publication bias was evaluated. Seven RCTs involving 532 patients were ultimately included. The results of meta-analysis（random-effects model） revealed that IBTs had a significant reduction in serum ALT（WMD –12.30, 95% CI –17.53~–7.06） and BMI（WMD –2.64, 95% CI –4.35~–0.94）. However, there was no significant difference in other outcomes including Hb A1 c, AST, TC, TG and HOMA-RA. IBTs were well tolerated by patients but the evidence was limited. The significant decrease in hepatic biochemical markers following treatment with IBTs, as well as improvements in BMI, suggested that IBTs may be an effective option for T2 DM with NAFLD.
基金the National Natural Science Foundation of China(21708025,81925034,91753117,and 81773793)the Open Fund of State Key Laboratory of Oncogenes and Related Genes,Shanghai Jiao Tong University School of Medicine+3 种基金the Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-01-E00036)the Shanghai Science and Technology Innovation Foundation(19431901600)the China Postdoctoral Science Foundation(2016M601618 and 2017T100303)the National Science and Technology Major Project of China(2018ZX09711001-005-022)。
文摘Thiazolidinediones(TZDs),such as rosiglitazone(RSG),which activates peroxisome proliferator activated receptor-y(PPARy),are a potent class of oral antidiabetic agents with good durability.However,the clinical use of TZDs is challenging because of their side effects,including weight gain and hepatotoxicity.Here,we found that bavachinin(BVC),a lead natural product,additively activates PPARγ with lowdose RSG to preserve the maximum antidiabetic effects while reducing weight gain and hepatotoxicity in db/db mice caused by RSG monotherapy.Structural and biochemical assays demonstrated that an unexplored hotspot around Met329 and Ser332 in helix 5 is triggered by BVC cobinding to RSG-bound PPARy,thereby allosterically stabilizing the active state of the activation-function 2 motif responsible for additive activation with RSG.Based on this hotspot,we discovered a series of new classes of allosteric agonists inducing the activity of TZDs in the same manner as BVC.Together,our data illustrate that the hotspot of PPARγ is druggable for the discovery of new allosteric synergists,and the combination thera py of allosteric synergists and TZD drugs may provide a potential alternative approach to the treatment of type 2 diabetes mellitus.
