Diabetes is often associated with vitamin A disorders.All-trans retinoic acid(ATRA)is the main active constituent of vitamin A.We aimed to investigate whether ATRA influences diabetic progression and its mechanisms using both Goto-Kazizazi(GK)rats and INS-1 cells.Rat experiments demonstrated that ATRA treatment worsened diabetes symptoms,as evidenced by an increase in fasting blood glucose(FBG)levels and impairment of glucose homeostasis.Importantly,ATRA impaired glucose-stimulated insulin secretion(GSIS)and increased the expression of sterol regulatory element-binding protein 1c(SREBP-1c)and uncoupling protein 2(UCP2)in the rat pancreas.Data from INS-1 cells also showed that ATRA upregulated SREBP-1c and UCP2 expression and impaired GSIS at 23 mM glucose.Srebp-1c or Ucp2 silencing attenuated GSIS impairment by reversing the ATRA-induced increase in UCP2 expression and decrease in ATP content.ATRA and the retinoid X receptor(RXR)agonists 9-cis RA and LG100268 induced the gene expression of Srebp-1c,which was almost completely abolished by the RXR antagonist HX531.RXRa-LBD luciferase reporter plasmid experiments also demonstrated that ATRA concentration-dependently activated RXRa,the EC50 of which was 1.37 μM,which was lower than the ATRA concentration in the pancreas of GK rats treated with a high dose of ATRA(approximately 3 μM),inferring that ATRA can upregulate Srebp-1c expression in the pancreas by activating RXR.In conclusion,ATRA impaired GSIS partly by activating the RXR/SREBP-1c/UCP2 pathway,thus worsening diabetic symptoms.The results highlight the roles of ATRA in diabetic progression and establish new strategies for diabetes treatment.

Han-yu Yang;Ming Liu;Yun Sheng;Liang Zhu;Meng-meng Jin;Tian-xin Jiang;Lu Yang;Pei-hua Liu;Xiao-dong Liu;Li Liu

Center of Drug Metabolism and Pharmacokinetics,School of Pharmacy,China Pharmaceutical University,Nanjing 210009,China

中国药理学报（英文版）

[1]Han-yu Yang;Ming Liu;Yun Sheng;Liang Zhu;Meng-meng Jin;Tian-xin Jiang;Lu Yang;Pei-hua Liu;Xiao-dong Liu;Li Liu-.All-trans retinoic acid impairs glucose-stimulated insulin secretion by activating the RXR/SREBP-1c/UCP2 pathway)[J].中国药理学报（英文版）,2022(06):1441-1452

Kazizazi,Ucp2,LG100268,HX531,RXRa

All,trans,retinoic,acid,impairs,glucose,stimulated,insulin,secretion,by,activating,SREBP,1c,UCP2,pathway,Diabetes,often,associated,vitamin,disorders,ATRA,main,active,constituent,We,aimed,investigate,whether,influences,diabetic,progression,its,mechanisms,using,both,Goto,GK,rats,INS,cells,Rat,experiments,demonstrated,that,treatment,worsened,diabetes,symptoms,evidenced,fasting,blood,FBG,levels,impairment,homeostasis,Importantly,impaired,GSIS,increased,expression,sterol,regulatory,element,binding,protein,uncoupling,pancreas,Data,from,also,showed,upregulated,mM,Srebp,silencing,attenuated,reversing,induced,decrease,ATP,content,retinoid,receptor,agonists,cis,gene,which,was,almost,completely,abolished,antagonist,LBD,luciferase,reporter,plasmid,concentration,dependently,activated,EC50,lower,than,treated,dose,approximately,inferring,can,In,conclusion,partly,thus,worsening,results,highlight,roles,establish,new,strategies

0.467453