Effect of Irisin on islet β cell function in type 2 diabetic rats by regulating autophagy through PI3K/AKT/mTOR pathway
Objective To investigate whether Irisin improves islet β cells function in rats with type 2 diabetes mellitus(T2DM)by enhancing autophagy through the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)pathway,so as to provide new ideas for clinical treatment of chronic metabolic diseases such as T2DM and metabolic syndrome.Methods Thirty SD male rats were randomly divided into normal group(NC group),T2DM group,and Irisin intervention group(T2DM+Irisin group).High-fat and high-sugar diet for 5 weeks plus low-dose(35 mg/kg)streptozotocin(STZ)induced T2DM rat model.After 8 weeks of intraperitoneal injection of Irisin,rats were tested for fast-ing blood glucose(FBG),fasting insulin(FINS),triglyceride(TG),total cholesterol(TC),low density lipoprotein choles-terol(LDL-C),and high-density lipoprotein cholesterol(HDL-C).The intraperitoneal glucose tolerance test(IPGTT),intraperitoneal insulin tolerance test(IPITT)and hyperglycemic clamp test were performed to assess the islet function and insulin resistance level of rats in each group.The expression levels of P13K/AKT/mTOR pathway proteins and autophagy-related proteins in the pancreas were subsequently detected by Western blot.The expression levels of insulin,microtubule-associated protein 1 light chain 3(MAP1LC3),p62,and lysosomal associated membrane protein-2(LAMP-2)in rat pan-creas were detected by immunohistochemistry(IHC).Results There was an interaction between FBG and intervention time in rats(F=11.751,P=0.000),and the FBG gradually decreased in the T2DM+Irisin group with the prolongation of the intervention time.From the 4th week of intervention,the FBG in the T2DM+Irisin group decreased significantly compared with that in the T2DM group(F=1 008.870,P=0.000).Compared with NC group,the serum concentrations of TC,TG,and LDL-C concentrations in the T2DM group significantly increased(each P=0.000),while the HDL-C concentrations significantly decreased(P=0.000).After Irisin intervention,the above indexes were all improved(P=0.010,0.000,0.000 and 0.000,respectively).Western blot results showed that compared with NC group,p62 protein expression and LC3 Ⅱ/LC3 Ⅰ increased significantly(P=0.008 and 0.048,respectively),and LAMP-2 protein expression decreased significantly(P=0.000)in T2DM group.LC3 Ⅱ/LC3 Ⅰ expression level further increased after Irisin intervention(P=0.000),but p62 protein level significantly decreased(P=0.047)and LAMP-2 protein expression increased significantly(P=0.000),and the IHC results were consistent with the Western blot results.The levels of p-PI3K/PI3K,p-AKT/AKT and p-mTOR/mTOR decreased significantly in the T2DM group compared with NC group(P=0.006,0.031 and 0.000,respectively),and the above indicators further decreased after Irisin intervention(P=0.033,0.013 and 0.000,respectively).Conclusion Irisin can enhance autophagy through PI3K/AKT/mTOR signaling pathway to improve islet βcells function,providing a new idea for the treatment of T2DM.
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