Therapeutic Effects And Molecular Mechanisms Of Chitooligosaccharide Biguanide On Type 2 Diabetic Rats

Diabetes mellitus,a common metabolic disorder,is characterized by chronic hyperglycemia with disturbances in the metabolism of carbohydrates,lipids and proteins,and this non-insulin-dependent diabetes mellitus(type 2 diabetes mellitus,T2DM)comprises 90～95% of diabetic individuals,whose two major characteristics are islet β-cell dysfunction and peripheral insulin resistance.In this study,by reference to the molecular structure of metformin(Met),different kinds of chitooligosaccharide biguanides(COSG)were synthesised by the microwave irradiation between chitooligosaccharide(COS)and dicyandiamide.FTIR,NMR and XRD were employed,conforming biguanide groups were successfully introduced into chitosan main chains.Then,T2 DM rat model was established,basic biochemical indexes,pancreaticassociated insulin signaling pathways and factors were measured to explore possible mechanisms of repairing islet β-cell dysfunction.The results inidicated COSG could control body weight,reduce glucose levels in blood and urine,improve insulin secretion.Then activated PI3K/Akt pathway would promote nuclear translocation of Fox O1 and increase insulin secretion by PDX-1-GLUT-2/GCK pathway,and prevent apoptosis by GSK-3β/Caspase-3 pathway,then repair β-cell dysfunction and injury.Furthermore,oxidative stress factors and liver-associated insulin signaling pathways and related factors were detected,and morphological changes of liver tissues were observed to explore molecular mechanisms of COSG in improving insulin resistance.The results demostrated that COSG could effectively increase the activity of SOD,CAT and GSH-Px,reduce that of MDA,then activating IRS-2/PI3K/Akt/GLUT-2 signaling pathway to enhance glucose uptake,and decrease PEPCK and G6 Pase kinase to promote the synthesis of hepatic glycogen to improve insulin resistant.Finally,COSG was fluorescently labeled with Cy5 SE to study its absorption and distribution in different tissues and organs in vivo.COSG in blood was significantly higher than Met,while that was lower in stools,indicating its good absorption effects.In addition,COSG was mainly distributed in organs such as stomach,intestine,pancreas and liver,and its strong absorption was demonstrated in pancreas and liver.