Therapeutic Effect And Mechanism Of Acyclovir On Type 2 Diabetes Mouse Model

Aims:Diabetes mellitus is a major global health threat characterized by insulin resistance.Currently,1 in 10 adults suffers from diabetes,of which 90-95%have type2 diabetes mellitus(T2DM).Nevertheless,the clinical drugs that have been marketed for the treatment of T2DM have many side effects and almost none of them are capable of alleviating diabetic complications.Consequently,it is imminent to develop new drugs that not only improve insulin sensitivity,but also prevent its complications.The purpose of this study is to provide a new strategy and target to remedy T2DM.Methods:In vivo,C57BL/6 N mice were raised with high-fat diet and infused with streptozotocin to induce diabetes.The fasting blood glucose,glycosylated hemoglobin,glucose tolerance and insulin resistance index were detected to evaluate the effect of acyclovir on diabetic mice.Besides,blood lipids and oxidative stress indicators were also examined.In vitro,we constructed human hepatocellular carcinomas(Hep G2)cell models of oxidation,glycation,and insulin resistance,and measured cell viability,reactive oxygen species(ROS),and advanced glycation end products(AGEs)levels.Moreover,the mechanism of acyclovir in the therapy of T2DM was explored through activity experiments in vitro,gene overexpression and knockout techniques.Results:(1)Acyclovir reduces fasting blood glucose,improve blood glucose homeostasis and insulin resistance in T2DM mice,at the same time,it decreases serum total cholesterol,triglyceride and low-density lipoprotein cholesterol,and safeguard cardiovascular.In addition,acyclovir plays role in diminishing the content of malondialdehyde in the liver of T2DM mice,elevating the activity of total superoxide dismutase,thus boosting the anti-oxidant capacity of liver.(2)Acyclovir lowers ROS level and AGEs protein expression in Hep G2 cells,enhance anti-oxidant as well as anti-glycation competence,alleviate insulin resistance and promote glucose metabolism simultaneously.(3)In terms of mechanism of action,acyclovir directly activates pyruvate kinase muscle isozyme 1(PKM1).Overexpression of PKM1 in Hep G2 cells has a potential to anti-oxidative and anti-glycation,meanwhile,augments the glucose consumption of cells and relieves insulin resistance,which is consistent with the effect of acyclovir.However,after PKM1 knockout,acyclovir loses its protective effect.Moreover,acyclovir facilitates AMP-dependent protein kinase(AMPK)phosphorylation and SIRT1,a member of NAD~+-dependent sirtuin family,expression.Whereas,there is no change in the protein expression level after deletion of PKM1 in Hep G2 cells.Conclusions:Acyclovir stimulates pyruvate kinase M1(PKM1)directly to activate AMPK/SIRT1 signaling pathway,thereby improving insulin resistance.Meanwhile,it ameliorates lipid metabolism and oxidative stress to remedy T2DM.