| Objective T2DM is a complicated metabolic dysregulation which is characterized by chronic hyperglycemia and varying degrees of insulin resistance in various organs or systems(brain,pancreas,liver,skeletal muscle and fat).Empagliflozin is a new class of antihyperglycemic drugs recently available for use in T2DM patients.The mechanism of empagliflozin is unique,which can maintain euglycemia by blocking the cotransport of renal sodium-glucose and excrete excess glucose through the urine.Metformin is usually proposed as the first-line oral hypoglycemic agent.The aim of the present study was to investigate the amelioration for glucose and lipid metabolism in T2DM mice,elicited by the combination therapy of empagliflozin plus metformin or by empagliflozin monotherapy.Methods At age of 9 weeks,a total of 32 db/db mice were randomly divided into four groups(n=8/group): the DMT1 group,treated with metformin(250 mg/kg/day);the DMT2 group,treated with metformin(250 mg/kg/day)plus empagliflozin(10 mg/kg/day);the DMT3 group,treated with empagliflozin(10 mg/kg/day);the T2DM control group(DM),received 0.5% Natrosol.Meanwhile,a total of 8 db/m mice were used as the normal control group(NC),and its administration pattern were identical to DM group.Metformin and empagliflozin were respectively dissolved in 0.5% Natrosol and administered once per day for 4 weeks by gavage.All animals have ad libitum access to standard food and water during the 4 weeks intervention.The 24-hour food and water intake were measured every three days and took the average.The murine body weights and fasting plasma glucose(FPG)levels were measured each week.At the end of the research,after 8h fasting,mice were euthanized via 10% chloral hydrate anesthesia and killed by cervical dislocation.Whole blood was collected from the orbital venous plexus for biochemical assays.Liver tissues were harvested from the sacrificed mice to detect the expression of protein related to glucose and lipid metabolism by Western blotting.Results After four-week treatments,compared with T2DM control(DM),the empagliflozin or its combination with metformin significantly improve the plasma glucose levels in T2DM mice.Similarly,the phosphorylation levels of proteins which involved with insulin signal pathway(PI3K、AKT、FoxO1)were drastically enhanced in liver,while the activity of glycogen synthesis kinase have been inhabited(GSK3β),but there was no significant difference between two therapies.Moreover,empagliflozin monotherapy exhibited more effective inhibition of hepatic gluconeogenesis than combined therapy.Meanwhile,the two intervention dramatically and equally alleviated the body weight and liver weight compared to DM group.The empagliflozin and its combination with metformin significantly and equally reduced the protein expression levels of SREBP1 c and APOC-Ⅲ in diabetic liver.In contrast,the CPT1 A protein levels were increased enormously.We also noticed that all the interventions shows no impact on cholesterol synthesis pathway(SREBP2).Conclusion Taken together,our current study demonstrated that empagliflozin monotherapy or combined with metformin reduce the glucose levels and body weight in T2DM mice.Correspondingly,the combined therapy could recover the insulin sensitivity and stimulate glycogen synthesis and fat oxidation,meanwhile the hepatic fatty acid synthesis and gluconeogenesis have been inhabited.However,combination therapy of empagliflozin plus metformin show no higher amelioration for the glucose and lipid homeostasis than empagliflozin single intervention in T2DM mice,at least based on the short to medium term drug treatment. |
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