Trimetazidine improves dexamethasone-induced insulin resistance and associated hepatic abnormalities in rats.

INTRODUCTION

Glucocorticoids (GC) are a widely prescribed anti-inflammatory and immunosuppressive medicine in clinics. The side effects GC of mostly insulin resistance (IR), dysregulated lipid metabolism and fatty liver, remain the major concern in patients. Understanding the mechanism of GC-induced hepatic steatosis is expected to provide an intervention target to avoid this side effect.

AIM: The present study aims to explore the beneficial effects of trimetazidine (TMZ) to combat DEXA-induced steatohepatitis and metabolic abnormalities.

METHODS

An in vivo IR model was established using male Wistar rats, which were administered TMZ at doses of 10 and 20 mg/kg for a duration of 14 days. Subsequently, from day 7 to day 14 of the study, the rats received DEXA (1 mg/kg, intraperitoneal (i.p.) injection). There were 5 groups, with each group consisting of 6 animals, as outlined: control group, TMZ control group, DEXA group, TMZ 10 + DEXA group, TMZ 20 + DEXA group. On the 14th day of the experiment, serum and hepatic samples were collected.

RESULTS

The findings indicate a marked reduction in OGTT results, fasting serum glucose and insulin levels, ALT and AST levels following treatment with TMZ. TMZ treatment also attenuated oxidative stress markers and improved the lipid profile. Additionally, the hepatic concentrations of high-mobility group box1 (HMGB1), phosphorylated Janus kinase 1 (p-JAK1), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and levels of NF-κB-p65 and interleukin-6 (IL-6) were significantly diminished by TMZ when compared with the DEXA-treated group. Furthermore, TMZ lowered B cell/lymphoma 2 (BCL-2) and caspase-3 levels and attenuated liver histopathological changes.

CONCLUSION

This study demonstrated that TMZ significantly improved DEXA-induced hepatic alterations by modulating the HMGB1/p-JAK1/p-STAT3/NF-κB pathway in liver. Our findings provide new evidence supporting the application of TMZ for treating DEXA-induced IR and hepatic steatosis.