Renoprotective effect of empagliflozin in cafeteria diet-induced insulin resistance in rats: Modulation of HMGB-1/TLR-4/NF-κB axis

Abstract

AimCafeteria diet (CAF) is a well-established model used to mimic what occurs in human upon eating junk and ultra-processed food. This study aimed to investigate the possible protective impact of empagliflozin (EMPA) against CAF-induced insulin resistance (IR) in rats and the possible underlying mechanisms. Main methodsRats were fed on CAF diet for 12 weeks while treatment with EMPA (10 & 30 mg/kg/day, orally) and/or metformin (MET) (100 mg/kg/day, orally) started at day 29. Key findingsOral administration of EMPA and/or MET significantly and dose-dependently succeeded to attenuate CAF-induced obesity which was evidenced by decreased oral glucose tolerance test (AUCOGTT), insulin tolerance test (AUCITT) and decreased fasting serum insulin level besides improving the histopathological alterations induced by CAF. Moreover, EMPA significantly mitigated CAF-induced elevation in serum levels of creatinine urea, transaminases (ALT and AST), and increased albumin level as well as improving dyslipidemia and oxidative stress. Furthermore, EMPA markedly reduced renal levels of high mobility group box 1 (HMGB-1), toll like receptor4 (TLR-4) and nuclear factor κB (NF-κB) as well as decreasing the expression of tumor necrosis factor α (TNF-α) and Caspase 3. Combining EMPA30 with MET synergistically improved dyslipidemia, oxidative stress and enhanced kidney function. SignificanceEMPA administration could confer protection against CAF-induced IR and its complications through its hypoglycemic, insulin-sensitizing, hypolipidemic, hepatoprotective, renoprotective, anti-inflammatory, anti-oxidant and anti-apoptotic properties. Also, our findings highlighted the synergistic effect of combining EMPA30 with MET so this combination might be promising in treatment of IR.