Insulin resistance is considered as an important clinical and biochemical determinant; not only of diabetes but also of many other clinical states e.g. obesity, CVD and CKD. Furthermore, IR plays a fundamental role in the pathogenesis of renal fibrosis that represents a common pathway of all progressive kidney disease regardless the initial cause of injury. The present work aims mainly to: 1. Clarify the role of empagliflozin in improving the induced renal insulin resistance. 2. Elucidate the effect of inhibiting SGLT2 by TNF-α inhibitor (infliximab) or TGf-β1 inhibitor (SB 431542) on the induced renal insulin resistance 3. Investigate whether infliximab or SB 431542 would add more benefits to empagliflozin in treating the induced renal insulin resistance and RF and clarify the underlying mechanisms. To fulfill such objectives, the following parameters were investigated:  Biochemical parameters:  In serum: glucose, insulin, lipid profile, kidney function parameters (BUN, creatinine and uric acid) levels.  In kidney tissue: - Inflammatory markers: TNF-α, IL-1β, IL-6 contentsProfibrotic marker: TGF-β1content. - SOCS3, SGLT2 contents - Renal Sirt 1 gene expression (in vivo) and both renal SGLT2 and Sirt 1 gene expression (in vitro) - Phosphorylated and total form of IRS1, PI3K p85 and Akt.  Histological study: Representative samples of kidney tissues were processed for histological examination under the light microscope using the following stains: 1. Hematoxylin and eosin (H&E): the renal sections from all experimental groups were examined in blind fashion for illustrating the general structural changes in renal tissues and tubular injury. 2. Periodic acid Schiff (PAS): for evaluation of brush border loss as well as the thickness of glomerular and renal tubule basement membrane.Masson ҆s Trichome stain and morphometric analysis: to indicate the presence and the percentage of collagen fibers. Induction of renal insulin resistance: Rats were randomly divided into two groups: healthy normal control group (n=12) and insulin resistance (IR) group (n= 66). 10% w/v fructose in drinking water for 20 weeks was used to induce IR which was confirmed in rats by a significant elevation in OGTT, lipid profile and HOMA-IR 2 values > 2.4. IR rats were further divided into two main groups for in vivo (n= 30) and in vitro (n= 36) studies.Experimental design: In vivo study: Both normal and IR rats were assigned into the following experimental groups (n = 6):  Normal control (NC) group: rats received standard chow diet and were orally injected daily with water during the experimental period.  Insulin resistance (IR) control group: IR rats received standard chow diet + 10% fructose in water and were injected daily with water for one month.  Insulin resistance + metformin (IR + MET) group: IR rats treated orally with 100 mg/kg body weight /day of metformin for four weeks.  Insulin resistance + empagliflozin (IR + EMPA) group: IR rats treated with 30mg/kg/day of empagliflozin orally for four weeks.  Insulin resistance + infliximab (IR + IFX) group: IR rats injected with one dose of infliximab (5mg/kg body weight) intraperitonely.  Insulin resistance + empagliflozin + infliximab (IR + EMPA+IFX) group: IR rats treated with empagliflozin and infliximab with the same doses as the monotherapy for four weeks. In vitro study: Normal and IR rats were assigned into the following experimental groups (n = 6):  Normal control (NC) group: renal cells of normal control rats.  Insulin resistance (IR) control group: renal cells of IR control rats.  Insulin resistance + metformin (IR + MET) group: renal cells of IR rats incubated with 500 μM of metforminInsulin resistance + empagliflozin (IR + EMPA) group: renal cells of IR rats incubated with 500 nM of empagliflozin.  Insulin resistance + SB 431542 (IR + SB 431542) group: renal cells of IR rats incubated with 10 μM of SB 431542 in DMSO.  Insulin resistance + empagliflozin+ SB 431542 (IR + EMPA+SB 431542) group: renal cells of IR rats incubated with 500 nM of empagliflozin + 10 μM SB 431542 in DMSO.  Insulin resistance + DMSO (IR + DMSO) group: renal cells of IR rats incubated with DMSO. All drugs were incubated with renal cells for 48 h. Results: Fructose - fed rats displayed hyperglycemia, hyperinsulinemia, dyslipidemia, elevated kidney function parameters as well as significant elevation of HOMA-IR 2 value as compared to NC group. Significant elevation in renal tissue contents of TNF-α, IL-1β, IL-6, TGF-β1, SOCS3, SGLT2 were observed. Significant downregulation of renal Sirt 1gene expression in addition to impairment in renal insulin signaling via IRS1/PI3K/Akt pathway in rats were also recorded. Histological examination of stained renal sections of IR rats revealed kidney damage as observed by areas of heamorraghe, cells infilteration, marked glomerulosclerosis, collagen fibers deposition besides loss of renal tubular brush border as compared with NC group. Treatment with metformin, empagliflozin, infliximab, SB 431542, and the combined treatments significantly decreased serum levels of glucose and insulin in addition to decrease the kidney function parameters and HOMA-IR 2 value. All treated groups also showed significant decrease in renal tissue TNF-α, IL-1β, IL-6, TGF-β1, SOCS3, SGLT2 as well as significant upregulation of renal Sirt 1gene expression in addition to a significant improvement in renal insulin signaling via IRS1/PI3K/Akt pathway. Additionally, the histological examination showed decreases in tubular and glomerular basement membrane thickness beside preserved tubular brush border and decreased percentage of collagen area. However, the combination of empagliflozin either with infliximab or SB 431542 showed marked improvement in all parameters than the individual treatments. Correlation results: Using the combined results from all experimental animals, it was found that serum glucose and insulin level were positively correlated with serum kidney function parameters, HOMA-IR 2, renal (TNF-α, IL-1β, IL-6, TGF-β1and SGLT2) as well as renal SOCS3 levels. On the contrary, negative correlation between renal Sirt 1 gene expression and all parameters were also demonstrated. Also positive correlation between renal IRS1 phosphorylation and all parameters were observed, while renal PI3K and Akt phosphorylated forms exhibited negative correlations with different biochemical and renal parameters. Conclusion: 1. Long term intake of fructose induced insulin resistance and chronic inflammatory state which resulted in severe complication like renal fibrosis. 2. All treatments showed significant amelioration in serum and renal tissue parameters as well as renal insulin signaling pathwayMetformin (standard antidiabetic drug) showed marked effect over empagliflozin regarding serum glucose and insulin levels. 4. Empagliflozin showed a better improvement over metformin regarding the renal inflammatory markers, SOCS3, TGF-β1, SGLT2, Sirt 1gene expression and renal insulin signaling via IRS1/PI3K/Akt pathway in fructose-induced insulin resistance rats. 5. Both infliximab and SB 431542 showed more remarkable effects than empagliflozin on the induced renal insulin resistance and its associated complication RF, probably due to their direct effects on renal TNF-α, IL-1β, IL-6, SOCS3 and TGF-β1 levels in addition to Sirt 1 gene expressionCombination of empagliflozin either with infliximab or SB 431542 exerted greater amelioration for the induced renal insulin resistance and greater antifibrotic effect than individual treatments and metformin. Collectively, the findings of this study suggest that the combination of empagliflozin with TNF-α inhibitor or TGF-β1 inhibitor may be a promising therapeutic approach to ameliorate the induced insulin resistance and RF. Noticeably; further clinical studies are needed to validate and confirm the observed results