A high-sugar diet-induced animal model for insulin resistance, oxidative stress, and diabetic nephropathy: insights into empagliflozin's therapeutic potential.

backgroundExcessive sugar consumption has been implicated in the development of insulin resistance and diabetic nephropathy (DN). The present study aimed to establish a novel animal model of DN using a high-sugar diet (HSD) and evaluate the renoprotective effects of empagliflozin.

methodsMale Wistar rats were divided into four groups: Normal, Normal + Empagliflozin, Diabetic, and Diabetic + Empagliflozin. Diabetes was induced using a 35% sugar-water solution and a low-dose of streptozotocin. Empagliflozin (15 mg/kg/day) was administered via gavage. Biochemical parameters, renal function markers, oxidative stress indicators, and histopathological assessments were performed.

resultsHSD significantly increased fasting blood glucose (FBS) (242.71 mg/dl in Diabetic vs. 96.6 mg/dl in Normal), insulin levels (0.63 vs. 0.288), and homeostatic model assessment for insulin resistance (HOMA-IR) (0.2716 vs. 0.0687), indicating severe insulin resistance. Empagliflozin treatment significantly reduced FBS (128 mg/dl), improved insulin sensitivity (insulin 0.2725, HOMA-IR 0.0854), and partially restored β-cell function (HOMA-B 1.5779). The diabetic group exhibited impaired renal function, with elevated blood urea nitrogen (BUN 38 mg/dl), creatinine (3.44 mg/dl), and proteinuria (2600 mg/24 h). Empagliflozin reduced these markers to near-normal levels (BUN 17 mg/dl, creatinine 0.44 mg/dl, proteinuria 135 mg/24 h). Oxidative stress parameters showed that empagliflozin increased antioxidant activities (SOD 83.31 U/ml, CAT 0.048 U/ml, GLT 0.341 nMol/ml) and decreased lipid peroxidation (MDA 7.69 nMol/ml). Histological analysis revealed that empagliflozin ameliorated glomerular and tubular damage, reducing necrosis and fibrosis in diabetic kidneys.

conclusionA high-sugar diet induced insulin resistance and diabetic nephropathy in rats, characterized by metabolic disturbances, oxidative stress, and renal dysfunction. Empagliflozin demonstrated significant renoprotective effects by enhancing insulin sensitivity, improving kidney function, reducing oxidative stress, and mitigating histopathological damage. These findings highlight HSD's potential as a key driver of insulin resistance and DN and empagliflozin's potential as a therapeutic agent in managing diabetes-induced kidney injury, particularly in the context of excessive dietary sugar intake.