Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, United States.
Am J Physiol Renal Physiol. 2023 Sep 1;325(3):F363-F376. doi: 10.1152/ajprenal.00078.2023. Epub 2023 Jul 27.
Prepubertal obesity is currently an epidemic and is considered as a major risk factor for renal injury. Previous studies have demonstrated that insulin resistance contributes to renal injury in obesity, independent of diabetes. However, studies examining the relationship between insulin resistance and renal injury in obese children are lacking. Recently, we reported that progressive renal injury in Dahl salt-sensitive (SS) leptin receptor mutant (SSmutant) rats was associated with insulin resistance before puberty. Therefore, the aim of the present study was to examine whether decreasing insulin resistance with metformin will reduce renal injury in SSmutant rats. Four-wk-old SS and SSmutant rats were separated into the following two groups: ) vehicle and ) metformin (300 mg/kg/day) via chow diet for 4 wk. Chronic administration of metformin markedly reduced insulin resistance and dyslipidemia in SSmutant rats. We did not detect any differences in mean arterial pressure between vehicle and metformin-treated SS and SSmutant rats. Proteinuria was significantly greater in SSmutant rats versus SS rats throughout the study, and metformin administration significantly reduced proteinuria in SSmutant rats. At the end of the protocol, metformin prevented the renal hyperfiltration observed in SSmutant rats versus SS rats. Glomerular and tubular injury and renal inflammation and fibrosis were significantly higher in vehicle-treated SSmutant rats versus SS rats, and metformin reduced these parameters in SSmutant rats. These data suggest that reducing insulin resistance with metformin prevents renal hyperfiltration and progressive renal injury in SSmutant rats before puberty and may be therapeutically useful in managing renal injury during prepubertal obesity. Childhood/prepubertal obesity is a public health concern that is associated with early signs of proteinuria. Insulin resistance has been described in obese children. However, studies investigating the role of insulin resistance during childhood obesity-associated renal injury are limited. This study provides evidence of an early relationship between insulin resistance and renal injury in a rat model of prepubertal obesity. These data also suggest that reducing insulin resistance with metformin may be renoprotective in obese children.
青春期前肥胖目前是一种流行疾病，被认为是肾脏损伤的一个主要危险因素。先前的研究表明，胰岛素抵抗是肥胖导致肾脏损伤的一个重要因素，与糖尿病无关。然而，目前缺乏研究检查肥胖儿童中胰岛素抵抗与肾脏损伤之间的关系。最近，我们报道了青春期前，Dahl 盐敏感性（SS）瘦素受体突变（SSmutant）大鼠的进行性肾脏损伤与胰岛素抵抗有关。因此，本研究的目的是研究用二甲双胍降低胰岛素抵抗是否会减少 SSmutant 大鼠的肾脏损伤。将 4 周龄的 SS 和 SSmutant 大鼠分为以下两组：）载体和）二甲双胍（300mg/kg/天）通过饮食给药 4 周。慢性给予二甲双胍可显著降低 SSmutant 大鼠的胰岛素抵抗和血脂异常。我们没有检测到载体和二甲双胍处理的 SS 和 SSmutant 大鼠之间的平均动脉压有任何差异。整个研究过程中，SSmutant 大鼠的蛋白尿明显大于 SS 大鼠，二甲双胍给药显著降低了 SSmutant 大鼠的蛋白尿。在方案结束时，二甲双胍预防了 SSmutant 大鼠相对于 SS 大鼠的肾脏高滤过。与 SS 大鼠相比，经载体处理的 SSmutant 大鼠的肾小球和肾小管损伤以及肾脏炎症和纤维化明显升高，而二甲双胍降低了 SSmutant 大鼠的这些参数。这些数据表明，用二甲双胍降低胰岛素抵抗可预防青春期前肥胖的 SSmutant 大鼠的肾脏高滤过和进行性肾脏损伤，并且在青春期前肥胖期间管理肾脏损伤可能具有治疗作用。儿童/青春期前肥胖是一个公共卫生问题，与早期蛋白尿有关。肥胖儿童中已描述了胰岛素抵抗。然而，研究肥胖相关儿童肾脏损伤中胰岛素抵抗作用的研究有限。本研究提供了青春期前肥胖大鼠模型中胰岛素抵抗与肾脏损伤之间早期关系的证据。这些数据还表明，用二甲双胍降低胰岛素抵抗可能对肥胖儿童具有肾脏保护作用。
