Metformin reduces insulin resistance and attenuates progressive renal injury in prepubertal obese Dahl salt-sensitive rats.

Abstract

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 (SS^LepRmutant) 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 SS^LepRmutant rats. Four-wk-old SS and SS^LepRmutant rats were separated into the following two groups: 1) vehicle and 2) metformin (300 mg/kg/day) via chow diet for 4 wk. Chronic administration of metformin markedly reduced insulin resistance and dyslipidemia in SS^LepRmutant rats. We did not detect any differences in mean arterial pressure between vehicle and metformin-treated SS and SS^LepRmutant rats. Proteinuria was significantly greater in SS^LepRmutant rats versus SS rats throughout the study, and metformin administration significantly reduced proteinuria in SS^LepRmutant rats. At the end of the protocol, metformin prevented the renal hyperfiltration observed in SS^LepRmutant rats versus SS rats. Glomerular and tubular injury and renal inflammation and fibrosis were significantly higher in vehicle-treated SS^LepRmutant rats versus SS rats, and metformin reduced these parameters in SS^LepRmutant rats. These data suggest that reducing insulin resistance with metformin prevents renal hyperfiltration and progressive renal injury in SS^LepRmutant rats before puberty and may be therapeutically useful in managing renal injury during prepubertal obesity.NEW & NOTEWORTHY 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.