Inhibition of NF-κB Reduces Renal Inflammation and Expression of PEPCK in Type 2 Diabetic Mice.

Renal gluconeogenesis is markedly promoted in patients with type 2 diabetes mellitus (T2DM); however, the underlying mechanism remains largely unknown. Renal gluconeogenesis is found to be negatively regulated by insulin. T2DM is characterized by chronic and subacute inflammation; however, inflammation has been well recognized to induce insulin resistance. Therefore, this study aimed to investigate whether the enhanced renal gluconeogenesis in T2DM was partially due to the renal inflammation-mediated insulin resistance. If so, whether inflammation inhibitor could partially reverse such change. Diabetic db/db mice and db/m mice were used in our study. Typically, diabetic db/db mice were intraperitoneally treated with 1 mg/kg NF-κB inhibitor parthenolide (PTN) or saline as control every other day. Twelve weeks after treatment, animal samples were collected for measurements. Our results suggested that the expression levels of the inflammatory factors and the gluconeogenic rate-limiting enzyme phosphoenolpyruvate carboxykinase (PEPCK) were up-regulated in renal cortex of both db/db mice and T2DM patients. Moreover, reduced insulin signaling, as well as up-regulated expression of downstream genes FOXO1 and PGC-1ɑ, could be detected in renal cortex of db/db mice compared with that of db/m mice. Consistent with our hypothesis, PTN treatment could alleviate renal inflammation and insulin resistance in db/db mice. Moreover, it could also down-regulate the renal expression of PEPCK, indicating that inflammation could be one of the triggers of insulin resistance and the enhanced renal gluconeogenesis in db/db mice. This study can shed light on the role of inflammation in the enhanced renal gluconeogenesis in T2DM, which may yield a novel target for hyperglycemia.