Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance
While mitogen-activated protein kinase kinase (MEK) plays a crucial role in signaling and acts as a negative regulator of insulin action, it remains unclear whether MEK inhibition can serve as a therapeutic strategy to alleviate insulin resistance (IR) in type 2 diabetes (T2D) in vivo. To explore this, we assessed the effects of continuous MEK inhibition using two structurally distinct MEK inhibitors, RO5126766 and RO4987655, in mouse models of T2D. Both inhibitors were administered through the diet. Treatment with either compound lowered blood glucose levels and improved glucose tolerance at doses sufficient to inhibit extracellular signal-regulated kinase (ERK)1/2 phosphorylation in insulin-sensitive tissues of db/db mice. In a hyperinsulinemic-euglycemic clamp test, db/db mice treated with these compounds showed an increased glucose infusion rate (GIR), with approximately 60% of this increase linked to the inhibition of endogenous glucose production, suggesting a key role for the liver in improving IR. Additionally, adenovirus-mediated expression of Mek1 shRNA confirmed that suppressing MEK1 in the liver of db/db mice reduced blood glucose levels. These findings collectively indicate that targeting the MEK signaling pathway could represent a novel therapeutic approach for developing new antidiabetic treatments.