Abstract
Although mitogen-activated protein kinase kinase (MEK) is a key signaling molecule and a negative regulator of insulin action, it is still uncertain whether MEK can be a therapeutic target for amelioration of insulin resistance (IR) in type 2 diabetes (T2D) in vivo. To clarify whether MEK inhibition improves T2D, we examined the effect of continuous MEK inhibition with two structurally different MEK inhibitors, RO5126766 and RO4987655, in mouse models of T2D. RO5126766 and RO4987655 were administered via dietary admixture. Both compounds decreased blood glucose and improved glucose tolerance in doses sufficient to sustain inhibition of extracellular signal-regulated kinase (ERK)1/2 phosphorylation downstream of MEK in insulin-responsive tissues in db/db mice. A hyperinsulinemic-euglycemic clamp test showed increased glucose infusion rate (GIR) in db/db mice treated with these compounds, and about 60% of the increase was attributed to the inhibition of endogenous glucose production, suggesting that the liver is responsible for the improvement of IR. By means of adenovirus-mediated Mek1 shRNA expression, we confirmed that blood glucose levels are reduced by suppression of MEK1 expression in the liver of db/db mice. Taken together, these results suggested that the MEK signaling pathway could be a novel therapeutic target for novel antidiabetic agents.
Highlights
The pathology of type 2 diabetes (T2D) is characterized by impaired insulin secretion from pancreatic beta cells and impaired insulin action, known as insulin resistance (IR)
We describe the antidiabetic effect of mitogen-activated protein kinase kinase (MEK) inhibition with these MEK inhibitors in db/db mice, a T2D animal model, and explore the mechanism underlying the glucose lowering effect of MEK1 inhibition
During treatment with RO4987655, no effects on food intake (FI, Figure 3(a)) or body weight (BW) gain (Figure 3(b)) were observed; during treatment with RO5126766, an approximately 30% reduction in mean FI was observed at the highest dose (Figure 2(a)) while there was no change in BW (Figure 2(b))
Summary
The pathology of type 2 diabetes (T2D) is characterized by impaired insulin secretion from pancreatic beta cells and impaired insulin action, known as insulin resistance (IR). Insulin initiates the regulation of various cell functions through the phosphoinositide 3-kinase (PI 3-K) pathway and the mitogen-activated protein kinase kinase (MEK) pathway after binding to insulin receptors and becoming phosphorylated [3, 4]. It is believed that the PI 3-K pathway is important in glucose metabolism [5], whereas the MEK pathway is considered to mainly control cell growth and differentiation [6, 7]; the precise role of MEK in the regulation of glucose metabolism by insulin is still not fully established. Journal of Diabetes Research N O (a) N OO S F K+ HO HN O H
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