Regulation of insulin resistance by Cyp2c44-derived lipids

Abstract

Type 2 diabetes affects 10% of the United States population, and patients with diabetes have an increased risk for diseases such as atherosclerosis and hypertension. Since all these diseases are associated with insulin resistance, finding therapies to improve insulin sensitivity could be beneficial for many patients. Studies have shown CYP450 metabolites called epoxyeicosatrienoic acids (EETs) positively regulate insulin action. The purpose of this study is to provide further evidence to support endogenous EETs regulation of insulin action in vivo and to determine how EETs regulate insulin action. To study this in mice, endogenous production of EETs was disrupted by deleting a major EET-producing epoxygenase, Cyp2c44.Glucose tolerance tests (GTTs) were performed with global and liver-specific deletions [Cyp2c44(-/-) and hepCyp2c44(-/-)] to assess glucose homeostasis. Cyp2c44(-/-) mice had impaired glucose tolerance, while hepCyp2c44(-/- ) mice had no alteration. This suggests that EETs increase insulin action but shows disruption of liver-produced EETs, where Cyp2c44 is highly expressed, is not sufficient to alter glucose homeostasis. Therefore, production of EETs within other tissues (e.g., skeletal muscle, vascular endothelium, or adipocytes) must be contributing to decreased glucose tolerance in Cyp2c44(-/-) mice. Insulin signaling in skeletal muscle has previously been shown to be impaired in Cyp2c44(-/-) mice. Therefore, we investigated the effect of endogenous EETs on a critical protein in the insulin signaling cascade, AKT, and a downstream effector, FoxO1. In the present studies, insulin-stimulated AKT and FoxO1 phosphorylation were unaltered in Cyp2c44(-/-) mice. Therefore the effect of EETs on insulin signaling in skeletal muscle could either occur at a different downstream AKT effector or within other insulin-stimulated pathways, like the MAP kinase pathway. Complementary studies will help determine the roles of gender, age, dietary modifications and other experimental conditions on these differences in insulin sensitivity.