Obesity caused by excess feeding (overnutrition) has become a problem of epidemic proportions and is the underlying cause in metabolic disorders and chronic diseases such as diabetes and cardiovascular disease. Overnutrition is associated with systemic and tissue-related insulin resistance, an abnormality that promotes vascular disease as well as the development of diabetes (1,2). Thus, there is considerable interest in factors that link overnutrition, insulin resistance, and hyperglycemia with vascular disease. There is emerging evidence that the expression of the Tribbles homolog 3 of Drosophila ( TRIB3 ) gene is increased in patients and animals with type 2 diabetes (3). The TRIB3 gene is located on the 20p13 region of the human chromosome. Its full-length translated mRNA is 1,074 base pairs, and its protein product is made up of 358 amino acids. Studies have shown that TRIB3 inhibits insulin metabolic signaling in liver (4–6), skeletal muscle (7), and vascular tissue (8). Further, these studies suggest that TRIB3 expression in skeletal muscle and liver tissue is increased with excessive nutrient intake as well as by hyperglycemia (3–7). Endoplasmic reticulum stress has also been shown to increase TRIB3 gene expression, and TRIB3 promotes cell death in response to endoplasmic reticulum stress (9) (Fig. 1). Several studies have shown that TRIB3 impairs insulin …