The trouble with tribbles

Type 2 diabetes is characterized by insulin resistance—defined as a failure of insulin to promote glucose uptake in muscle and to suppress glucose production in liver. The serine-threonine kinase Akt (PKB) is a key target of insulin signaling that inhibits hepatic glucose output when glucose is available from food, but its impact in the development of diabetes has been unclear. In the June 6 Science, Keyong Du and colleagues at the Salk Institute show that TRB3 (which bears a strong resemblance to tribbles, a Drosophila protein that inhibits mitosis) interferes with Akt activation and contributes to insulin resistance in individuals with susceptibility to type 2 diabetes (Science, 300:1574-1577, June 6, 2003).

Du et al. used in vitro assays and observed that TRB3 is induced in the liver under fasting conditions and that it disrupts insulin signaling by interfering with Akt phosphorylation. They also observed that livers of db/db diabetic mice ...