ADD-1 provides major new insight into the mechanism of insulin action
- Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
We evolved to live in a world in which food supplies are unpredictable in availability and often insufficient to meet immediate needs. Consequently, it is critical to be able to switch between the distinct metabolic programs that are appropriate to either the fasted or the fed state. Although many endocrine systems are involved in this transition, insulin is a preeminent hormonal mediator of this nutritional switch. Insulin levels rise postprandially to mediate anabolism and energy storage and fall between meals to permit the release of adipose energy stores and the switch from glucose use to production. The relevant actions of insulin take place in adipose tissue, muscle, and liver, where insulin receptor signaling exerts tissue-specific effects on an array of metabolic pathways that impact on carbohydrate, lipid, and protein metabolism. The cellular mechanism of insulin action has been a topic of major interest for many years. The greatest emphasis has been on the early steps of signal transduction, involving the insulin receptor substrate (IRS) proteins, which when tyrosine phosphorylated by the insulin receptor kinase serve as docking proteins for assembly of signaling complexes for downstream pathways such as ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and others (1). Many classic actions of insulin (e.g., glucose transport and glycogen synthesis) occur very rapidly and require the mediation of rapid changes in the state of protein phosphorylation or dephosphorylation. It is established that, alongside these rapid nongenomic effects, changes in gene expression play critical roles in insulin action in adipose cells, liver, and other tissues (2).
Although insulin-responsive DNA elements have been identified in the promoters of several insulin-regulated genes, the identity of transcription factors responsible for mediating key insulin actions on gene expression has been, until recently, obscure. Two recent papers in PNAS (3, 4) provide important new information on the …
