Double Tribble

Insulin signaling under normal physiological conditions as well as its disruption in response to oxidative stress represents a field of intense research interest. It is generally accepted that insulin, on binding to its receptor, initiates the tyrosine phosphorylation of cellular substrates including the insulin receptor substrate (IRS) family members, which in turn modulate the activation of the phosphatidylinositol 3-kinase (PI 3-K) and downstream kinases such as PKCζ and Akt, which are responsible for initiating a number of cellular effects.1 It follows that defects in this signaling cascade lead to an altered cellular responsiveness to insulin and to insulin resistance, the earliest detectable abnormality in the development of diabetes.See accompanying article on page 1355 Recently, a protein called TRIB3, a mammalian tribbles homolog also known as TRB3/NIPK, was reported to interfere with insulin signaling by binding to and inhibiting the serine kinase Akt.2,3 TRIB3 expression can be increased by several stimuli including starvation,2 PPAR-α activation,3 and chronic alcohol ingestion,4 and in all of the conditions listed is linked to insulin insensitivity. Moreover, a relatively frequent (minor allele frequency 15%) missense TRIB3 polymorphism has also been described in which a glutamine residue is substituted by an arginine at position 84 (Q84R), to result in a protein that more readily binds to the pleckstrin homology domain of Akt to prevent its plasma membrane association. Overexpression of this TRIB3 variant in a cell line moderately decreases (≈22%) the insulin-induced phosphorylation …