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Tissue resistance to insulin action results from abnormalities affecting the insulin signalling cascade. This intricate molecular pathway, controlled by positive and negative regulators, affects most major areas of metabolism (Fig. 1). Our growing comprehension of the complexity of these biochemical mechanisms makes it difficult to ascertain exactly what is happening in the insulin-resistant patient. Tribbles are a family of signal-regulating proteins shown to coordinate the activation and the suppression of different pathways [1]. In cells, tribbles play a key role in determining cell fate while responding to environmental challenges [1]. In particular, mammalian tribbles homologue 3 (TRIB3), the best-studied member of the mammalian tribbles family, has been reported to protect cells from starvation-mediated apoptosis [2] and to impact negatively on AKT/protein kinase B (PKB) activation [3, 4]. Indeed, TRIB3 has been reported by most [3, 5], though not all [6] studies to impair insulin action by binding and inhibiting AKT/PKB phosphorylation in murine models of diabetes. These same studies have provided initial evidence that increasing levels of TRIB3 may contribute to the onset of insulin resistance in mice [3, 5]. In humans, the functional Q84R polymorphism in TRB3 (also known as TRIB3) has been identified, and is associated with insulin resistance [4, 7] and type 2 diabetes [8]. This gain-of-function polymorphism is accompanied by enhanced inhibition of insulin signalling and AKT/PKB activation in different tissues, including the beta cells [3, 4, 9]. Indeed, the TRIB3 Q84R polymorphism has been found to associate with defective insulin secretion in addition to insulin resistance [8]. Thus, TRIB3 adds to the growing list of molecules which, through tightly regulated action, enable normal beta cell function and insulin signalling in humans (Fig. 2). Such molecules also now include phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15 (PEA-15 [also known as PED]) [10] and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) [11] as well as IRS1 [12]. However, the discovery of TRIB3 action on insulin signalling has highlighted the specific significance of AKT/PKB for beta Electronic supplementary material The online version of this article (doi:10.1007/s00125-010-1824-7) contains supplementary material, which is available to authorised users.

Tribbles homologue 3 (TRIB3) and the insulin-resistance genes in type 2 diabetes