Insulin resistance (IR) and Diabetes are well known risk factors for many cardiovascular diseases. IR is a result of dysregulated signaling downstream of the insulin receptor (InsR). Binding of insulin to its receptor triggers the activation of IRS1, which in turn activates the PI3K-Akt pathway and trimeric G protein, Gi, both prerequisites for the translocation of glucose transporters, GLUT4, to the plasma membrane (PM) and glucose uptake. In IR, circulating fatty acids activate PKC[theta], which phosphorylates and antagonizes IRS1- mediated responses. Efforts at reinstating sensitivity in IR simply by targeting the known players within the insulin signaling pathway have failed, and thus, the search for new targets continues. GIV (a.k.a. Girdin) has recently been identified as a multimodular signal transducer and a guanine nucleotide exchange factor (GEF) for Galphai, which enhances the PI3K-Akt pathway downstream of the InsR. Here we show that activation of Gi and PI3K-Akt signals via GIV's GEF function is critical for enhancing IRS1 activation and GLUT4 translocation to the PM. Phosphoinhibition of GIV's GEF function by PKC[theta] antagonized GIV-dependent IRS1 and Akt activation and translocation of GLUT4 to the PM. We conclude that GIV is one of the key mediators of insulin response that activates PI3K-Akt and Gi to maintain insulin sensitivity, and that its phosphoinhibition by the fatty-acid-PKC[theta] pathway contributes significantly to the development of IR. Future work unraveling how GIV-GEF mediates insulin response, and how its inhibition can trigger IR will offer a new target to combat IR and reverse/halt the progression of cardiovascular diseases

Insulin resistance (IR) is a metabolic disorder characterized by impaired glucose uptake in response to insulin. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the chief conduit for post-receptor signaling. We recently demonstrated that GIV, a Guanidine Exchange Factor (GEF) for the trimeric G protein, Gαi, is a major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind the InsR, IRS1 and PI3K, GIV enhances the InsR-IRS1-Akt-AS160 (RabGAP) signaling cascade and cellular glucose uptake via its GEF function. Phosphoinhibition of GIV-GEF by the fatty-acid/PKCθ pathway inhibits the cascade and impairs glucose uptake. Here we show that GIV directly and constitutively binds the exocyst complex subunit Exo-70 and also associates with GLUT4-storage vesicles (GSVs) exclusively upon insulin stimulation. Without GIV or its GEF function, membrane association of Exo-70 as well as exocytosis of GSVs in response to insulin are impaired. Thus, GIV is an essential component within the insulin signaling cascade that couples upstream signal transducers within the InsR and G-Protein signaling cascade to downstream vesicular trafficking events within the exocytic pathway. These findings suggest a role of GIV in coordinating key signaling and trafficking events of metabolic insulin response.

Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles.