ASPET Meeting Report Meeting Report of the ASPET-Ray Fuller Symposium: Insulin Resistance in Diabetes and Hypertension: Syndrome X and Beyond

The second ASPET-Ray Fuller Symposium was held in London, Ontario, Canada at Spencer Hall on March 24–26, 2000. This symposium focused on three main themes: interaction of the insulin signaling pathway with the cytoskeleton, nontyrosine kinase-mediated insulin receptor (IR) signaling and the specificity of the response to insulin, and the interaction between metabolism and hemodynamics. Domenico Accilli (Columbia University, New York, NY) reminded the audience that the specificity of the insulin signaling pathway to induce glucose uptake is not well understood. The current paradigm is that the number of IR, the intracellular signaling pathway, and the machinery in place are the determinants of the biologic effect of insulin. However, dominant negative IR in adipose and skeletal muscle tissues (but not in liver) resulted only in mild glucose intolerance. These data, together with others, indicate a high degree of redundancy in the insulin signaling pathway or, at the level of the whole organism, to maintain glucose homeostasis. He reviewed the effect of combined IR and IR substrate (IRS) mutations on glucose and insulin metabolism and the risk for the development of diabetes. Currently, four IRS homologs are known. IRS-1 knockout (KO) mice are small with mild insulin resistance, IRS-2 KO exhibit impaired b cell growth and impaired insulin action in liver and skeletal muscle, IRS-3 KO appear normal, and IRS-4 KO display mild insulin resistance. Generation of double KO mice for IRS-1 or IRS-2 demonstrated an additive effect on the risk of developing diabetes. Importantly, the combined KO exhibited marked differences in insulin levels and phosphatidylinositol 3(PI3-) kinase activity in liver and muscle. These findings indicate that the genetic background modifies the biologic response to disruptions of this system. When mice with a null IR allele who had robust insulin levels were back-crossed, quantitative trait loci analysis showed association at chromosomes 2 and 10. Because the insulin-like growth factor (IGF) receptor gene is located on chromosome 10, it is postulated that it may play a role in b cell growth to allow for robust production under conditions of impaired insulin action, preventing the occurrence of diabetes. Michal Czech (University of Massachusetts, Amherst, MA) challenged the audience that although a number of “factoids” were known about insulin resistance, there have been few advances in the understanding of insulin resistance over the last 25 years. For example, it has only recently become clear that functional adipose tissue may be required to have normal insulin sensitivity. Furthermore, there are data suggesting that the classic insulin signaling pathway (IRS-1, PI3kinase, Akt, etc.) may not be sufficient to explain insulininduced glucose transporter (glut) 4 translocation. To learn more about other pathways mediating insulininduced glucose uptake, the genomic and proteonomic approach was used. Purification of proteins in microsomal vesicles associated with glut 4 led to the discovery of a number of previously unknown substances. Not surprisingly, one observation suggested that there is cytoskeletal involvement in glut 4 trafficking. Moreover, inhibition of dynein action prevented normal localization of intracellular glut 4, and disruption of normal dynein function/structure disrupted insulininduced glut 4 translocation. Thus, it is possible that insulinresistant states are associated with impaired cytoskeletal microtubular function, resulting in inefficient intracellular glut 4 trafficking and translocation. Continuing the theme of interaction between structural proteins and insulin action, Amira Klip (University of Toronto, Ontario, Canada) presented data showing that glut 4-containing vesicles associate with actin filaments before translocation to the cell membrane. Within 3 min of insulin stimulation, actin and Akt are colocalized on the membrane surface with synaptosome-associated 23-kDa protein (SNAP 23) and syntaxin-4. Shortly thereafter, glut 4 can be detected Received for publication April 12, 2000.