Insulin and insulin-like growth factor 1 (IGF1) are ubiquitous growth factors that regulate proliferation in most mammalian tissues including pancreatic islets. To explore the specificity of insulin receptors in compensatory ␤-cell growth, we examined two models of insulin resistance. In the first model, we used liverspecific insulin receptor knockout (LIRKO) mice, which exhibit hyperinsulinemia without developing diabetes due to a compensatory increase in ␤-cell mass. LIRKO mice, also lacking functional insulin receptors in ␤-cells (␤IRKO/LIRKO), exhibited severe glucose intolerance but failed to develop compensatory islet hyperplasia, together leading to early death. In the second model, we examined the relative significance of insulin versus IGF1 receptors in islet growth by feeding high-fat diets to ␤IRKO and ␤-cell-specific IGF1 receptor knockout (␤IGFRKO) mice. Although both groups on the high-fat diet developed insulin resistance, ␤IRKO, but not ␤IG-FRKO, mice exhibited poor islet growth consistent with insulinstimulated phosphorylation, nuclear exclusion of FoxO1, and reduced expression of Pdx-1. Together these data provide direct genetic evidence that insulin/FoxO1/Pdx-1 signaling is one pathway that is crucial for islet compensatory growth response to insulin resistance.␤-cell growth ͉ compensatory hyperplasia ͉ ␤-cell apoptosis I nsulin resistance is a common feature of type 2 diabetes, obesity, and hyperlipidemias (1). In patients with type 2 diabetes and mouse models of diabetes and obesity, the ␤-cells compensate for the insulin resistance by increasing their mass (2, 3). One of these models, the liver-specific insulin receptor knockout (LIRKO) mouse, manifests severe insulin resistance and glucose intolerance, but the mutants do not become overtly diabetic due, in part, to a significant increase in ␤-cell mass (4). Although lineage tracing experiments in normal mice and studies in cyclin D2 knockouts indicate that ␤-cell replication is a major mechanism for regeneration of adult ␤-cells (5, 42), the signals that induce ␤-cell replication are not fully defined.Insulin and IGFI and the proteins in their signaling pathways regulate cell growth and function (6), but their specificity in modulating ␤-cell proliferation is not fully explored. Thus, ␤-cellspecific insulin receptor (␤IRKO) (7), IGF1 receptor knockout (␤IGFRKO) (8, 9), or double mutants (10) surprisingly exhibited normal growth and development of ␤-cells consistent with data from global knockouts of insulin receptor or IGF1 receptor genes (11). Mice with global knockout of IRS1 (12, 13) or IRS2 genes (12, 14) also do not manifest defects in the development of islet cells, whereas overexpression of Akt in ␤-cells promotes an increase in cell size (15). Together these studies indicate that insulin/IGF1 signaling is not critical for early development and growth of ␤-cells.Our follow-up studies showed that ␤IRKO, but not ␤IGFRKO, mice developed an age-dependent decrease in ␤-cell mass and a susceptibility to develop overt diabetes (7,16,17). F...

In record time, microRNAs (miRNAs) have acquired the respected stature of important natural regulators of global gene expression. Multiple studies have demonstrated that a large number of miRNAs are under the control of various metabolic stimuli, including nutrients, hormones, and cytokines. Conversely, it is now well recognized that miRNAs control metabolism, thereby generating a bidirectional functional link, which perturbs energy homeostasis in case of disconnection in the miRNA-metabolism interplay. A challenging road lies ahead for defining the role of miRNAs in the pathogenesis of diseases such as diabetes and for establishing their usefulness as new medications and clinically reliable biomarkers.

Summary Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to non-pathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focussing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential.