| Type 2 diabetes is an increasingly common metabolic disease that is associated with a number of deleterious health conditions, including obesity, increased risk for cardio- and cerebrovascular disease, impaired wound healing, and difficulty resolving infection. Importantly, type 2 diabetes and many of the associated complications are characterized by a chronic, subclinical elevation in circulating proinflammatory cytokines and acute phase proteins. While the relationships between the innate immune system, type 2 diabetes and several prominent complications (vascular disease and impaired wound repair) have received a great deal of focus, the potential consequences of type 2 diabetes on neuroimmunity are poorly understood.; Neuroimmunity is mediated by activated macrophages that secrete proinflammatory cytokines in response to immune insult. These messenger molecules communicate immune status to the brain to elicit important metabolic and behavioral changes that act to minimize transmission of infection and maximize the host's efficiency in resolving the infection. Disruption of intracellular signaling pathways utilized by cytokines and augmentation of macrophage responses to cytokines or infectious agents, as a result of type 2 diabetes, may play a critical role in disrupting the neuroimmune response. This literature review focuses on neuroimmune implications of type 2 diabetes. Chapters 2 through 4 establish that (1) multiple mechanisms are in place to counter-regulate insulin signaling at the level of IRS, including tyrosine dephosphorylation by protein tyrosine phosphatases, serine phosphorylation, and proteasomal degradation, (2) chronic hyperglycemia and hyperinsulinemia disrupt specific anti-inflammatory functions of IL-4 in macrophages as a result of diminished IRS-2 mediated signaling and increased SOCS-3 expression, and (3) the IL-1beta-mediated neuroimmune response is amplified in db/db mice due to diabetes-associated loss of IL-1beta counter-regulation. Taken together these findings indicate that chronic hyperglycemia and hyperinsulinemia associated with type 2 diabetes impair important anti-inflammatory pathways that signal through IRS proteins potentially giving rise to macrophages that are hyper-responsive to proinflammatory stimuli and leading to exacerbated neuroimmune responses. Importantly, an imbalanced inflammatory phenotype is associated with type 2 diabetes, which likely plays an important pathogenic role in many complications of type 2 diabetes, including altered neuroimmunity. |
