Galectin-3 and LTB4 are pro-inflammatory molecules recently shown to directly cause insulin resistance in mouse and human cells. They are highly expressed in the obese state, and can be targeted both genetically and pharmacologically to improve insulin sensitivity in vivo. This expands on previous research showing that targeting inflammatory cytokines can be insulin sensitizing in animal models. However, translating these potential therapies into the human setting remains challenging. Here we review this latest research, and discuss how balancing their pleiotropic functions, (...) the action of the microbiome, and the ability to identify relevant patient populations are vital considerations for successful anti-inflammatory insulin sensitizing therapy. Recent advances have indicated that a diverse range of inflammatory molecules, including leukotriene B4 and Galectin-3 can cause insulin resistance. Key challenges for translating these new targets into therapies include their pleiotropic effects and likely patient heterogeneity, such as is caused by the intestinal microbiome. (shrink)

Clonal expansion of T‐lymphocyte populations results from interactions of antigenic structures presented in combination with accessory cells (macrophages) and antibody recognition sites on the surface of T cells. The resulting activation of a membrane phospholipase C plays a crucial role in lymphocyte responses by releasing diglyceride and PIP3. The released diglyceride activates a cellular protein kinase C while PIP3 stimulates Ca2+ influx. Arachidonic acid released by the action of diglyceride lipase serves as substrate for the synthesis of bioactive eicosanoids (prostaglandins (...) and leukotrienes) which in turn modulate cellular adenyl and guanyl cyclases. The eicosanoids serve as both intra‐ and extra‐cellular signals for lymphocytes, regulating the production and expression of lymphokines and mediating the complex interactions between the monocyte‐macrophage components and helper and suppressor T cells.Aspirin and other anti‐inflammatory drugs stimulate mitogenesis by inhibiting production of the negative modulator prostaglandin E2 in accessory cells and by enhancing the production of the lymphokine 1L‐2 by producer T‐cells. (shrink)