Nature Medicine | Spoonful of Medicine

Michael’s insight and beyond

In addition to the Insight on Cardiovascular Disease, edited by Nature Medicine‘s own Michael Basson, a couple of papers caught my attention from this past Thursday’s issue of Nature.

First, the analysis of multiple sclerosis (MS) lesions by laser-capture microdissection and proteomics, which led May Han and colleagues to identify two potential therapeutic targets for the disease — tissue factor and protein C inhibitor — both of which participate during coagulation. Indeed, the authors went on to show that blocking the action of thrombin (which signals downstream of tissue factor) or administering activated protein C (to counter the increased levels of its inhibitor) ameliorated pathology in an animal model of MS. The image below, from the Nature paper, shows astrogliosis in a chronic MS plaque, revealed by and anti-GFAP antibody.

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Second, the discovery by Xiaoyong Yang and colleagues of a link between O-GlcNac transferase and insulin resistance. We already knew that glucose flux through the hexosamine biosynthetic pathway leads O-GlcNac transferase to attach the sugar O-linked beta-N-acetylglucosamine (O-GlcNac) to proteins, thereby acting as a nutrient sensor. The new study shows that O-GlcNac transferase has a binding site for phosphatidylinositol 3,4,5-trisphosphate (PIP3), a key mediator of insulin signaling. Upon binding, PIP3 recruits O-GlcNac transferase to the plasma membrane, where it sticks O-GlcNac to proteins of the insulin signaling pathway, reducing their responsiveness to insulin (see the figure below, which I borrowed from the paper; O-GlcNac transferase is labeled as OGT). In vivo, liver overexpression of O-GlcNac transferase causes insulin resistance, pointing to the likely functional relevance of this mechanism.

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