IGFBP3 and Hyperglycemia: Although these effects could be indirectly mediated by minor endocrine abnormalities in these animals, for example hyperglycemia [33], the in vitro findings that IGFBP3 expression suppresses HCRT promotor activity (Fig. 3E) and that the functional IGFBP3 polymorphism rs2854744 is associated with reduced hypocretin transmission, observed as lower levels of Hcrt-1 in human CSF (Fig. 3F), makes this hypothesis unlikely.