Expression of the Type I diabetes-associated gene LRP5 in macrophages, vitamin A system cells, and the islets of Langerhans suggests multiple potential roles in diabetes

LRP5 is a novel member of the low-density lipoprotein receptor family that is genetically associated with Type 1 diabetes. As a start to defining the normal function of LRP5 and to generate testable hypotheses of its potentia l role in Type 1 diabetes pathogenesis, we carried out an extensive express ion analysis of this gene at the mRNA and protein levels in normal human, m onkey, and mouse, as well as in non-obese diabetic (NOD) mice at several st ages of diabetes development. In all species, expression of LRP5 was found in four functionally important cell types: the distributed mononuclear phag ocyte system, the islets of Langerhans, vitamin A-metabolizing cells, and C NS neurons. Given the critical role of macrophages in the onset and progres sion of islet cell destruction in Type 1 diabetes and the hypothesized role of retinoids as modifiers of diabetes progression, these findings suggest that LRP5 may confer Type 1 diabetes risk by altering the normal functionin g of one or more of these regulatory systems. Specifically, given that the LRP5 polymorphisms associated with diabetes are in the promoter region of t he gene, alterations in LRP5 expression may be responsible for diabetes sus ceptibility and therefore may be potential targets for therapeutic interven tion.