Functional ABCA1 mutations in both Tangier disease and familial HDL deficiency lead to very low levels of circulating HDL, almost all of which is lipid-poor, as newly synthesised apo-A1 fails to acquire cholesterol and phospholipids. ABCA1 expression in several tissues is up-regulated by oxysterol interaction with the liver X receptor-a. Stimulation of LXRa transcription by peroxisome proliferator-activated receptorc upregulates ABCA1 expression and increases apo-A1- mediated cholesterol efflux from macrophages. ABCA1 expression is decreased in the liver and peritoneal macrophages of diabetic compared to control mice and protein levels have been reported to be reduced in mouse models of diabetes. In human studies, fibroblast ABCAI function has been shown to be impaired by advanced glycation end products and we have previously observed an inverse relationship between ABCA1 expression in peripheral leucocytes and fasting glucose in healthy young and middle-aged men. These findings suggested a potential mechanism for the hyperglycaemia-induced increased risk of early vascular disease. In the present study, we explore relationships between glycaemia, expression of ABCA1 and ABCG1, ABCA1 protein concentrations and ABCA1 function in people with varying degrees of hyperglycaemia, and whether these relationships are influenced by LXRa or PPARc expression. We have demonstrated that ABCA1 gene expression, protein concentrations and transporter function are reduced in drug naive men with T2DM. Gene expression and protein concentrations were reduced in blood leukocytes, and cellular cholesterol removal to Apo-A1 was reduced in skin fibroblasts. These relationships were independent of variation in LXRa or PPARc expression. These observations suggest novel mechanisms whereby hyperglycaemia could adversely influence cellular cholesterol metabolism. Such mechanisms could contribute to the well-established association between elevated glucose levels and risk of vascular disease. ABCA1 is highly expressed in macrophages. Ideally, ABCA1 expression and protein content should be studied in arterial wall macrophages, but this was not possible for ethical reasons. Leukocyte ABCA1 RNA levels in humans reflect ABCA1 expression in circulating monocytes and can be used as a marker for this. It should be noted that gene expression increases 4-fold in monocytes during differentiation into macrophages. Peripheral blood leukocytes have the advantage of being readily obtained from large numbers of subjects and leukocyte ABCA1 has proven a useful surrogate in other clinical situations where the variations in ABCA1 expression have been observed in man.No specific role for Wnt/bcatenin BKM120 signalling in later stages of cerebellum development has yet been described.