Medicine: Endocrinology and Metabolic Medicine, Imperial College London
Doi
Abstract
Increased glucose levels are associated with increased risk of vascular disease.
The risk is elevated 2-4 fold in type 2 diabetes and there is a positive
relationship between glucose (or HbA1c) levels and vascular disease in the
general population. We tested the hypothesis that there is a glycaemia-mediated
impairment of reverse cholesterol transport (RCT) by studying an
early key step, notably the expression and activity of the ATP binding cassette
transporter-A1 (ABCA1). This protein exports cellular cholesterol to
apolipoprotein A1 (ApoA-I), thereby forming nascent HDL. In this thesis, it is
shown that ABCA1 gene expression in leukocytes in men is reduced in Type 2
diabetes and correlates negatively with circulating HbA1c levels and fasting
glucose. This confirms our earlier findings in healthy men. An independent
relationship between glycaemia and leukocyte ABCG1 gene expression was not
seen. ABCA1 protein concentrations in blood leukocytes were reduced in
patients with diabetes. ApoA-I-mediated cholesterol efflux in cultured fibroblasts
taken from subjects was studied as a measure of ABCA1 function. This
negatively associated with fasting glucose at the time of sampling as well as
adiposity. Cellular cholesterol removal was reduced in subjects with diabetes
compared with controls. There was a positive relationship between both ABCA1
function and leukocyte protein concentration with circulating HDL cholesterol.
These relationships were independent of expression of liver X receptor-α
(LXRα) and peroxisome proliferator-activated receptor-γ (PPARγ). These data
imply a persistent glycaemia-mediated suppression of an early step in RCT
which may contribute to the excess vascular disease observed in such patients.
It further proposes impaired cholesterol efflux may contribute to the low
circulating HDL cholesterol which is commonly seen in patients with impaired
glucose regulation