Abstract

Objective: Abnormal cellular cholesterol handling in islets may contribute to beta-cell dysfunction in type 2 diabetes. Beta-cell deficiency for the ATP Binding Cassette transporter A1 (ABCA1), which mediates the efflux of cellular cholesterol, leads to altered intracellular cholesterol homeostasis and impaired insulin secretion in mice. We aimed to assess the impact of ABCA1 dysfunction on glucose homeostasis in humans.

Research design and methods: In heterozygous carriers of disruptive mutations in ABCA1 and family-based non-carriers of similar age, gender and body mass index we performed oral glucose tolerance tests (OGTT; N=15 vs. 14) and hyperglycemic clamps (N=8 vs. 8).

Results: HDL-C levels in carriers were less than half those in non-carriers but low density lipoprotein cholesterol (LDL-C) levels did not differ. Although fasting plasma glucose was similar between groups, glucose curves after OGTT were mildly higher in carriers than in non-carriers. During hyperglycemic clamps, carriers demonstrated lower first phase insulin secretion than non-carriers but no difference in insulin sensitivity. Disposition index of the carriers – a measure of beta-cell function adjusted for insulin sensitivity – was significantly reduced in ABCA1 heterozygotes.

Conclusions: Carriers of loss-of-function mutations in ABCA1 show impaired insulin secretion without insulin resistance. Our data provide evidence that ABCA1 is important for normal β cell function in humans.