Effects of ABCA1 Mutations on Glucose Tolerance

The ATP Binding Cassette A1 (ABCA1) has been shown to play a pivotal role in
high-density lipoprotein (HDL) metabolism, by its capacity to transport
intracellular free cholesterol to nascent HDL. Individuals with ABCA1
dysfunction due to hetero- or homozygosity for mutations in the gene encoding
for ABCA1 are at increased risk for coronary artery disease. (van Dam et al.
Lancet 2002;359:37-42) ABCA1 is widely expressed throughout the body
(Wellington et al. Lab Invest 2002;82:273-83), but the contributions of ABCA1
in specific tissues is currently unknown.
Based on its function as a trans-membrane transporter, ABCA1, however, could
conceptually be crucial in non-lipoprotein related processes as well.
Recently, Brunham and co-workers have been able to generate a mouse-model, in
which ABCA1 is selectively knocked out in specific tissues and organs (J Clin
Invest. 2006 Apr;116(4):1052-62). In mice in which ABCA1 was solely knocked out
in the pancreas, cholesterol accumulation in beta cells was noticed
(unpublished, confidential data). Of special interest was the finding that
insulin secretion was significantly reduced in these mice, compared to the wild
type controls.
This finding suggests that cholesterol accumulation in beta cells due to ABCA1
dysfunction could be important in the pathophysiology of diabetes.

Aim of this study is to address the role of pancreatic ABCA1 dysfunction in
humans. We hypothesize that beta cell capacity (insulin production) is reduced
in subjects with loss-of-function-mutations in ABCA1.

Subjects with different degrees of ABCA1 dysfunction and controls will be
subjected to a standard oral glucose tolerance test.

75 grams of glucose, dissolved in water, for oral use (standard for OGTT)

Burden and risks are minimal