Carriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction

Menno Vergeer, Liam R. Brunham, Joris Koetsveld, Janine K. Kruit, C. Bruce Verchere, John J. P. Kastelein, Michael R. Hayden, Erik S. G. Stroes

Research output: Contribution to journalArticleAcademicpeer-review

106 Citations (Scopus)

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 noncarriers of similar age, sex, and BMI, we performed oral glucose tolerance tests (OGTTs) (n = 15 vs. 14) and hyperglycemic clamps (n = 8 vs. 8). RESULTS: HDL cholesterol levels in carriers were less than half those in noncarriers, but LDL cholesterol levels did not differ. Although fasting plasma glucose was similar between groups, glucose curves after an OGTT were mildly higher in carriers than in noncarriers. During hyperglycemic clamps, carriers demonstrated lower first-phase insulin secretion than noncarriers but no difference in insulin sensitivity. The disposition index (a measure of beta-cell function adjusted for insulin sensitivity) of the carriers 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 beta-cell function in humans
Original languageEnglish
Pages (from-to)869-874
JournalDiabetes Care
Volume33
Issue number4
DOIs
Publication statusPublished - 2010

Cite this