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

TitleCarriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction.
Publication TypeJournal Article
Year of Publication2010
AuthorsVergeer, M, Brunham, LR, Koetsveld, J, Kruit, JK, C Verchere, B, Kastelein, JJP, Hayden, MR, Stroes, ESG
JournalDiabetes Care
Volume33
Issue4
Pagination869-74
Date Published2010 Apr
ISSN1935-5548
KeywordsAdult, ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Blood Glucose, Female, Genotype, Glucose Tolerance Test, Humans, Insulin, Insulin-Secreting Cells, Lipids, Male, Middle Aged, Mutation, Polymerase Chain Reaction
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.

DOI10.2337/dc09-1562
Alternate JournalDiabetes Care
PubMed ID20067955
PubMed Central IDPMC2845043
Grant List / / Canadian Institutes of Health Research / Canada