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


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.
Vergeer
Menno
M
Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands.
Brunham
Liam R
LR
Koetsveld
Joris
J
Kruit
Janine K
JK
Verchere
C Bruce
CB
Kastelein
John J P
JJ
Hayden
Michael R
MR
Stroes
Erik S G
ES
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D001786:Blood Glucose; D005260:Female; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D007328:Insulin; D008055:Lipids