title: Loss-of-function mutations in ABCA1 and enhanced β-cell secretory capacity in young adults.
abstract: Loss-of-function mutations affecting the cholesterol transporter ATP-binding cassette transporter subfamily A member 1 (ABCA1) impair cellular cholesterol efflux and are associated with reduced HDL-cholesterol (HDL-C) levels. ABCA1 may also be important in regulating β-cell cholesterol homeostasis and insulin secretion. We sought to determine whether loss-of-function ABCA1 mutations affect β-cell secretory capacity in humans by performing glucose-potentiated arginine tests in three subjects homozygous for ABCA1 mutations (age 25 ± 11 years), eight heterozygous subjects (28 ± 7 years), and eight normal control subjects pair-matched to the heterozygous carriers. To account for any effect of low HDL-C on insulin secretion, we studied nine subjects with isolated low HDL-C with no ABCA1 mutations (age 26 ± 6 years) and nine pair-matched control subjects. Homozygotes for ABCA1 mutations exhibited enhanced oral glucose tolerance and dramatically increased β-cell secretory capacity that was also greater in ABCA1 heterozygous subjects than in control subjects, with no differences in insulin sensitivity. Isolated low HDL-C subjects also demonstrated an increase in β-cell secretory capacity but in contrast to those with ABCA1 mutations, exhibited impaired insulin sensitivity, supporting β-cell compensation for increased insulin demand. These data indicate that loss-of-function mutations in ABCA1 in young adults may be associated with enhanced β-cell secretory capacity and normal insulin sensitivity and support the importance of cellular cholesterol homeostasis in regulating β-cell insulin secretion.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA mcuchel@mail.med.upenn.edu rickels@mail.med.upenn.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rickels
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Eugen S
authors.initials: ES
authors.lastname: Goeser
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Carissa
authors.initials: C
authors.lastname: Fuller
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Christine
authors.initials: C
authors.lastname: Lord
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bowler
authors.affiliation: Department of Biochemistry and Biophysics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Nicolai M
authors.initials: NM
authors.lastname: Doliba
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA mcuchel@mail.med.upenn.edu rickels@mail.med.upenn.edu.
authors.forename: Marina
authors.initials: M
authors.lastname: Cuchel
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D005951:Glucose Tolerance Test; D006579:Heterozygote; D006706:Homeostasis / Q000502:physiology; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D009154:Mutation; D055815:Young Adult
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D001786:Blood Glucose; D007328:Insulin; D002784:Cholesterol