Article abstract
Nature Medicine 13, 340 - 347 (2007)
Published online: 18 February 2007 | doi:10.1038/nm1546
-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment
Liam R Brunham1, Janine K Kruit1, Terry D Pape1, Jenelle M Timmins2, Anne Q Reuwer1, Zainisha Vasanji3, Brad J Marsh4, Brian Rodrigues5, James D Johnson6, John S Parks2, C Bruce Verchere3 & Michael R Hayden1
Abstract
Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by 
-cells. The reasons for -cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within this cell type. We examined the role of Abca1, a cellular cholesterol transporter, in cholesterol homeostasis and insulin secretion in -cells. Mice with specific inactivation of Abca1 in -cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro. We found that rosiglitazone, an activator of the peroxisome proliferator–activated receptor-
, which upregulates Abca1 in -cells, requires -cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in -cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to -cell dysfunction in type 2 diabetes.
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, British Columbia V5Z 4H4, Canada.
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
- Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, British Columbia V5Z 4H4, Canada.
- Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane Q 4072, Australia.
- Faculty of Pharmaceutical Sciences, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z4 Canada.
- Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z4 Canada.
Correspondence to: Michael R Hayden1 e-mail: mrh@cmmt.ubc.ca
Correspondence to: C Bruce Verchere3 e-mail: verchere@interchange.ubc.ca
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