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β-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment

Abstract

Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by β-cells. The reasons for β-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 β-cells. Mice with specific inactivation of Abca1 in β-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-γ, which upregulates Abca1 in β-cells, requires β-cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in β-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to β-cell dysfunction in type 2 diabetes.

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Figure 1: Glucose homeostasis in Abca1 global knockout mice (Abca1−/−) and Abca1 expression in islets.
Figure 2: Generation of mice lacking Abca1 in β-cells (Abca1−P/−P).
Figure 3: Glucose homeostasis in β-cell–specific Abca1 knockout mice.
Figure 4: Absence of β-cell Abca1 results in altered cholesterol homeostasis in isolated islets.
Figure 5: Insulin secretion is impaired in isolated islets lacking β-cell Abca1.
Figure 6: β-cell Abca1 is essential for the response to rosiglitazone treatment.

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Acknowledgements

Special thanks to G. Soukhatcheva for performing islet isolations, to A.K. Gebre for technical assistance with islet lipid assays and to A. Plesner for helpful discussions. We thank O. Francone (Pfizer Global Research) for providing the Abca1 global knockout mice. This work was supported by grants from the Canadian Institutes of Health Research (CIHR; to C.B.V. and M.R.H.), the US National Institutes of Health (grant HL 49373 to J.S.P. and B.J.M) and the Juvenile Diabetes Research Foundation (to B.J.M.). L.R.B. is supported by a CIHR studentship and is a doctoral trainee at the Michael Smith Foundation for Health Research (MSFHR). J.K.K. is supported by a Child and Family Research Institute fellowship. Z.V. is supported by the Canadian Diabetes Association (CDA) and MSFHR. C.B.V. is a MSFHR Senior Scholar. J.D.J. is a CIHR, MSFHR and CDA Scholar. M.R.H. holds a Canada Research Chair in Human Genetics and is a University of British Columbia Killam Professor.

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Authors and Affiliations

Authors

Contributions

L.R.B. and J.K.K. conducted the in vitro and in vivo experiments and contributed to manuscript writing. T.D.P. and A.Q.R. assisted in conducting experiments. J.M.T. performed measurements of islet cholesterol. Z.V. performed filipin staining. J.D.J. performed islet perifusion studies. B.J.M., B.R. and J.S.P. made conceptual contributions and provided crucial reagents. M.R.H. and C.B.V. supervised the studies and contributed to manuscript writing.

Corresponding authors

Correspondence to C Bruce Verchere or Michael R Hayden.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Cre-mediated recombination of islet Abca1. (PDF 27 kb)

Supplementary Fig. 2

Western blot of Abca1 expression in hypothalamus of Abca1+/+ and Abca1−P/−P mice. (PDF 86 kb)

Supplementary Fig. 3

β-cell mass in mice lacking β-cell Abca1. (PDF 63 kb)

Supplementary Fig. 4

Plasma total cholesterol levels in Abca1+/+ and Abca1−P/−P mice receiving a chow diet, and following high-fat or high-fat+rosiglitazone feeding. (PDF 20 kb)

Supplementary Table 1

Plasma metabolic parameters in Abca1+/+ and Abca1−P/−P mice. (PDF 10 kb)

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Brunham, L., Kruit, J., Pape, T. et al. β-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat Med 13, 340–347 (2007). https://doi.org/10.1038/nm1546

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