Low HDL is a risk factor for the development of type 2 diabetes. Hepatic ABCA1 is the rate-limiting protein in HDL biogenesis, and mice lacking hepatic ABCA1 (ABCA1-l/-l) have very low plasma HDL concentrations. To investigate the role of hepatic ABCA1 in glucose tolerance and β-cell function, we used ABCA1-l/-l mice, which showed impaired glucose tolerance without changes in insulin sensitivity. Insulin secretion was reduced following glucose gavage. Ex vivo, glucose stimulated insulin secretion from β-cells from wild-type (WT) and ABCA1-l/-l mice was similar. Insulin secretion was, however, reduced upon addition of ABCA1-l/-l serum to the medium compared with WT serum, whereas islets lacking β-cell ABCA1 were not affected differently by ABCA1-l/-l or WT serum. After high-fat feeding, WT and ABCA1-l/-l mice showed no difference in glucose tolerance or insulin secretion, and serum from ABCA1-l/-l and WT mice fed a high-fat diet did not affect insulin secretion differently. We conclude that hepatic ABCA1 improves glucose tolerance by improving β-cell function through both HDL production and interaction with β-cell ABCA1. The beneficial effect of hepatic ABCA1 is decreased under metabolic stress. Increasing hepatic ABCA1 may represent a novel therapeutic strategy for improving glucose homeostasis in diabetes.
- Received April 6, 2014.
- Accepted July 10, 2014.
- © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.