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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 levels. To investigate the role of hepatic ABCA1 in glucose tolerance and β-cell function, we used ABCA1-l/-l mice. ABCA1-l/-l mice 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 to wt serum, whereas islets lacking β-cell ABCA1 were not differently affected by ABCA1-l/-l or wt serum. After high fat feeding, wt and ABCA