Loss of Both ABCA1 and ABCG1 Results in Increased Disturbances in Islet Sterol Homeostasis, Inflammation, and Impaired b-Cell Function

Cellular cholesterol homeostasis is important for normal b-cell function. Disruption of cholesterol transport by decreased function of the ATP-binding cassette (ABC) transporter ABCA1 results in impaired insulin secretion. Mice lacking b-cell ABCA1 have increased islet expression of ABCG1, another cholesterol trans-porter implicated in b-cell function. To determine whether ABCA1 and ABCG1 have complementary roles in b-cells, mice lacking ABCG1 and b-cell ABCA1 were generated and glucose tolerance, islet sterol levels, and b-cell function were assessed. Lack of both ABCG1 and b-cell ABCA1 resulted in increased fasting glucose levels and a greater impairment in glucose tolerance compared with either ABCG1 deletion or loss of ABCA1 in b-cells alone. In addition, glucose-stimulated insulin secretion was decreased and sterol accumulation increased in islets lacking both transporters compared with those isolated from knockout mice with each gen